Skip to main content

Cellular and molecular mechanisms implicated in pathogenesis of selective neurodegeneration in Huntington’s disease

Frontiers in Biology volume 7, pages 459–476 (2012)Cite this article

Abstract

Huntington’s disease (HD) is one of the most common dominantly-inherited neurodegenerative disorders and is caused by a CAG repeat expansion in the huntingtin gene. HD is characterized by selective degeneration of subpopulations of neurons in the brain, however the precise underlying mechanisms how a ubiquitously expressed disease protein could target specific types of neurons for degeneration remains a critical, yet unanswered question for HD and other major neurodegenerative disorders. In this review, we describe the expanding view of selective neuronal vulnerability in HD, based on recent neuropathological and neuroimaging studies. We will also summarize the systematic effort to define the cell types in which mutant Huntingtin expression is critical for pathogenesis of vulnerable neurons in the striatum and cortex. Finally, we will describe selected, emerging molecular mechanisms that are implicated in selective disease processes in HD. Together, the field has begun to appreciate the distinct molecular pathogenic roles of mutant huntingtin in different cell types that may contribute to the selective neuronal vulnerability, with dissection of such mechanisms likely to yield novel molecular targets for HD therapy.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price includes VAT (USA)
Tax calculation will be finalised during checkout.

References

  • Aiken C T, Steffan J S, Guerrero C M, Khashwji H, Lukacsovich T, Simmons D, Purcell J M, Menhaji K, Zhu Y Z, Green K, Laferla F, Huang L, Thompson L M, Marsh J L (2009). Phosphorylation of threonine 3: implications for Huntingtin aggregation and neurotoxicity. J Biol Chem, 284(43): 29427–29436

    PubMed  CAS  Article  Google Scholar 

  • Albin R L, Reiner A, Anderson K D, Dure L S 4th, Handelin B, Balfour R, Whetsell W O Jr, Penney J B, Young A B (1992). Preferential loss of striato-external pallidal projection neurons in presymptomatic Huntington’s disease. Ann Neurol, 31(4): 425–430

    PubMed  CAS  Article  Google Scholar 

  • Albin R L, Reiner A, Anderson K D, Penney J B, Young A B (1990). Striatal and nigral neuron subpopulations in rigid Huntington’s disease: implications for the functional anatomy of chorea and rigidity-akinesia. Ann Neurol, 27(4): 357–365

    PubMed  CAS  Article  Google Scholar 

  • Altar C A, Cai N, Bliven T, Juhasz M, Conner J M, Acheson A L, Lindsay R M, Wiegand S J (1997). Anterograde transport of brainderived neurotrophic factor and its role in the brain. Nature, 389(6653): 856–860

    PubMed  CAS  Article  Google Scholar 

  • Arning L, Saft C, Wieczorek S, Andrich J, Kraus P H, Epplen J T (2007). NR2A and NR2B receptor gene variations modify age at onset in Huntington disease in a sex-specific manner. Hum Genet, 122(2): 175–182

    PubMed  CAS  Article  Google Scholar 

  • Arregui L, Benítez J A, Razgado L F, Vergara P, Segovia J (2011). Adenoviral astrocyte-specific expression of BDNF in the striata of mice transgenic for Huntington’s disease delays the onset of the motor phenotype. Cell Mol Neurobiol, 31(8): 1229–1243

    PubMed  CAS  Article  Google Scholar 

  • Atwal R S, Desmond C R, Caron N, Maiuri T, Xia J, Sipione S, Truant R (2011). Kinase inhibitors modulate huntingtin cell localization and toxicity. Nat Chem Biol, 7(7): 453–460

    PubMed  CAS  Article  Google Scholar 

  • Averback P (1980). Histopathology of acute cell loss in Huntington’s chorea brain. J Pathol, 132(1): 55–61

    PubMed  CAS  Article  Google Scholar 

  • Aylward E H, Sparks B F, Field K M, Yallapragada V, Shpritz B D, Rosenblatt A, Brandt J, Gourley L M, Liang K, Zhou H, Margolis R L, Ross C A (2004). Onset and rate of striatal atrophy in preclinical Huntington disease. Neurology, 63(1): 66–72

    PubMed  CAS  Article  Google Scholar 

  • Beal MF, Kowall NW, Ellison DW, Mazurek MF, Swartz K J, Martin J B (1986). Replication of the neurochemical characteristics of Huntington’s disease by quinolinic acid. Nature, 321(6066): 168–171

    PubMed  CAS  Article  Google Scholar 

  • Behrens P F, Franz P, Woodman B, Lindenberg K S, Landwehrmeyer G B (2002). Impaired glutamate transport and glutamate-glutamine cycling: downstream effects of the Huntington mutation. Brain, 125(Pt 8): 1908–1922

    PubMed  CAS  Article  Google Scholar 

  • Bezprozvanny I, Hayden M R (2004). Deranged neuronal calcium signaling and Huntington disease. Biochem Biophys Res Commun, 322(4): 1310–1317

    PubMed  CAS  Article  Google Scholar 

  • Bezzi P, Gundersen V, Galbete J L, Seifert G, Steinhäuser C, Pilati E, Volterra A (2004). Astrocytes contain a vesicular compartment that is competent for regulated exocytosis of glutamate. Nat Neurosci, 7(6): 613–620

    PubMed  CAS  Article  Google Scholar 

  • Biglan K M, Ross C A, Langbehn D R, Aylward E H, Stout J C, Queller S, Carlozzi N E, Duff K, Beglinger L J, Paulsen J S, PREDICT-HD Investigators of the Huntington Study Group (2009). Motor abnormalities in premanifest persons with Huntington’s disease: the PREDICT-HD study. Mov Disord, 24(12): 1763–1772

    PubMed  Article  Google Scholar 

  • Bradford J, Shin J Y, Roberts M, Wang C E, Li X J, Li S (2009). Expression of mutant huntingtin in mouse brain astrocytes causes age-dependent neurological symptoms. Proc Natl Acad Sci U S A, 106(52): 22480–22485

    PubMed  CAS  Article  Google Scholar 

  • Bradford J, Shin J Y, Roberts M, Wang C E, Sheng G, Li S, Li X J (2010). Mutant huntingtin in glial cells exacerbates neurological symptoms of Huntington disease mice. J Biol Chem, 285(14): 10653–10661

    PubMed  CAS  Article  Google Scholar 

  • Brown A M, Ransom B R (2007). Astrocyte glycogen and brain energy metabolism. Glia, 55(12): 1263–1271

    PubMed  Article  Google Scholar 

  • Brown T B, Bogush A I, Ehrlich M E (2008). Neocortical expression of mutant huntingtin is not required for alterations in striatal gene expression or motor dysfunction in a transgenic mouse. Hum Mol Genet, 17(20): 3095–3104

    PubMed  CAS  Article  Google Scholar 

  • Browne S E, Beal M F (2004). The energetics of Huntington’s disease. Neurochem Res, 29(3): 531–546

    PubMed  CAS  Article  Google Scholar 

  • Burnett C, Valentini S, Cabreiro F, Goss M, Somogyvári M, Piper M D, Hoddinott M, Sutphin G L, Leko V, McElwee J J, Vazquez-Manrique R P, Orfila A M, Ackerman D, Au C, Vinti G, Riesen M, Howard K, Neri C, Bedalov A, Kaeberlein M, Soti C, Partridge L, Gems D (2011). Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila. Nature, 477(7365): 482–485

    CAS  Google Scholar 

  • Bydder G M, Steiner R E, Young I R, Hall A S, Thomas D J, Marshall J, Pallis C A, Legg N J (1982). Clinical NMR imaging of the brain: 140 cases. AJR Am J Roentgenol, 139(2): 215–236

    PubMed  CAS  Google Scholar 

  • Campesan S, Green E W, Breda C, Sathyasaikumar K V, Muchowski P J, Schwarcz R, Kyriacou C P, Giorgini F (2011). The kynurenine pathway modulates neurodegeneration in a Drosophila model of Huntington’s disease. Curr Biol, 21(11): 961–966

    PubMed  CAS  Article  Google Scholar 

  • Canals J M, Pineda J R, Torres-Peraza J F, Bosch M, Martín-Ibañez R, Muñoz M T, Mengod G, Ernfors P, Alberch J (2004). Brain-derived neurotrophic factor regulates the onset and severity of motor dysfunction associated with enkephalinergic neuronal degeneration in Huntington’s disease. J Neurosci, 24(35): 7727–7739

    PubMed  CAS  Article  Google Scholar 

  • Cha J H J, Frey A S, Alsdorf S A, Kerner J A, Kosinski C M, Mangiarini L, Penney J B Jr, Davies SW, Bates G P, Young A B (1999). Altered neurotransmitter receptor expression in transgenic mouse models of Huntington’s disease. Philos Trans R Soc Lond B Biol Sci, 354(1386): 981–989

    PubMed  CAS  Article  Google Scholar 

  • Che H V B, Metzger S, Portal E, Deyle C, Riess O, Nguyen H P (2011). Localization of sequence variations in PGC-1α influence their modifying effect in Huntington disease. Mol Neurodegener, 6(1): 1

    PubMed  CAS  Article  Google Scholar 

  • Cho S R, Benraiss A, Chmielnicki E, Samdani A, Economides A, Goldman S A (2007). Induction of neostriatal neurogenesis slows disease progression in a transgenic murine model of Huntington disease. J Clin Invest, 117(10): 2889–2902

    PubMed  CAS  Article  Google Scholar 

  • Choi Y S, Lee B, Cho H Y, Reyes I B, Pu X A, Saido T C, Hoyt K R, Obrietan K (2009). CREB is a key regulator of striatal vulnerability in chemical and genetic models of Huntington’s disease. Neurobiol Dis, 36(2): 259–268

    PubMed  CAS  Article  Google Scholar 

  • Chou S Y, Weng J Y, Lai H L, Liao F, Sun S H, Tu P H, Dickson D W, Chern Y (2008). Expanded-polyglutamine huntingtin protein suppresses the secretion and production of a chemokine (CCL5/RANTES) by astrocytes. J Neurosci, 28(13): 3277–3290

    PubMed  CAS  Article  Google Scholar 

  • Crook Z R, Housman D (2011). Huntington’s disease: can mice lead the way to treatment? Neuron, 69(3): 423–435

    PubMed  CAS  Article  Google Scholar 

  • Cudkowicz M, Kowall N W (1990). Degeneration of pyramidal projection neurons in Huntington’s disease cortex. Ann Neurol, 27(2): 200–204

    PubMed  CAS  Article  Google Scholar 

  • Cui L, Jeong H, Borovecki F, Parkhurst C N, Tanese N, Krainc D (2006). Transcriptional repression of PGC-1αby mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration. Cell, 127(1): 59–69

    PubMed  CAS  Article  Google Scholar 

  • Damiano M, Galvan L, Déglon N, Brouillet E (2010). Mitochondria in Huntington’s disease. Biochim Biophys Acta, 1802(1): 52–61

    PubMed  CAS  Article  Google Scholar 

  • de la Monte SM, Vonsattel J P, Richardson E P Jr, (1988). Morphometric demonstration of atrophic changes in the cerebral cortex, white matter, and neostriatum in Huntington’s disease. J Neuropathol Exp Neurol, 47(5): 516–525

    PubMed  Article  Google Scholar 

  • Di Pardo A, Maglione V, Alpaugh M, Horkey M, Atwal R S, Sassone J, Ciammola A, Steffan J S, Fouad K, Truant R, Sipione S (2012). Ganglioside GM1 induces phosphorylation of mutant huntingtin and restores normal motor behavior in Huntington disease mice. Proc Natl Acad Sci U S A, 109(9): 3528–3533

    PubMed  Article  Google Scholar 

  • DiFiglia M, Sapp E, Chase K, Schwarz C, Meloni A, Young C, Martin E, Vonsattel J P, Carraway R, Reeves S A, et al (1995). Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons. Neuron, 14(5): 1075–1081

    PubMed  CAS  Article  Google Scholar 

  • DiFiglia M, Sapp E, Chase K O, Davies S W, Bates G P, Vonsattel J P, Aronin N (1997). Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science, 277(5334): 1990–1993

    PubMed  CAS  Article  Google Scholar 

  • DiFiglia M, Sena-Esteves M, Chase K, Sapp E, Pfister E, Sass M, Yoder J, Reeves P, Pandey R K, Rajeev K G, Manoharan M, Sah D W, Zamore P D, Aronin N (2007). Therapeutic silencing of mutant huntingtin with siRNA attenuates striatal and cortical neuropathology and behavioral deficits. Proc Natl Acad Sci U S A, 104(43): 17204–17209

    PubMed  CAS  Article  Google Scholar 

  • Donmez G (2012). The neurobiology of sirtuins and their role in neurodegeneration. Trends Pharmacol Sci, 33(9): 494–501

    PubMed  CAS  Article  Google Scholar 

  • Duff K, Paulsen J S, Beglinger L J, Langbehn D R, Wang C, Stout J C, Ross C A, Aylward E, Carlozzi N E, Queller S, and the Predict-HD Investigators of the Huntington Study Group (2010). “Frontal” behaviors before the diagnosis of Huntington’s disease and their relationship to markers of disease progression: evidence of early lack of awareness. J Neuropsychiatry Clin Neurosci, 22(2): 196–207

    PubMed  Article  Google Scholar 

  • Dumas EM, Van den Bogaard S J A, Ruber ME, Reilman R R, Stout J C, Craufurd D, Hicks S L, Kennard C, Tabrizi S J, Van Buchem M A, Van der Grond J, Roos R A (2012). Early changes in white matter pathways of the sensorimotor cortex in premanifest Huntington’s disease. Hum Brain Mapp, 33(1): 203–212

    PubMed  Article  Google Scholar 

  • Duyao MP, Auerbach A B, Ryan A, Persichetti F, Barnes G T, McNeil S M, Ge P, Vonsattel J P, Gusella J F, Joyner A L, et al (1995). Inactivation of the mouse Huntington’s disease gene homolog Hdh. Science, 269(5222): 407–410

    PubMed  CAS  Article  Google Scholar 

  • Ehrnhoefer D E, Sutton L, Hayden M R (2011). Small Changes, Big Impact: Posttranslational Modifications and Function of Huntingtin in Huntington Disease. Neuroscientist, 17(5): 475–492

    PubMed  CAS  Article  Google Scholar 

  • Faideau M, Kim J, Cormier K, Gilmore R, Welch M, Auregan G, Dufour N, Guillermier M, Brouillet E, Hantraye P, Déglon N, Ferrante R J, Bonvento G (2010). In vivo expression of polyglutamine-expanded huntingtin by mouse striatal astrocytes impairs glutamate transport: a correlation with Huntington’s disease subjects. Hum Mol Genet, 19(15): 3053–3067

    PubMed  CAS  Article  Google Scholar 

  • Ferrante R J, Kowall NW, Beal MF, Martin J B, Bird E D, Richardson E P Jr (1987). Morphologic and histochemical characteristics of a spared subset of striatal neurons in Huntington’s disease. J Neuropathol Exp Neurol, 46(1): 12–27

    PubMed  CAS  Article  Google Scholar 

  • Ferrante R J, Kowall N W, Beal M F, Richardson E P Jr, Bird E D, Martin J B (1985). Selective sparing of a class of striatal neurons in Huntington’s disease. Science, 230(4725): 561–563

    PubMed  CAS  Article  Google Scholar 

  • Fiacco T A, McCarthy K D (2004). Intracellular astrocyte calcium waves in situ increase the frequency of spontaneous AMPA receptor currents in CA1 pyramidal neurons. J Neurosci, 24(3): 722–732

    PubMed  CAS  Article  Google Scholar 

  • Fusco F R, Chen Q, Lamoreaux W J, Figueredo-Cardenas G, Jiao Y, Coffman J A, Surmeier D J, Honig M G, Carlock L R, Reiner A (1999). Cellular localization of huntingtin in striatal and cortical neurons in rats: lack of correlation with neuronal vulnerability in Huntington’s disease. J Neurosci, 19(4): 1189–1202

    PubMed  CAS  Google Scholar 

  • Gafni J, Papanikolaou T, Degiacomo F, Holcomb J, Chen S, Menalled L, Kudwa A, Fitzpatrick J, Miller S, Ramboz S, Tuunanen P I, Lehtimäki K K, Yang X W, Park L, Kwak S, Howland D, Park H, Ellerby L M (2012). Caspase-6 activity in a BACHD mouse modulates steady-state levels of mutant huntingtin protein but is not necessary for production of a 586 amino acid proteolytic fragment. J Neurosci, 32(22): 7454–7465

    PubMed  CAS  Article  Google Scholar 

  • Gauthier L R, Charrin B C, Borrell-Pagès M, Dompierre J P, Rangone H, Cordelières F P, De Mey J, MacDonald M E, Lessmann V, Humbert S, Saudou F (2004). Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell, 118(1): 127–138

    PubMed  CAS  Article  Google Scholar 

  • Glass C K, Saijo K, Winner B, Marchetto M C, Gage F H (2010). Mechanisms underlying inflammation in neurodegeneration. Cell, 140(6): 918–934

    PubMed  CAS  Article  Google Scholar 

  • Gorski J A, Talley T, Qiu M, Puelles L, Rubenstein J L R, Jones K R (2002). Cortical excitatory neurons and glia, but not GABAergic neurons, are produced in the Emx1-expressing lineage. J Neurosci, 22(15): 6309–6314

    PubMed  CAS  Google Scholar 

  • Graham R K, Deng Y, Carroll J, Vaid K, Cowan C, Pouladi M A, Metzler M, Bissada N, Wang L, Faull R L M, Gray M, Yang X W, Raymond L A, Hayden M R (2010). Cleavage at the 586 amino acid caspase-6 site in mutant huntingtin influences caspase-6 activation in vivo. J Neurosci, 30(45): 15019–15029

    PubMed  CAS  Article  Google Scholar 

  • Graham R K, Deng Y, Slow E J, Haigh B, Bissada N, Lu G, Pearson J, Shehadeh J, Bertram L, Murphy Z, Warby S C, Doty C N, Roy S, Wellington C L, Leavitt B R, Raymond L A, Nicholson DW, Hayden M R (2006). Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin. Cell, 125(6): 1179–1191

    PubMed  CAS  Article  Google Scholar 

  • Gray M, Shirasaki D I, Cepeda C, André VM, Wilburn B, Lu X H, Tao J, Yamazaki I, Li S H, Sun Y E, Li X J, Levine M S, Yang XW (2008). Full-length human mutant huntingtin with a stable polyglutamine repeat can elicit progressive and selective neuropathogenesis in BACHD mice. J Neurosci, 28(24): 6182–6195

    PubMed  CAS  Article  Google Scholar 

  • Graybiel A M (2000). The basal ganglia. Curr Biol, 10(14): R509–R511

    PubMed  CAS  Article  Google Scholar 

  • Greiner E R, Yang X W (2011). Huntington’s disease: flipping a switch on huntingtin. Nat Chem Biol, 7(7): 412–414

    PubMed  CAS  Article  Google Scholar 

  • Gu X, André V M, Cepeda C, Li S H, Li X J, Levine M S, Yang X W (2007). Pathological cell-cell interactions are necessary for striatal pathogenesis in a conditional mouse model of Huntington’s disease. Mol Neurodegener, 2: 8

    PubMed  Article  CAS  Google Scholar 

  • Gu X, Greiner E R, Mishra R, Kodali R, Osmand A, Finkbeiner S, Steffan J S, Thompson L M, Wetzel R, Yang X W (2009). Serines 13 and 16 are critical determinants of full-length human mutant huntingtin induced disease pathogenesis in HD mice. Neuron, 64(6): 828–840

    PubMed  CAS  Article  Google Scholar 

  • Gu X, Li C, Wei W, Lo V, Gong S, Li S H, Iwasato T, Itohara S, Li X J, Mody I, Heintz N, Yang X W (2005). Pathological cell-cell interactions elicited by a neuropathogenic form of mutant Huntingtin contribute to cortical pathogenesis in HD mice. Neuron, 46(3): 433–444

    PubMed  CAS  Article  Google Scholar 

  • Guarente L (2007). Sirtuins in aging and disease. Cold Spring Harb Symp Quant Biol, 72: 483–488

    PubMed  CAS  Article  Google Scholar 

  • Guidetti P, Bates G P, Graham R K, Hayden M R, Leavitt B R, MacDonald M E, Slow E J, Wheeler V C, Woodman B, Schwarcz R (2006). Elevated brain 3-hydroxykynurenine and quinolinate levels in Huntington disease mice. Neurobiol Dis, 23(1): 190–197

    PubMed  CAS  Article  Google Scholar 

  • Gutekunst C A, Li S H, Yi H, Mulroy J S, Kuemmerle S, Jones R, Rye D, Ferrante R J, Hersch S M, Li X J (1999). Nuclear and neuropil aggregates in Huntington’s disease: relationship to neuropathology. J Neurosci, 19(7): 2522–2534

    PubMed  CAS  Google Scholar 

  • Hardingham G E, Bading H (2003). The Yin and Yang of NMDA receptor signalling. Trends Neurosci, 26(2): 81–89

    PubMed  CAS  Article  Google Scholar 

  • Hardingham G E, Bading H (2010). Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat Rev Neurosci, 682(11): 1–15

    Google Scholar 

  • Harper S Q, Staber P D, He X, Eliason S L, Martins I H, Mao Q, Yang L, Kotin R M, Paulson H L, Davidson B L (2005). RNA interference improves motor and neuropathological abnormalities in a Huntington’s disease mouse model. Proc Natl Acad Sci U S A, 102(16): 5820–5825

    PubMed  CAS  Article  Google Scholar 

  • Harris G J, Pearlson G D, Peyser C E, Aylward E H, Roberts J, Barta P E, Chase G A, Folstein S E (1992). Putamen volume reduction on magnetic resonance imaging exceeds caudate changes in mild Huntington’s disease. Ann Neurol, 31(1): 69–75

    PubMed  CAS  Article  Google Scholar 

  • Harrison L M (2012). Rhes: A GTP-Binding Protein Integral to Striatal Physiology and Pathology. Cell Mol Neurobiol, 32(6): 907–918

    PubMed  CAS  Article  Google Scholar 

  • Hedreen J C, Peyser C E, Folstein S E, Ross C A (1991). Neuronal loss in layers V and VI of cerebral cortex in Huntington’s disease. Neurosci Lett, 133(2): 257–261

    PubMed  CAS  Article  Google Scholar 

  • Heng M Y, Detloff P J, Albin R L (2008). Rodent genetic models of Huntington disease. Neurobiol Dis, 32(1): 1–9

    PubMed  CAS  Article  Google Scholar 

  • Heng M Y, Detloff P J, Wang P L, Tsien J Z, Albin R L (2009). In vivo evidence for NMDA receptor-mediated excitotoxicity in a murine genetic model of Huntington disease. J Neurosci, 29(10): 3200–3205

    PubMed  CAS  Article  Google Scholar 

  • Hodgson J G, Agopyan N, Gutekunst C A, Leavitt B R, LePiane F, Singaraja R, Smith D J, Bissada N, McCutcheon K, Nasir J, Jamot L, Li X J, Stevens M E, Rosemond E, Roder J C, Phillips A G, Rubin E M, Hersch S M, Hayden M R (1999). A YAC mouse model for Huntington’s disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration. Neuron, 23(1): 181–192

    PubMed  CAS  Article  Google Scholar 

  • Holmes S E, O’Hearn E, Rosenblatt A, Callahan C, Hwang H S, Ingersoll-Ashworth R G, Fleisher A, Stevanin G, Brice A, Potter N T, Ross C A, Margolis R L (2001). A repeat expansion in the gene encoding junctophilin-3 is associated with Huntington disease-like 2. Nat Genet, 29(4): 377–378

    PubMed  CAS  Article  Google Scholar 

  • Houtkooper R H, Pirinen E, Auwerx J (2012). Sirtuins as regulators of metabolism and healthspan. Nat Rev Mol Cell Biol, 13(4): 225–238

    PubMed  CAS  Google Scholar 

  • Hult S, Soylu R, Björklund T, Belgardt B F, Mauer J, Brüning J C, Kirik D, Petersén Å (2011). Mutant huntingtin causes metabolic imbalance by disruption of hypothalamic neurocircuits. Cell Metab, 13(4): 428–439

    PubMed  CAS  Article  Google Scholar 

  • Humbert S, Bryson E A, Cordelières F P, Connors N C, Datta S R, Finkbeiner S, Greenberg M E, Saudou F (2002). The IGF-1/Akt pathway is neuroprotective in Huntington’s disease and involves Huntingtin phosphorylation by Akt. Dev Cell, 2(6): 831–837

    PubMed  CAS  Article  Google Scholar 

  • Iwasato T, Datwani A, Wolf A M, Nishiyama H, Taguchi Y, Tonegawa S, Knöpfel T, Erzurumlu R S, Itohara S (2000). Cortex-restricted disruption of NMDAR1 impairs neuronal patterns in the barrel cortex. Nature, 406(6797): 726–731

    PubMed  CAS  Article  Google Scholar 

  • Jauch D, Urbańska E M, Guidetti P, Bird E D, Vonsattel J P, WhetsellW O Jr, Schwarcz R (1995). Dysfunction of brain kynurenic acid metabolism in Huntington’s disease: focus on kynurenine aminotransferases. J Neurol Sci, 130(1): 39–47

    PubMed  CAS  Article  Google Scholar 

  • Jeong H, Cohen D E, Cui L, Supinski A, Savas J N, Mazzulli J R, Yates J R 3rd, Bordone L, Guarente L, Krainc D (2012). Sirt1 mediates neuroprotection from mutant huntingtin by activation of the TORC1 and CREB transcriptional pathway. Nat Med, 18(1): 159–165

    CAS  Article  Google Scholar 

  • Jeong H, Then F, Melia T J Jr, Mazzulli J R, Cui L, Savas J N, Voisine C, Paganetti P, Tanese N, Hart A C, Yamamoto A, Krainc D (2009). Acetylation targets mutant huntingtin to autophagosomes for degradation. Cell, 137(1): 60–72

    PubMed  CAS  Article  Google Scholar 

  • Jernigan T L, Salmon D P, Butters N, Hesselink J R (1991). Cerebral structure on MRI, Part II: Specific changes in Alzheimer’s and Huntington’s diseases. Biol Psychiatry, 29(1): 68–81

    PubMed  CAS  Article  Google Scholar 

  • Jiang M, Wang J, Fu J, Du L, Jeong H, West T, Xiang L, Peng Q, Hou Z, Cai H, Seredenina T, Arbez N, Zhu S, Sommers K, Qian J, Zhang J, Mori S, Yang X W, Tamashiro K L, Aja S, Moran T H, Luthi-Carter R, Martin B, Maudsley S, Mattson M P, Cichewicz R H, Ross C A, Holtzman D M, Krainc D, Duan W (2012). Neuroprotective role of Sirt1 in mammalian models of Huntington’s disease through activation of multiple Sirt1 targets. Nat Med, 18(1): 153–158

    CAS  Article  Google Scholar 

  • Johri A, Calingasan N Y, Hennessey T M, Sharma A, Yang L, Wille E, Chandra A, Beal M F (2012). Pharmacologic activation of mitochondrial biogenesis exerts widespread beneficial effects in a transgenic mouse model of Huntington’s disease. Hum Mol Genet, 21(5): 1124–1137

    PubMed  CAS  Article  Google Scholar 

  • Kim J, Moody J P, Edgerly C K, Bordiuk O L, Cormier K, Smith K, Beal MF, Ferrante R J (2010). Mitochondrial loss, dysfunction and altered dynamics in Huntington’s disease. Hum Mol Genet, 19(20): 3919–3935

    PubMed  CAS  Article  Google Scholar 

  • Kita H, Kitai S T (1988). Glutamate decarboxylase immunoreactive neurons in rat neostriatum: their morphological types and populations. Brain Res, 447(2): 346–352

    PubMed  CAS  Article  Google Scholar 

  • Klöppel S, Draganski B, Golding C V, Chu C, Nagy Z, Cook P A, Hicks S L, Kennard C, Alexander D C, Parker G J M, Tabrizi S J, Frackowiak R S (2008). White matter connections reflect changes in voluntary-guided saccades in pre-symptomatic Huntington’s disease. Brain, 131(Pt 1): 196–204

    PubMed  Google Scholar 

  • Kolodziej L R, Paleolog E M, Williams R O (2011). Kynurenine metabolism in health and disease. Amino Acids, 41(5): 1173–1183

    PubMed  CAS  Article  Google Scholar 

  • Kordasiewicz H B, Stanek LM, Wancewicz E V, Mazur C, McAlonis M M, Pytel K A, Artates J W, Weiss A, Cheng S H, Shihabuddin L S, Hung G, Bennett C F, Cleveland D W (2012). Sustained Therapeutic Reversal of Huntington’s Disease by Transient Repression of Huntingtin Synthesis. Neuron, 74(6): 1031–1044

    PubMed  CAS  Article  Google Scholar 

  • Kovács K A, Steullet P, Steinmann M, Do K Q, Magistretti P J, Halfon O, Cardinaux J R (2007). TORC1 is a calcium- and cAMP-sensitive coincidence detector involved in hippocampal long-term synaptic plasticity. Proc Natl Acad Sci U S A, 104(11): 4700–4705

    PubMed  Article  CAS  Google Scholar 

  • Lange H, Thörner G, Hopf A, Schröder K F (1976). Morphometric studies of the neuropathological changes in choreatic diseases. J Neurol Sci, 28(4): 401–425

    PubMed  CAS  Article  Google Scholar 

  • Levine M S, Klapstein G J, Koppel A, Gruen E, Cepeda C, Vargas M E, Jokel E S, Carpenter E M, Zanjani H, Hurst R S, Efstratiadis A, Zeitlin S, Chesselet MF (1999). Enhanced sensitivity to N-methyl-Daspartate receptor activation in transgenic and knockin mouse models of Huntington’s disease. J Neurosci Res, 58(4): 515–532

    PubMed  CAS  Article  Google Scholar 

  • Li H, Li S H, Johnston H, Shelbourne P F, Li X J (2000). Aminoterminal fragments of mutant huntingtin show selective accumulation in striatal neurons and synaptic toxicity. Nat Genet, 25(4): 385–389

    PubMed  CAS  Article  Google Scholar 

  • Li L, Fan M, Icton C D, Chen N, Leavitt B R, Hayden MR, Murphy T H, Raymond L A (2003). Role of NR2B-type NMDA receptors in selective neurodegeneration in Huntington disease. Neurobiol Aging, 24(8): 1113–1121

    PubMed  CAS  Article  Google Scholar 

  • Li S, Zhang C, Takemori H, Zhou Y, Xiong Z Q (2009). TORC1 regulates activity-dependent CREB-target gene transcription and dendritic growth of developing cortical neurons. J Neurosci, 29(8): 2334–2343

    PubMed  CAS  Article  Google Scholar 

  • Liévens J C, Woodman B, Mahal A, Spasic-Boscovic O, Samuel D, Kerkerian-Le Goff L, Bates G P (2001). Impaired glutamate uptake in the R6 Huntington’s disease transgenic mice. Neurobiol Dis, 8(5): 807–821

    PubMed  Article  CAS  Google Scholar 

  • Lin J, Wu P H, Tarr P T, Lindenberg K S, St-Pierre J, Zhang C Y, Mootha V K, Jäger S, Vianna C R, Reznick R M, Cui L, Manieri M, Donovan M X, Wu Z, Cooper M P, Fan M C, Rohas L M, Zavacki A M, Cinti S, Shulman G I, Lowell B B, Krainc D, Spiegelman B M (2004). Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1alpha null mice. Cell, 119(1): 121–135

    PubMed  CAS  Article  Google Scholar 

  • Lin J, Yang R, Tarr P T, Wu P H, Handschin C, Li S, Yang W, Pei L, Uldry M, Tontonoz P, Newgard C B, Spiegelman B M (2005). Hyperlipidemic effects of dietary saturated fats mediated through PGC-1β coactivation of SREBP. Cell, 120(2): 261–273

    PubMed  CAS  Article  Google Scholar 

  • Lu X H, Yang X W (2012). “Huntingtin Holiday”: Progress toward an Antisense Therapy for Huntington’s Disease. Neuron, 74(6): 964–966

    PubMed  CAS  Article  Google Scholar 

  • Lunkes A, Lindenberg K S, Ben-Haïem L, Weber C, Devys D, Landwehrmeyer G B, Mandel J L, Trottier Y (2002). Proteases acting on mutant huntingtin generate cleaved products that differentially build up cytoplasmic and nuclear inclusions. Mol Cell, 10(2): 259–269

    PubMed  CAS  Article  Google Scholar 

  • Luthi-Carter R, Strand A, Peters N L, Solano S M, Hollingsworth Z R, Menon A S, Frey A S, Spektor B S, Penney E B, Schilling G, Ross C A, Borchelt D R, Tapscott S J, Young A B, Cha J H, Olson J M (2000). Decreased expression of striatal signaling genes in a mouse model of Huntington’s disease. Hum Mol Genet, 9(9): 1259–1271

    PubMed  CAS  Article  Google Scholar 

  • Macdonald V, Halliday G (2002). Pyramidal cell loss in motor cortices in Huntington’s disease. Neurobiol Dis, 10(3): 378–386

    PubMed  Article  Google Scholar 

  • Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A, Hetherington C, Lawton M, Trottier Y, Lehrach H, Davies S W, Bates G P (1996). Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell, 87(3): 493–506

    PubMed  CAS  Article  Google Scholar 

  • Mann D M, Oliver R, Snowden J S (1993). The topographic distribution of brain atrophy in Huntington’s disease and progressive supranuclear palsy. Acta Neuropathol, 85(5): 553–559

    PubMed  CAS  Article  Google Scholar 

  • Mantamadiotis T, Lemberger T, Bleckmann S C, Kern H, Kretz O, Martin Villalba A, Tronche F, Kellendonk C, Gau D, Kapfhammer J, Otto C, Schmid W, Schütz G (2002). Disruption of CREB function in brain leads to neurodegeneration. Nat Genet, 31(1): 47–54

    PubMed  CAS  Article  Google Scholar 

  • Mattsson B, Gottfries C G, Roos B E, Winblad B (1974). Huntington’s chorea: pathology and brain amines. Acta Psychiatr Scand Suppl, 255: 269–277

    PubMed  CAS  Article  Google Scholar 

  • McBride J L, Boudreau R L, Harper S Q, Staber P D, Monteys A M, Martins I, Gilmore B L, Burstein H, Peluso RW, Polisky B, Carter B J, Davidson B L (2008). Artificial miRNAs mitigate shRNAmediated toxicity in the brain: implications for the therapeutic development of RNAi. Proc Natl Acad Sci U S A, 105(15): 5868–5873

    PubMed  CAS  Article  Google Scholar 

  • McGill J K, Beal M F (2006). PGC-1α, a new therapeutic target in Huntington’s disease? Cell, 127(3): 465–468

    PubMed  CAS  Article  Google Scholar 

  • Menalled L, El-Khodor B F, Patry M, Suárez-Fariñas M, Orenstein S J, Zahasky B, Leahy C, Wheeler V, Yang X W, MacDonald M E, Morton A J, Bates G, Leeds J, Park L, Howland D, Signer E, Tobin A, Brunner D (2009). Systematic behavioral evaluation of Huntington’s disease transgenic and knock-in mouse models. Neurobiol Dis, 35(3): 319–336

    PubMed  CAS  Article  Google Scholar 

  • Menalled L B, Sison J D, Dragatsis I, Zeitlin S, Chesselet M F O (2003). Time course of early motor and neuropathological anomalies in a knock-in mouse model of Huntington’s disease with 140 CAG repeats. J Comp Neurol, 465(1): 11–26

    PubMed  CAS  Article  Google Scholar 

  • Metzler M, Gan L, Mazarei G, Graham R K, Liu L, Bissada N, Lu G, Leavitt B R, Hayden M R (2010). Phosphorylation of huntingtin at Ser421 in YAC128 neurons is associated with protection of YAC128 neurons from NMDA-mediated excitotoxicity and is modulated by PP1 and PP2A. J Neurosci, 30(43): 14318–14329

    PubMed  CAS  Article  Google Scholar 

  • Miller B R, Dorner J L, Shou M, Sari Y, Barton S J, Sengelaub D R, Kennedy R T, Rebec G V (2008). Up-regulation of GLT1 expression increases glutamate uptake and attenuates the Huntington’s disease phenotype in the R6/2 mouse. Neuroscience, 153(1): 329–337

    PubMed  CAS  Article  Google Scholar 

  • Miller J P, Holcomb J, Al-Ramahi I, de Haro M, Gafni J, Zhang N, Kim E, Sanhueza M, Torcassi C, Kwak S, Botas J, Hughes R E, Ellerby L M (2010). Matrix metalloproteinases are modifiers of huntingtin proteolysis and toxicity in Huntington’s disease. Neuron, 67(2): 199–212

    PubMed  CAS  Article  Google Scholar 

  • Milnerwood A J, Cummings DM, Dallérac GM, Brown J Y, Vatsavayai S C, Hirst M C, Rezaie P, Murphy K P (2006). Early development of aberrant synaptic plasticity in a mouse model of Huntington’s disease. Hum Mol Genet, 15(10): 1690–1703

    PubMed  CAS  Article  Google Scholar 

  • Milnerwood A J, Gladding C M, Pouladi M A, Kaufman A M, Hines R M, Boyd J D, Ko R W Y, Vasuta O C, Graham R K, Hayden M R, Murphy T H, Raymond L A (2010). Early increase in extrasynaptic NMDA receptor signaling and expression contributes to phenotype onset in Huntington’s disease mice. Neuron, 65(2): 178–190

    PubMed  CAS  Article  Google Scholar 

  • Milnerwood A J, Raymond L A (2010). Early synaptic pathophysiology in neurodegeneration: insights from Huntington’s disease. Trends Neurosci, 33(11): 513–523

    PubMed  CAS  Article  Google Scholar 

  • Myers R H, Vonsattel J P, Paskevich P A, Kiely D K, Stevens T J, Cupples L A, Richardson E P Jr, Bird E D (1991). Decreased neuronal and increased oligodendroglial densities in Huntington’s disease caudate nucleus. J Neuropathol Exp Neurol, 50(6): 729–742

    PubMed  CAS  Article  Google Scholar 

  • Okamoto S I, Pouladi M A, Talantova M, Yao D, Xia P, Ehrnhoefer D E, Zaidi R, Clemente A, Kaul M, Graham R K, Zhang D, Vincent Chen H S, Tong G, Hayden M R, Lipton S A (2009). Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin. Nat Med

  • Orr H T, Zoghbi H Y (2007). Trinucleotide repeat disorders. Annu Rev Neurosci, 30: 575–621

    PubMed  CAS  Article  Google Scholar 

  • Parker J A, Arango M, Abderrahmane S, Lambert E, Tourette C, Catoire H, Néri C (2005). Resveratrol rescues mutant polyglutamine cytotoxicity in nematode and mammalian neurons. Nat Genet, 37(4): 349–350

    PubMed  CAS  Article  Google Scholar 

  • Paulsen J S, Hayden M, Stout J C, Langbehn D R, Aylward E, Ross C A, Guttman M, Nance M, Kieburtz K, Oakes D, Shoulson I, Kayson E, Johnson S, Penziner E, Predict-HD Investigators of the Huntington Study Group (2006). Preparing for preventive clinical trials: the Predict-HD study. Arch Neurol, 63(6): 883–890

    PubMed  Article  Google Scholar 

  • Paulsen J S, Langbehn D R, Stout J C, Aylward E, Ross C A, Nance M, Guttman M, Johnson S, MacDonald M, Beglinger L J, Duff K, Kayson E, Biglan K, Shoulson I, Oakes D, Hayden M, Predict-HD Investigators and Coordinators of the Huntington Study Group (2008). Detection of Huntington’s disease decades before diagnosis: the Predict-HD study. J Neurol Neurosurg Psychiatry, 79(8): 874–880

    PubMed  CAS  Article  Google Scholar 

  • Paulsen J S, Wang C, Duff K, Barker R, Nance M, Beglinger L, Moser D, Williams J K, Simpson S, Langbehn D, Van Kammen D P, and the PREDICT-HD Investigators of the Huntington Study Group (2010). Challenges assessing clinical endpoints in early Huntington disease. Mov Disord, 25(15): 2595–2603

    PubMed  Article  Google Scholar 

  • Petersén Å, Björkqvist M (2006). Hypothalamic-endocrine aspects in Huntington’s disease. Eur J Neurosci, 24(4): 961–967

    PubMed  Article  Google Scholar 

  • Pfrieger F W, Ungerer N (2011). Cholesterol metabolism in neurons and astrocytes. Prog Lipid Res, 50(4): 357–371

    PubMed  CAS  Article  Google Scholar 

  • Ramos, E. M., Latourelle, J. C., Lee, J.-H., Gillis, T., Mysore, J. S., Squitieri, F., Pardo, A., Donato, S., Hayden, M. R., Morrison, P. J., et al. (2012). Population stratification may bias analysis of PGC-1α as a modifier of age at Huntington disease motor onset. Hum. Genet.

  • Ratovitski T, Gucek M, Jiang H, Chighladze E, Waldron E, D’Ambola J, Hou Z, Liang Y, Poirier MA, Hirschhorn R R, Graham R, Hayden M R, Cole R N, Ross C A (2009). Mutant huntingtin N-terminal fragments of specific size mediate aggregation and toxicity in neuronal cells. J Biol Chem, 284(16): 10855–10867

    PubMed  CAS  Article  Google Scholar 

  • Raymond L A, André V M, Cepeda C, Gladding C M, Milnerwood A J, Levine M S (2011). Pathophysiology of Huntington’s disease: timedependent alterations in synaptic and receptor function. Neuroscience, 198: 252–273

    PubMed  CAS  Article  Google Scholar 

  • Reading S A J, Yassa M A, Bakker A, Dziorny A C, Gourley L M, Yallapragada V, Rosenblatt A, Margolis R L, Aylward E H, Brandt J, Mori S, Van Zijl P, Bassett S S, Ross C A (2005). Regional white matter change in pre-symptomatic Huntington’s disease: a diffusion tensor imaging study. Psychiatry Res, 140(1): 55–62

    PubMed  Article  Google Scholar 

  • Reiner A, Albin R L, Anderson K D, D’Amato C J, Penney J B, Young A B (1988). Differential loss of striatal projection neurons in Huntington disease. Proc Natl Acad Sci U S A, 85(15): 5733–5737

    PubMed  CAS  Article  Google Scholar 

  • Reiner A, Dragatsis I, Zeitlin S, Goldowitz D (2003). Wild-type huntingtin plays a role in brain development and neuronal survival. Mol Neurobiol, 28(3): 259–276

    PubMed  CAS  Article  Google Scholar 

  • Roos R A, Bots G T, Hermans J (1986). Quantitative analysis of morphological features in Huntington’s disease. Acta Neurol Scand, 73(2): 131–135

    PubMed  CAS  Article  Google Scholar 

  • Rosas H D, Feigin A S, Hersch S M (2004). Using advances in neuroimaging to detect, understand, and monitor disease progression in Huntington’s disease. NeuroRx, 1(2): 263–272

    PubMed  CAS  Article  Google Scholar 

  • Rosas H D, Koroshetz W J, Chen Y I, Skeuse C, Vangel M, Cudkowicz M E, Caplan K, Marek K, Seidman L J, Makris N, Jenkins B G, Goldstein J M (2003). Evidence for more widespread cerebral pathology in early HD: an MRI-based morphometric analysis. Neurology, 60(10): 1615–1620

    PubMed  CAS  Article  Google Scholar 

  • Rosas H D, Lee S Y, Bender A C, Zaleta A K, Vangel M, Yu P, Fischl B, Pappu V, Onorato C, Cha J H, Salat D H, Hersch SM (2010). Altered white matter microstructure in the corpus callosum in Huntington’s disease: implications for cortical “disconnection”. Neuroimage, 49(4): 2995–3004

    PubMed  Article  Google Scholar 

  • Rosas H D, Salat D H, Lee S Y, Zaleta A K, Hevelone N, Hersch S M (2008). Complexity and heterogeneity: what drives the everchanging brain in Huntington’s disease? Ann N Y Acad Sci, 1147: 196–205

    PubMed  Article  Google Scholar 

  • Rosas H D, Tuch D S, Hevelone N D, Zaleta A K, Vangel M, Hersch S M, Salat D H (2006). Diffusion tensor imaging in presymptomatic and early Huntington’s disease: Selective white matter pathology and its relationship to clinical measures. Mov Disord, 21(9): 1317–1325

    PubMed  Article  Google Scholar 

  • Ross C A, Tabrizi S J (2011). Huntington’s disease: from molecular pathogenesis to clinical treatment. Lancet Neurol, 10(1): 83–98

    PubMed  CAS  Article  Google Scholar 

  • Runne H, Régulier E, Kuhn A, Zala D, Gokce O, Perrin V, Sick B, Aebischer P, Déglon N, Luthi-Carter R (2008). Dysregulation of gene expression in primary neuron models of Huntington’s disease shows that polyglutamine-related effects on the striatal transcriptome may not be dependent on brain circuitry. J Neurosci, 28(39): 9723–9731

    PubMed  CAS  Article  Google Scholar 

  • Savoiardo M, Strada L, Oliva D, Girotti F, D’Incerti L (1991). Abnormal MRI signal in the rigid form of Huntington’s disease. J Neurol Neurosurg Psychiatry, 54(10): 888–891

    PubMed  CAS  Article  Google Scholar 

  • Schilling G, Becher MW, Sharp A H, Jinnah H A, Duan K, Kotzuk J A, Slunt H H, Ratovitski T, Cooper J K, Jenkins N A, Copeland N G, Price D L, Ross C A, Borchelt D R (1999). Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant Nterminal fragment of huntingtin. Hum Mol Genet, 8(3): 397–407

    PubMed  CAS  Article  Google Scholar 

  • Schwarcz R, Bennett J P Jr, Coyle J T Jr (1977). Loss of striatal serotonin synaptic receptor binding induced by kainic acid lesions: correlations with Huntington’s Disease. J Neurochem, 28(4): 867–869

    PubMed  CAS  Article  Google Scholar 

  • Schwarcz R, Guidetti P, Sathyasaikumar K V, Muchowski P J (2010). Of mice, rats and men: Revisiting the quinolinic acid hypothesis of Huntington’s disease. Prog Neurobiol, 90(2): 230–245

    PubMed  CAS  Article  Google Scholar 

  • Sharma P, Savy L, Britton J, Taylor R, Howick A, Patton M (1996). Huntington’s disease: a molecular genetic and CT comparison. J Neurol Neurosurg Psychiatry, 60(2): 206–208

    PubMed  CAS  Article  Google Scholar 

  • Shaywitz A J, Greenberg M E (1999). CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals. Annu Rev Biochem, 68: 821–861

    PubMed  CAS  Article  Google Scholar 

  • Shin J Y, Fang Z H, Yu Z X, Wang C E, Li S H, Li X J (2005). Expression of mutant huntingtin in glial cells contributes to neuronal excitotoxicity. J Cell Biol, 171(6): 1001–1012

    PubMed  CAS  Article  Google Scholar 

  • Simmons D A, Mehta R A, Lauterborn J C, Gall C M, Lynch G (2011). Brief ampakine treatments slow the progression of Huntington’s disease phenotypes in R6/2 mice. Neurobiol Dis, 41(2): 436–444

    PubMed  CAS  Article  Google Scholar 

  • Simmons D A, Rex C S, Palmer L, Pandyarajan V, Fedulov V, Gall CM, Lynch G (2009). Up-regulating BDNF with an ampakine rescues synaptic plasticity and memory in Huntington’s disease knockin mice. Proc Natl Acad Sci U S A, 106(12): 4906–4911

    PubMed  CAS  Article  Google Scholar 

  • Slow E J, Van Raamsdonk J, Rogers D, Coleman S H, Graham R K, Deng Y, Oh R, Bissada N, Hossain S M, Yang Y Z, Li X J, Simpson E M, Gutekunst C A, Leavitt B R, Hayden M R (2003). Selective striatal neuronal loss in a YAC128 mouse model of Huntington disease. Hum Mol Genet, 12(13): 1555–1567

    PubMed  CAS  Article  Google Scholar 

  • Spampanato J, Gu X, Yang X W, Mody I (2008). Progressive synaptic pathology of motor cortical neurons in a BAC transgenic mouse model of Huntington’s disease. Neuroscience, 157(3): 606–620

    PubMed  CAS  Article  Google Scholar 

  • Steffan J S, Agrawal N, Pallos J, Rockabrand E, Trotman L C, Slepko N, Illes K, Lukacsovich T, Zhu Y Z, Cattaneo E, Pandolfi P P, Thompson L M, Marsh J L (2004). SUMO modification of Huntingtin and Huntington’s disease pathology. Science, 304(5667): 100–104

    PubMed  CAS  Article  Google Scholar 

  • Strand A D, Baquet Z C, Aragaki A K, Holmans P, Yang L, Cleren C, Beal M F, Jones L, Kooperberg C, Olson J M, Jones K R (2007). Expression profiling of Huntington’s disease models suggests that brain-derived neurotrophic factor depletion plays a major role in striatal degeneration. J Neurosci, 27(43): 11758–11768

    PubMed  CAS  Article  Google Scholar 

  • Subramaniam S, Sixt KM, Barrow R, Snyder S H (2009). Rhes, a striatal specific protein, mediates mutant-huntingtin cytotoxicity. Science, 324(5932): 1327–1330

    PubMed  CAS  Article  Google Scholar 

  • Subramaniam S, Snyder S H (2011). Huntington’s disease is a disorder of the corpus striatum: focus on Rhes (Ras homologue enriched in the striatum). Neuropharmacology, 60(7–8): 1187–1192

    PubMed  CAS  Article  Google Scholar 

  • Tabrizi S J, Langbehn D R, Leavitt B R, Roos R A, Durr A, Craufurd D, Kennard C, Hicks S L, Fox N C, Scahill R I, Borowsky B, Tobin A J, Rosas H D, Johnson H, Reilmann R, Landwehrmeyer B, Stout J C, TRACK-HD investigators (2009). Biological and clinical manifestations of Huntington’s disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data. Lancet Neurol, 8(9): 791–801

    PubMed  Article  Google Scholar 

  • Tabrizi S J, Reilmann R, Roos R A C, Durr A, Leavitt B, Owen G, Jones R, Johnson H, Craufurd D, Hicks S L, Kennard C, Landwehrmeyer B, Stout J C, Borowsky B, Scahill R I, Frost C, Langbehn D R, TRACK-HD investigators (2012). Potential endpoints for clinical trials in premanifest and early Huntington’s disease in the TRACKHD study: analysis of 24 month observational data. Lancet Neurol, 11(1): 42–53

    PubMed  Article  Google Scholar 

  • Tallaksen-Greene S J, Janiszewska A, Benton K, Ruprecht L, Albin R L (2010). Lack of efficacy of NMDA receptor-NR2B selective antagonists in the R6/2 model of Huntington disease. Exp Neurol, 225(2): 402–407

    PubMed  CAS  Article  Google Scholar 

  • Tebbenkamp A T N, Green C, Xu G, Denovan-Wright E M, Rising A C, Fromholt S E, Brown H H, Swing D, Mandel R J, Tessarollo L, Borchelt D R (2011). Transgenic mice expressing caspase-6-derived N-terminal fragments of mutant huntingtin develop neurologic abnormalities with predominant cytoplasmic inclusion pathology composed largely of a smaller proteolytic derivative. Hum Mol Genet, 20(14): 2770–2782

    PubMed  CAS  Article  Google Scholar 

  • The Huntington’s Disease Collaborative Research Group (1993). A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell, 72(6): 971–983

    Article  Google Scholar 

  • Thomas E A, Coppola G, Tang B, Kuhn A, Kim S, Geschwind D H, Brown T B, Luthi-Carter R, Ehrlich M E (2011). In vivo cellautonomous transcriptional abnormalities revealed in mice expressing mutant huntingtin in striatal but not cortical neurons. Hum Mol Genet, 20(6): 1049–1060

    PubMed  CAS  Article  Google Scholar 

  • Thompson L M, Aiken C T, Kaltenbach L S, Agrawal N, Illes K, Khoshnan A, Martinez-Vincente M, Arrasate M, O’Rourke J G, Khashwji H, Lukacsovich T, Zhu Y Z, Lau A L, Massey A, Hayden M R, Zeitlin S O, Finkbeiner S, Green K N, LaFerla F M, Bates G, Huang L, Patterson P H, Lo D C, Cuervo AM, Marsh J L, Steffan J S (2009). IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome. J Cell Biol, 187(7): 1083–1099

    PubMed  CAS  Article  Google Scholar 

  • Tsunemi T, Ashe T D, Morrison B E, Soriano K R, Au J, Roque R A V, Lazarowski E R, Damian V A, Masliah E, La Spada A R (2012). PGC-1 rescues Huntington’s disease proteotoxicity by preventing oxidative stress and promoting TFEB function. Sci Transl Med, 142(4): 142ra97

    Article  CAS  Google Scholar 

  • Valenza M, Leoni V, Karasinska J M, Petricca L, Fan J, Carroll J, Pouladi M A, Fossale E, Nguyen H P, Riess O, MacDonald M, Wellington C, DiDonato S, Hayden M, Cattaneo E (2010). Cholesterol defect is marked across multiple rodent models of Huntington’s disease and is manifest in astrocytes. J Neurosci, 30(32): 10844–10850

    PubMed  CAS  Article  Google Scholar 

  • van den Bogaard S J A, Dumas EM, Acharya T P, Johnson H, Langbehn D R, Scahill R I, Tabrizi S J, Van Buchem M A, Van der Grond J, Roos R A C, the TRACK-HD Investigator Group (2011a). Early atrophy of pallidum and accumbens nucleus in Huntington’s disease. J Neurol, 258(3): 412–420

    PubMed  Article  Google Scholar 

  • van den Bogaard S J A, Dumas E M, Ferrarini L, Milles J, van Buchem M A, van der Grond J, Roos R A C (2011b). Shape analysis of subcortical nuclei in Huntington’s disease, global versus local atrophy—results from the TRACK-HD study. J Neurol Sci, 307(1–2): 60–68

    PubMed  Article  Google Scholar 

  • Vonsattel J P, DiFiglia M (1998). Huntington disease. J Neuropathol Exp Neurol, 57(5): 369–384

    PubMed  CAS  Article  Google Scholar 

  • Vonsattel J P, Myers R H, Stevens T J, Ferrante R J, Bird E D, Richardson E P Jr (1985). Neuropathological classification of Huntington’s disease. J Neuropathol Exp Neurol, 44(6): 559–577

    PubMed  CAS  Article  Google Scholar 

  • Vonsattel J P G (2008). Huntington disease models and human neuropathology: similarities and differences. Acta Neuropathol, 115(1): 55–69

    PubMed  Article  Google Scholar 

  • Waldron-Roby E, Ratovitski T, Wang X, Jiang M, Watkin E, Arbez N, Graham R K, Hayden M R, Hou Z, Mori S, Swing D, Pletnikov M, Duan W, Tessarollo L, Ross C A (2012). Transgenic mouse model expressing the caspase 6 fragment of mutant huntingtin. J Neurosci, 32(1): 183–193

    PubMed  CAS  Article  Google Scholar 

  • Wang L, Lin F, Wang J, Wu J, Han R, Zhu L, Zhang G, DiFiglia M, Qin Z (2012). Truncated N-terminal huntingtin fragment with expandedpolyglutamine (htt552-100Q) suppresses brain-derived neurotrophic factor transcription in astrocytes. Acta Biochim Biophys Sin (Shanghai), 44(3): 249–258

    CAS  Article  Google Scholar 

  • Warby S C, Doty C N, Graham R K, Shively J, Singaraja R R, Hayden M R (2009). Phosphorylation of huntingtin reduces the accumulation of its nuclear fragments. Mol Cell Neurosci, 40(2): 121–127

    PubMed  CAS  Article  Google Scholar 

  • Wellington C L, Ellerby L M, Leavitt B R, Roy S, Nicholson D W, Hayden M R (2003). Huntingtin proteolysis in Huntington disease. Clin Neurosci Res, 3: 129–139

    CAS  Article  Google Scholar 

  • Weydt P, Pineda V V, Torrence A E, Libby R T, Satterfield T F, Lazarowski E R, Gilbert M L, Morton G J, Bammler T K, Strand A D, Cui L, Beyer R P, Easley C N, Smith A C, Krainc D, Luquet S, Sweet I R, Schwartz M W, La Spada A R (2006). Thermoregulatory and metabolic defects in Huntington’s disease transgenic mice implicate PGC-1alpha in Huntington’s disease neurodegeneration. Cell Metab, 4(5): 349–362

    PubMed  CAS  Article  Google Scholar 

  • White J K, Auerbach W, Duyao MP, Vonsattel J P, Gusella J F, Joyner A L, MacDonald M E (1997). Huntingtin is required for neurogenesis and is not impaired by the Huntington’s disease CAG expansion. Nat Genet, 17(4): 404–410

    PubMed  CAS  Article  Google Scholar 

  • Wilburn B, Rudnicki D D, Zhao J, Weitz T M, Cheng Y, Gu X, Greiner E, Park C S, Wang N, Sopher B L, La Spada A R, Osmand A, Margolis R L, Sun Y E, Yang X W (2011). An antisense CAG repeat transcript at JPH3 locus mediates expanded polyglutamine protein toxicity in Huntington’s disease-like 2 mice. Neuron, 70(3): 427–440

    PubMed  CAS  Article  Google Scholar 

  • Woodman B, Butler R, Landles C, Lupton M K, Tse J, Hockly E, Moffitt H, Sathasivam K, Bates G P (2007). The Hdh(Q150/Q150) knock-in mouse model of HD and the R6/2 exon 1 model develop comparable and widespread molecular phenotypes. Brain Res Bull, 72(2–3): 83–97

    PubMed  CAS  Article  Google Scholar 

  • Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V, Troy A, Cinti S, Lowell B, Scarpulla R C, Spiegelman B M (1999). Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell, 98(1): 115–124

    PubMed  CAS  Article  Google Scholar 

  • Xie Y, Hayden M R, Xu B (2010). BDNF overexpression in the forebrain rescues Huntington’s disease phenotypes in YAC128 mice. J Neurosci, 30(44): 14708–14718

    PubMed  CAS  Article  Google Scholar 

  • Yanai A, Huang K, Kang R, Singaraja R R, Arstikaitis P, Gan L, Orban P C, Mullard A, Cowan C M, Raymond L A, Drisdel R C, Green W N, Ravikumar B, Rubinsztein D C, El-Husseini A, Hayden M R (2006). Palmitoylation of huntingtin by HIP14 is essential for its trafficking and function. Nat Neurosci, 9(6): 824–831

    PubMed  CAS  Article  Google Scholar 

  • Yang, X. W., and Gray, M. (2011). Mouse Models for Validating Preclinical Candidates for Huntington’s Disease. Neurobiology of Huntington’s Disease: Applications to Drug Discovery.

  • Zeron M M, Hansson O, Chen N, Wellington C L, Leavitt B R, Brundin P, Hayden M R, Raymond L A (2002). Increased sensitivity to Nmethyl-D-aspartate receptor-mediated excitotoxicity in a mouse model of Huntington’s disease. Neuron, 33(6): 849–860

    PubMed  CAS  Article  Google Scholar 

  • Zheng, B., Liao, Z., Locascio, J. J., Lesniak, K. A., Roderick, S. S., Watt, M. L., Eklund, A. C., Zhang-James, Y., Kim, P. D., Hauser, M. A., et al. (2010). PGC-1, A Potential Therapeutic Target for Early Intervention in Parkinson’s Disease. Sci. Transl. Med. 2, 52ra73–52ra73.

    PubMed  Article  CAS  Google Scholar 

  • Zuccato C, Ciammola A, Rigamonti D, Leavitt B R, Goffredo D, Conti L, MacDonald M E, Friedlander R M, Silani V, Hayden M R, Timmusk T, Sipione S, Cattaneo E (2001). Loss of huntingtinmediated BDNF gene transcription in Huntington’s disease. Science, 293(5529): 493–498

    PubMed  CAS  Article  Google Scholar 

  • Zuccato C, Tartari M, Crotti A, Goffredo D, Valenza M, Conti L, Cataudella T, Leavitt B R, Hayden M R, Timmusk T, Rigamonti D, Cattaneo E (2003). Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes. Nat Genet, 35(1): 76–83

    PubMed  CAS  Article  Google Scholar 

  • Zuccato C, Valenza M, Cattaneo E (2010). Molecular mechanisms and potential therapeutical targets in Huntington’s disease. Physiol Rev, 90(3): 905–981

    PubMed  CAS  Article  Google Scholar 

  • Zwilling D, Huang S Y, Sathyasaikumar K V, Notarangelo FM, Guidetti P, Wu H Q, Lee J, Truong J, Andrews-Zwilling Y, Hsieh EW, Louie J Y, Wu T, Scearce-Levie K, Patrick C, Adame A, Giorgini F, Moussaoui S, Laue G, Rassoulpour A, Flik G, Huang Y, Muchowski J M, Masliah E, Schwarcz R, Muchowski P J (2011). Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration. Cell, 145(6): 863–874

    PubMed  CAS  Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Center for Neurobehavioral Genetics, Semel Institute for Neuroscience & Human Behavior, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA, 90095, USA

    Jeffrey P. Cantle, Xiao-Hong Lu, Xiaofeng Gu & X. William Yang

  2. Department of Psychiatry & Biobehavioral Sciences, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA, 90095, USA

    Xiao-Hong Lu, Xiaofeng Gu & X. William Yang

  3. Brain Research Institute, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA, 90095, USA

    Xiao-Hong Lu, Xiaofeng Gu & X. William Yang

  4. Interdepartmental Program for Neuroscience, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA, 90095, USA

    Jeffrey P. Cantle

Authors
  1. Jeffrey P. Cantle
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiao-Hong Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiaofeng Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. X. William Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to X. William Yang.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Cantle, J.P., Lu, XH., Gu, X. et al. Cellular and molecular mechanisms implicated in pathogenesis of selective neurodegeneration in Huntington’s disease. Front. Biol. 7, 459–476 (2012). https://doi.org/10.1007/s11515-012-1246-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11515-012-1246-7

Keywords

  • Huntington’s disease
  • neurodegeneration
  • selective neuronal vulnerability
  • cortex
  • striatum
  • conditional mouse model
  • cell-autonomous toxicity
  • pathological cell-cell interaction
  • pathogenesis
  • therapeutic targets