Abstract
Background
Cortical motor neurons, also known as upper motor neurons, are large projection neurons whose axons convey signals to lower motor neurons to control the muscle movements. Degeneration of cortical motor neuron axons is implicated in several debilitating disorders including hereditary spastic paraplegia (HSP). Since the discovery of the first HSP gene, SPAST that encodes spastin, over 70 distinct genetic loci associated with HSP have been identified. How the mutations of these functionally diverse genes result in axonal degeneration and why certain axons are affected in HSP remain largely unknown. The development of induced pluripotent stem cell (iPSC) technology has provided researchers an excellent resource to generate patient-specific human neurons to model human neuropathological processes including axonal defects.
Methods
In this article, we will first review the pathology and pathways affected in the common forms of HSP subtypes by searching the PubMed database. We will then summarize the findings and insights gained from studies using iPSC-based models, and discuss challenges and future directions.
Results
HSPs, a heterogeneous group of genetic neurodegenerative disorders, exhibit similar pathological changes that result from retrograde axonal degeneration of cortical motor neurons. Recently, iPSCs have been generated from several common forms of HSP including SPG4, SPG3A, and SPG11 patients. Neurons derived from HSP iPSCs exhibit impaired neurite outgrowth, increased axonal swellings, and reduced axonal transport, recapitulating disease-specific axonal defects.
Conclusions
These patient-derived neurons offer a unique tool to study the pathogenic mechanisms and explore the treatments for rescuing axonal defects in HSP, as well as other diseases involving axonopathy.
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References
Ben-David U, Kopper O, Benvenisty N (2012). Expanding the boundaries of embryonic stem cells. Cell Stem Cell, 10(6): 666–677
Bilican B, Serio A, Barmada S J, Nishimura A L, Sullivan G J, Carrasco M, Phatnani H P, Puddifoot C A, Story D, Fletcher J, Park I H, Friedman B A, Daley G Q, Wyllie D J, Hardingham G E, Wilmut I, Finkbeiner S, Maniatis T, Shaw C E, Chandran S (2012). Mutant induced pluripotent stem cell lines recapitulate aspects of TDP-43 proteinopathies and reveal cell-specific vulnerability. Proc Natl Acad Sci USA, 109(15): 5803–5808
Blackstone C (2012). Cellular pathways of hereditary spastic paraplegia. Annu Rev Neurosci, 35(1): 25–47
Blackstone C, O’Kane C J, Reid E (2011). Hereditary spastic paraplegias: membrane traffic and the motor pathway. Nat Rev Neurosci, 12(1): 31–42
Boulting G L, Kiskinis E, Croft G F, Amoroso M W, Oakley D H, Wainger B J, Williams D J, Kahler D J, Yamaki M, Davidow L, Rodolfa C T, Dimos J T, Mikkilineni S, MacDermott A B, Woolf C J, Henderson C E, Wichterle H, Eggan K (2011). A functionally characterized test set of human induced pluripotent stem cells. Nat Biotechnol, 29(3): 279–286
Chen H, Chan D C (2009). Mitochondrial dynamics—fusion, fission, movement, and mitophagy—in neurodegenerative diseases. Hum Mol Genet, 18(R2): R169–R176
Claudiani P, Riano E, Errico A, Andolfi G, Rugarli E I (2005). Spastin subcellular localization is regulated through usage of different translation start sites and active export from the nucleus. Exp Cell Res, 309(2): 358–369
Crosby A H, Proukakis C (2002). Is the transportation highway the right road for hereditary spastic paraplegia? Am J Hum Genet, 71(5): 1009–1016
De Vos K J, Grierson A J, Ackerley S, Miller C C (2008). Role of axonal transport in neurodegenerative diseases. Annu Rev Neurosci, 31(1): 151–173
Deluca G C, Ebers G C, Esiri M M (2004). The extent of axonal loss in the long tracts in hereditary spastic paraplegia. Neuropathol Appl Neurobiol, 30(6): 576–584
Denton K R, Lei L, Grenier J, Rodionov V, Blackstone C, Li X J (2014). Loss of spastin function results in disease-specific axonal defects in human pluripotent stem cell-based models of hereditary spastic paraplegia. Stem Cells, 32(2): 414–423
Dimos J T, Rodolfa K T, Niakan K K, Weisenthal L M, Mitsumoto H, Chung W, Croft G F, Saphier G, Leibel R, Goland R, Wichterle H, Henderson C E, Eggan K (2008). Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science, 321(5893): 1218–1221
Ebert A D, Yu J, Rose F F Jr, Mattis V B, Lorson C L, Thomson J A, Svendsen C N (2009). Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature, 457(7227): 277–280
Errico A, Ballabio A, Rugarli E I (2002). Spastin, the protein mutated in autosomal dominant hereditary spastic paraplegia, is involved in microtubule dynamics. Hum Mol Genet, 11(2): 153–163
Evans M J, Kaufman M H (1981). Establishment in culture of pluripotential cells from mouse embryos. Nature, 292(5819): 154–156
Falk J, Rohde M, Bekhite MM, Neugebauer S, Hemmerich P, Kiehntopf M, Deufel T, Hübner C A, Beetz C (2014). Functional mutation analysis provides evidence for a role of REEP1 in lipid droplet biology. Hum Mutat, 35(4): 497–504
Fan Y, Wali G, Sutharsan R, Bellette B, Crane D I, Sue C M, Mackay-Sim A (2014). Low dose tubulin-binding drugs rescue peroxisome trafficking deficit in patient-derived stem cells in Hereditary Spastic Paraplegia. Biol Open, 3(6): 494–502
Fassier C, Hutt J A, Scholpp S, Lumsden A, Giros B, Nothias F, Schneider-Maunoury S, Houart C, Hazan J (2010). Zebrafish atlastin controls motility and spinal motor axon architecture via inhibition of the BMP pathway. Nat Neurosci, 13(11): 1380–1387
Fink J K (1993). Hereditary Spastic Paraplegia Overview. In: Pagon R A, Adam M P, Ardinger H H, Wallacc S E, Amemiya A, Beau L J H, Bird T D, Fong C T, Mefford H C, Smith R J H, Stephens K, Eds. Gene Reviews [Internet]. Seatlle (WA): University of Washington, Seattle 1993–2016
Fink J K (2003). Advances in the hereditary spastic paraplegias. Exp Neurol, 184(Suppl 1): S106–S110
Fink J K (2006). Hereditary spastic paraplegia. Curr Neurol Neurosci Rep, 6(1): 65–76
Fonknechten N, Mavel D, Byrne P, Davoine C S, Cruaud C, Bönsch D, Samson D, Coutinho P, Hutchinson M, McMonagle P, Burgunder J M, Tartaglione A, Heinzlef O, Feki I, Deufel T, Parfrey N, Brice A, Fontaine B, Prud’homme J F, Weissenbach J, Dürr A, Hazan J (2000). Spectrum of SPG4 mutations in autosomal dominant spastic paraplegia. Hum Mol Genet, 9(4): 637–644
Grove E A, Fukuchi-Shimogori T (2003). Generating the cerebral cortical area map. Annu Rev Neurosci, 26(1): 355–380
Guha P, Morgan J W, Mostoslavsky G, Rodrigues N P, Boyd A S (2013). Lack of immune response to differentiated cells derived from syngeneic induced pluripotent stem cells. Cell Stem Cell, 12(4): 407–412
Guidubaldi A, Piano C, Santorelli F M, Silvestri G, Petracca M, Tessa A, Bentivoglio A R (2011). Novel mutations in SPG11 cause hereditary spastic paraplegia associated with early-onset levodopa-responsive Parkinsonism. Mov Disord, 26(3): 553–556
Hallett P J, Deleidi M, Astradsson A, Smith G A, Cooper O, Osborn T M, Sundberg M, Moore M A, Perez-Torres E, Brownell A L, Schumacher J M, Spealman R D, Isacson O (2015). Successful function of autologous iPSC-derived dopamine neurons following transplantation in a non-human primate model of Parkinson’s disease. Cell Stem Cell, 16(3): 269–274
Halliwell B (2014). Cell culture, oxidative stress, and antioxidants: avoiding pitfalls. Biomed J, 37(3): 99–105
Hanein S, Martin E, Boukhris A, Byrne P, Goizet C, Hamri A, Benomar A, Lossos A, Denora P, Fernandez J, Elleuch N, Forlani S, Durr A, Feki I, Hutchinson M, Santorelli F M, Mhiri C, Brice A, Stevanin G (2008). Identification of the SPG15 gene, encoding spastizin, as a frequent cause of complicated autosomal-recessive spastic paraple-gia, including Kjellin syndrome. Am J Hum Genet, 82(4): 992–1002
Harding A E (1983). Classification of the hereditary ataxias and paraplegias. Lancet, 1(8334): 1151–1155
Harding A E (1993). Hereditary spastic paraplegias. Semin Neurol, 13(4): 333–336
Havlicek S, Kohl Z, Mishra H K, Prots I, Eberhardt E, Denguir N, Wend H, Plötz S, Boyer L, Marchetto M C, Aigner S, Sticht H, Groemer T W, Hehr U, Lampert A, Schlötzer-Schrehardt U, Winkler J, Gage F H, Winner B (2014). Gene dosage-dependent rescue of HSP neurite defects in SPG4 patients’ neurons. Hum Mol Genet, 23(10): 2527–2541
Hazan J, Fonknechten N, Mavel D, Paternotte C, Samson D, Artiguenave F, Davoine C S, Cruaud C, Dürr A, Wincker P, Brottier P, Cattolico L, Barbe V, Burgunder J M, Prud’homme J F, Brice A, Fontaine B, Heilig B, Weissenbach J (1999). Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia. Nat Genet, 23(3): 296–303
Hedera P, Eldevik O P, Maly P, Rainier S, Fink J K (2005). Spinal cord magnetic resonance imaging in autosomal dominant hereditary spastic paraplegia. Neuroradiology, 47(10): 730–734
Hirst J, Borner G H, Edgar J, Hein MY, Mann M, Buchholz F, Antrobus R, Robinson M S (2013). Interaction between AP-5 and the hereditary spastic paraplegia proteins SPG11 and SPG15. Mol Biol Cell, 24(16): 2558–2569
Hockemeyer D, Wang H, Kiani S, Lai C S, Gao Q, Cassady J P, Cost G J, Zhang L, Santiago Y, Miller J C, Zeitler B, Cherone J M, Meng X, Hinkley S J, Rebar E J, Gregory P D, Urnov F D, Jaenisch R (2011). Genetic engineering of human pluripotent cells using TALE nucleases. Nat Biotechnol, 29(8): 731–734
Hollenbeck P J (2005). Mitochondria and neurotransmission: evacuating the synapse. Neuron, 47(3): 331–333
Hu J, Shibata Y, Zhu P P, Voss C, Rismanchi N, Prinz W A, Rapoport T A, Blackstone C (2009). A class of dynamin-like GTPases involved in the generation of the tubular ER network. Cell, 138(3): 549–561
Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna J A, Charpentier E (2012). A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science, 337(6096): 816–821
Kanekura K, Suzuki H, Aiso S, Matsuoka M (2009). ER stress and unfolded protein response in amyotrophic lateral sclerosis. Mol Neurobiol, 39(2): 81–89
Kasher P R, De Vos K J, Wharton S B, Manser C, Bennett E J, Bingley M, Wood J D, Milner R, McDermott C J, Miller C C, Shaw P J, Grierson A J (2009). Direct evidence for axonal transport defects in a novel mouse model of mutant spastin-induced hereditary spastic paraplegia (HSP) and human HSP patients. J Neurochem, 110(1): 34–44
Kiskinis E, Eggan K (2010). Progress toward the clinical application of patient-specific pluripotent stem cells. J Clin Invest, 120(1): 51–59
Kiskinis E, Sandoe J, Williams L A, Boulting G L, Moccia R, Wainger B J, Han S, Peng T, Thams S, Mikkilineni S, Mellin C, Merkle F T, Davis-Dusenbery B N, Ziller M, Oakley D, Ichida J, Di Costanzo S, Atwater N, Maeder M L, Goodwin M J, Nemesh J, Handsaker R E, Paull D, Noggle S, McCarroll S A, Joung J K, Woolf C J, Brown R H, Eggan K (2014). Pathways disrupted in human ALS motor neurons identified through genetic correction of mutant SOD1. Cell Stem Cell, 14(6): 781–795
Klemm R W, Norton J P, Cole R A, Li C S, Park S H, Crane M M, Li L, Jin D, Boye-Doe A, Liu T Y, Shibata Y, Lu H, Rapoport T A, Farese R V Jr, Blackstone C, Guo Y, Mak H Y (2013). A conserved role for atlastin GTPases in regulating lipid droplet size. Cell Reports, 3(5): 1465–1475
Knott A B, Perkins G, Schwarzenbacher R, Bossy-Wetzel E (2008). Mitochondrial fragmentation in neurodegeneration. Nat Rev Neurosci, 9(7): 505–518
Kola I, Landis J (2004). Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov, 3(8): 711–715
Kondo T, Asai M, Tsukita K, Kutoku Y, Ohsawa Y, Sunada Y, Imamura K, Egawa N, Yahata N, Okita K, Takahashi K, Asaka I, Aoi T, Watanabe A, Watanabe K, Kadoya C, Nakano R, Watanabe D, Maruyama K, Hori O, Hibino S, Choshi T, Nakahata T, Hioki H, Kaneko T, Naitoh M, Yoshikawa K, Yamawaki S, Suzuki S, Hata R, Ueno S, Seki T, Kobayashi K, Toda T, Murakami K, Irie K, Klein W L, Mori H, Asada T, Takahashi R, Iwata N, Yamanaka S, Inoue H (2013). Modeling Alzheimer’s disease with iPSCs reveals stress phenotypes associated with intracellular Aβ and differential drug responsiveness. Cell Stem Cell, 12(4): 487–496
Lee H, Shamy G A, Elkabetz Y, Schofield C M, Harrsion N L, Panagiotakos G, Socci N D, Tabar V, Studer L (2007). Directed differentiation and transplantation of human embryonic stem cellderived motoneurons. Stem Cells, 25(8): 1931–1939
Lefebvre S, Bürglen L, Reboullet S, Clermont O, Burlet P, Viollet L, Benichou B, Cruaud C, Millasseau P, Zeviani M, Le Paslier D, Frézal J, Cohen D, Weissenbach J, Munnich A, Melki J (1995). Identification and characterization of a spinal muscular atrophydetermining gene. Cell, 80(1): 155–165
Li X J, Du Z W, Zarnowska E D, Pankratz M, Hansen L O, Pearce R A, Zhang S C (2005). Specification of motoneurons from human embryonic stem cells. Nat Biotechnol, 23(2): 215–221
Lindsey J C, Lusher M E, McDermott C J, White K D, Reid E, Rubinsztein D C, Bashir R, Hazan J, Shaw P J, Bushby K M (2000). Mutation analysis of the spastin gene (SPG4) in patients with hereditary spastic paraparesis. J Med Genet, 37(10): 759–765
Ling S C, Polymenidou M, Cleveland D W (2013). Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron, 79(3): 416–438
Liu G H, Qu J, Suzuki K, Nivet E, Li M, Montserrat N, Yi F, Xu X, Ruiz S, Zhang W, Wagner U, Kim A, Ren B, Li Y, Goebl A, Kim J, Soligalla R D, Dubova I, Thompson J, Yates J 3rd, Esteban C R, Sancho-Martinez I, Izpisua Belmonte J C (2012). Progressive degeneration of human neural stem cells caused by pathogenic LRRK2. Nature, 491(7425): 603–607
Lumb J H, Connell J W, Allison R, Reid E (2012). The AAA ATPase spastin links microtubule severing to membrane modelling. Biochim Biophys Acta, 1823(1): 192–197
Lunn M R, Wang C H (2008). Spinal muscular atrophy. Lancet, 371(9630): 2120–2133
Ly CV, Verstreken P (2006) Mitochondria at the synapse. The Neuroscientist: a review journal bringing neurobiology, neurology and psychiatry 12: 291–299.
Ma L, Hu B, Liu Y, Vermilyea S C, Liu H, Gao L, Sun Y, Zhang X, Zhang S C (2012). Human embryonic stem cell-derived GABA neurons correct locomotion deficits in quinolinic acid-lesioned mice. Cell Stem Cell, 10(4): 455–464
Magrané J, Cortez C, Gan W B, Manfredi G (2014). Abnormal mitochondrial transport and morphology are common pathological denominators in SOD1 and TDP43 ALS mouse models. Hum Mol Genet, 23(6): 1413–1424
Mali P, Yang L, Esvelt K M, Aach J, Guell M, DiCarlo J E, Norville J E, Church G M (2013). RNA-guided human genome engineering via Cas9. Science, 339(6121): 823–826
Mancuso G, Rugarli E I (2008). A cryptic promoter in the first exon of the SPG4 gene directs the synthesis of the 60-kDa spastin isoform. BMC Biol, 6(1): 31
Manfredi G, Xu Z (2005). Mitochondrial dysfunction and its role in motor neuron degeneration in ALS. Mitochondrion, 5(2): 77–87
Martin G R (1981). Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci USA, 78(12): 7634–7638
Miller J C, Tan S, Qiao G, Barlow K A, Wang J, Xia D F, Meng X, Paschon D E, Leung E, Hinkley S J, Dulay G P, Hua K L, Ankoudinova I, Cost G J, Urnov F D, Zhang H S, Holmes M C, Zhang L, Gregory P D, Rebar E J (2011). A TALE nuclease architecture for efficient genome editing. Nat Biotechnol, 29(2): 143–148
Miller J D, Ganat Y M, Kishinevsky S, Bowman R L, Liu B, Tu E Y, Mandal P K, Vera E, Shim J W, Kriks S, Taldone T, Fusaki N, Tomishima M J, Krainc D, Milner T A, Rossi D J, Studer L (2013). Human iPSC-based modeling of late-onset disease via progerininduced aging. Cell Stem Cell, 13(6): 691–705
Mishra HK, Prots I, Havlicek S, Kohl Z, Perez-Branguli F, Boerstler T, Anneser L, Minakaki G, Wend H, Hampl M, Leone M, Bruckner M, Klucken J, Reis A, Boyer L, Schuierer G, Behrens J, Lampert A, Engel FB, Gage FH, Winkler J, Winner B (2016) GSK3ss-dependent dysregulation of neurodevelopment in SPG11-patient iPSC model. Ann Neurol.
Montague K, Malik B, Gray A L, La Spada A R, Hanna M G, Szabadkai G, Greensmith L (2014). Endoplasmic reticulum stress in spinal and bulbar muscular atrophy: a potential target for therapy. Brain, 137(Pt 7): 1894–1906
Montenegro G, Rebelo A P, Connell J, Allison R, Babalini C, D’Aloia M, Montieri P, Schüle R, Ishiura H, Price J, Strickland A, Gonzalez M A, Baumbach-Reardon L, Deconinck T, Huang J, Bernardi G, Vance J M, Rogers M T, Tsuji S, De Jonghe P, Pericak-Vance M A, Schöls L, Orlacchio A, Reid E, Züchner S (2012). Mutations in the ER-shaping protein reticulon 2 cause the axon-degenerative disorder hereditary spastic paraplegia type 12. J Clin Invest, 122(2): 538–544
Moss T J, Daga A, McNew J A (2011). Fusing a lasting relationship between ER tubules. Trends Cell Biol, 21(7): 416–423
Murmu R P, Martin E, Rastetter A, Esteves T, Muriel MP, El Hachimi K H, Denora P S, Dauphin A, Fernandez J C, Duyckaerts C, Brice A, Darios F, Stevanin G (2011). Cellular distribution and subcellular localization of spatacsin and spastizin, two proteins involved in hereditary spastic paraplegia. Mol Cell Neurosci, 47(3): 191–202
Murry C E, Keller G (2008). Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development. Cell, 132(4): 661–680
Nadar V C, Ketschek A, Myers K A, Gallo G, Baas PW (2008). Kinesin-5 is essential for growth-cone turning. Curr Biol, 18(24): 1972–1977
Namekawa M, Ribai P, Nelson I, Forlani S, Fellmann F, Goizet C, Depienne C, Stevanin G, Ruberg M, Dürr A, Brice A (2006). SPG3A is the most frequent cause of hereditary spastic paraplegia with onset before age 10 years. Neurology, 66(1): 112–114
Nguyen H N, Byers B, Cord B, Shcheglovitov A, Byrne J, Gujar P, Kee K, Schüle B, Dolmetsch R E, Langston W, Palmer T D, Pera R R (2011). LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress. Cell Stem Cell, 8(3): 267–280
Niu J, Zhang B, Chen H (2014). Applications of TALENs and CRISPR/Cas9 in human cells and their potentials for gene therapy. Mol Biotechnol, 56(8): 681–688
Novarino G, Fenstermaker A G, Zaki M S, Hofree M, Silhavy J L, Heiberg A D, Abdellateef M, Rosti B, Scott E, Mansour L, Masri A, Kayserili H, Al-Aama J Y, Abdel-Salam G M, Karminejad A, Kara M, Kara B, Bozorgmehri B, Ben-Omran T, Mojahedi F, Mahmoud I G, Bouslam N, Bouhouche A, Benomar A, Hanein S, Raymond L, Forlani S, Mascaro M, Selim L, Shehata N, Al-Allawi N, Bindu P S, Azam M, Gunel M, Caglayan A, Bilguvar K, Tolun A, Issa M Y, Schroth J, Spencer E G, Rosti R O, Akizu N, Vaux K K, Johansen A, Koh A A, Megahed H, Durr A, Brice A, Stevanin G, Gabriel S B, Ideker T, Gleeson J G (2014). Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science, 343(6170): 506–511
O’Leary D D, Nakagawa Y (2002). Patterning centers, regulatory genes and extrinsic mechanisms controlling arealization of the neocortex. Curr Opin Neurobiol, 12(1): 14–25
Okita K, Ichisaka T, Yamanaka S (2007). Generation of germlinecompetent induced pluripotent stem cells. Nature, 448(7151): 313–317
Pantakani D V, Swapna L S, Srinivasan N, Mannan A U (2008). Spastin oligomerizes into a hexamer and the mutant spastin (E442Q) redistribute the wild-type spastin into filamentous microtubule. J Neurochem, 106(2): 613–624
Park I H, Arora N, Huo H, Maherali N, Ahfeldt T, Shimamura A, Lensch M W, Cowan C, Hochedlinger K, Daley G Q (2008). Diseasespecific induced pluripotent stem cells. Cell, 134(5): 877–886
Park S, Lee K S, Lee Y J, Shin H A, Cho H Y, Wang K C, Kim Y S, Lee H T, Chung K S, Kim E Y, Lim J (2004). Generation of dopaminergic neurons in vitro from human embryonic stem cells treated with neurotrophic factors. Neurosci Lett, 359(1-2): 99–103
Park S H, Zhu P P, Parker R L, Blackstone C (2010). Hereditary spastic paraplegia proteins REEP1, spastin, and atlastin-1 coordinate microtubule interactions with the tubular ER network. J Clin Invest, 120(4): 1097–1110
Pérez-Brangulí F, Mishra H K, Prots I, Havlicek S, Kohl Z, Saul D, Rummel C, Dorca-Arevalo J, Regensburger M, Graef D, Sock E, Blasi J, Groemer T W, Schlötzer-Schrehardt U, Winkler J, Winner B (2014). Dysfunction of spatacsin leads to axonal pathology in SPG11-linked hereditary spastic paraplegia. Hum Mol Genet, 23(18): 4859–4874
Perrier A L, Tabar V, Barberi T, Rubio M E, Bruses J, Topf N, Harrison N L, Studer L (2004). Derivation of midbrain dopamine neurons from human embryonic stem cells. Proc Natl Acad Sci USA, 101(34): 12543–12548
Piaceri I, Rinnoci V, Bagnoli S, Failli Y, Sorbi S (2012). Mitochondria and Alzheimer’s disease. J Neurol Sci, 322(1–2): 31–34
Polleux F, Dehay C, Goffinet A, Kennedy H (2001). Pre-and postmitotic events contribute to the progressive acquisition of areaspecific connectional fate in the neocortex. Cereb Cortex, 11(11): 1027–1039
Reid E (2003). Science in motion: common molecular pathological themes emerge in the hereditary spastic paraplegias. J Med Genet, 40(2): 81–86
Renvoisé B, Blackstone C (2010). Emerging themes of ER organization in the development and maintenance of axons. Curr Opin Neurobiol, 20(5): 531–537
Reubinoff B E, Itsykson P, Turetsky T, Pera M F, Reinhartz E, Itzik A, Ben-Hur T (2001). Neural progenitors from human embryonic stem cells. Nat Biotechnol, 19(12): 1134–1140
Roy N S, Cleren C, Singh S K, Yang L, Beal M F, Goldman S A (2006). Functional engraftment of human ES cell-derived dopaminergic neurons enriched by coculture with telomerase-immortalized midbrain astrocytes. Nat Med, 12(11): 1259–1268
Salinas S, Proukakis C, Crosby A, Warner T T (2008). Hereditary spastic paraplegia: clinical features and pathogenetic mechanisms. Lancet Neurol, 7(12): 1127–1138
Schicks J, Synofzik M, Pétursson H, Huttenlocher J, Reimold M, Schöls L, Bauer P (2011). Atypical juvenile parkinsonism in a consanguineous SPG15 family. Mov Disord, 26(3): 564–566
Singh Roy N, Nakano T, Xuing L, Kang J, Nedergaard M, Goldman S A (2005). Enhancer-specified GFP-based FACS purification of human spinal motor neurons from embryonic stem cells. Exp Neurol, 196(2): 224–234
Soderblom C, Blackstone C (2006). Traffic accidents: molecular genetic insights into the pathogenesis of the hereditary spastic paraplegias. Pharmacol Ther, 109(1–2): 42–56
Solowska J M, Morfini G, Falnikar A, Himes B T, Brady S T, Huang D, Baas P W (2008). Quantitative and functional analyses of spastin in the nervous system: implications for hereditary spastic paraplegia. J Neurosci, 28(9): 2147–2157
Stevanin G, Santorelli F M, Azzedine H, Coutinho P, Chomilier J, Denora P S, Martin E, Ouvrard-Hernandez A M, Tessa A, Bouslam N, Lossos A, Charles P, Loureiro J L, Elleuch N, Confavreux C, Cruz V T, Ruberg M, Leguern E, Grid D, Tazir M, Fontaine B, Filla A, Bertini E, Durr A, Brice A (2007). Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum. Nat Genet, 39(3): 366–372
Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 131(5): 861–872
Takahashi K, Yamanaka S (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126(4): 663–676
Tarrade A, Fassier C, Courageot S, Charvin D, Vitte J, Peris L, Thorel A, Mouisel E, Fonknechten N, Roblot N, Seilhean D, Diérich A, Hauw J J, Melki J (2006). A mutation of spastin is responsible for swellings and impairment of transport in a region of axon characterized by changes in microtubule composition. Hum Mol Genet, 15(24): 3544–3558
Thomson J A, Itskovitz-Eldor J, Shapiro S S, Waknitz M A, Swiergiel J J, Marshall V S, Jones J M (1998). Embryonic stem cell lines derived from human blastocysts. Science, 282(5391): 1145–1147
Valente E M, Abou-Sleiman P M, Caputo V, Muqit M M, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio A R, Healy D G, Albanese A, Nussbaum R, Gonzlez-Maldonado R, Deller T, Salvi S, Cortelli P, Gilks W P, Latchman D S, Harvey R J, Dallapiccola B, Auburger G, Wood N W (2004). Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science, 304(5674): 1158–1160
Vidal R, Caballero B, Couve A, Hetz C (2011). Converging pathways in the occurrence of endoplasmic reticulum (ER) stress in Huntington’s disease. Curr Mol Med, 11(1): 1–12
Walther T C, Farese R V Jr (2012). Lipid droplets and cellular lipid metabolism. Annu Rev Biochem, 81(1): 687–714
Wang D, Lagerstrom R, Sun C, Bishof L, Valotton P, Götte M (2010). HCA-vision: Automated neurite outgrowth analysis. J Biomol Screen, 15(9): 1165–1170
Wang H, Yang H, Shivalila C S, Dawlaty M M, Cheng A W, Zhang F, Jaenisch R (2013a). One-step generation of mice carrying mutations in multiple genes by CRISPR/Cas-mediated genome engineering. Cell, 153(4): 910–918
Wang Z B, Zhang X, Li X J (2013b). Recapitulation of spinal motor neuron-specific disease phenotypes in a human cell model of spinal muscular atrophy. Cell Res, 23(3): 378–393
Wilfling F, Wang H, Haas J T, Krahmer N, Gould T J, Uchida A, Cheng J X, Graham M, Christiano R, Fröhlich F, Liu X, Buhman K K, Coleman R A, Bewersdorf J, Farese R V Jr, Walther T C (2013). Triacylglycerol synthesis enzymes mediate lipid droplet growth by relocalizing from the ER to lipid droplets. Dev Cell, 24(4): 384–399
Xu C C, Denton K R, Wang Z B, Zhang X, Li X J (2016). Abnormal mitochondrial transport and morphology as early pathological changes in human models of spinal muscular atrophy. Dis Model Mech, 9(1): 39–49
Yagi T, Ito D, Okada Y, Akamatsu W, Nihei Y, Yoshizaki T, Yamanaka S, Okano H, Suzuki N (2011). Modeling familial Alzheimer’s disease with induced pluripotent stem cells. Hum Mol Genet, 20(23): 4530–4539
Yan Y, Yang D, Zarnowska E D, Du Z, Werbel B, Valliere C, Pearce R A, Thomson J A, Zhang S C (2005). Directed differentiation of dopaminergic neuronal subtypes from human embryonic stem cells. Stem Cells, 23(6): 781–790
Yang Y M, Gupta S K, Kim K J, Powers B E, Cerqueira A, Wainger B J, Ngo H D, Rosowski K A, Schein P A, Ackeifi C A, Arvanites A C, Davidow L S, Woolf C J, Rubin L L (2013). A small molecule screen in stem-cell-derived motor neurons identifies a kinase inhibitor as a candidate therapeutic for ALS. Cell Stem Cell, 12(6): 713–726
Yu J, Vodyanik M A, Smuga-Otto K, Antosiewicz-Bourget J, Frane J L, Tian S, Nie J, Jonsdottir G A, Ruotti V, Stewart R, Slukvin I I, Thomson J A (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science, 318(5858): 1917–1920
Zeng H, Guo M, Martins-Taylor K, Wang X, Zhang Z, Park J W, Zhan S, Kronenberg MS, Lichtler A, Liu H X, Chen F P, Yue L, Li X J, Xu R H (2010). Specification of region-specific neurons including forebrain glutamatergic neurons from human induced pluripotent stem cells. PLoS ONE, 5(7): e11853
Zhang N, An M C, Montoro D, Ellerby L M (2010). Characterization of Human Huntington’s Disease Cell Model from Induced Pluripotent Stem Cells. PLoS Curr, 2: RRN1193
Zhang S C (2006). Neural subtype specification from embryonic stem cells. Brain Pathol, 16(2): 132–142
Zhang S C, Wernig M, Duncan I D, Brüstle O, Thomson J A (2001). In vitro differentiation of transplantable neural precursors from human embryonic stem cells. Nat Biotechnol, 19(12): 1129–1133
Zhao X, Alvarado D, Rainier S, Lemons R, Hedera P, Weber C H, Tukel T, Apak M, Heiman-Patterson T, Ming L, Bui M, Fink J K (2001). Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia. Nat Genet, 29(3): 326–331
Zhu P P, Denton K R, Pierson T M, Li X J, Blackstone C (2014). Pharmacologic rescue of axon growth defects in a human iPSC model of hereditary spastic paraplegia SPG3A. Hum Mol Genet, 23(21): 5638–5648
Zhu P P, Patterson A, Lavoie B, Stadler J, Shoeb M, Patel R, Blackstone C (2003). Cellular localization, oligomerization, and membrane association of the hereditary spastic paraplegia 3A (SPG3A) protein atlastin. J Biol Chem, 278(49): 49063–49071
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Denton, K.R., Xu, C., Shah, H. et al. Modeling axonal defects in hereditary spastic paraplegia with human pluripotent stem cells. Front. Biol. 11, 339–354 (2016). https://doi.org/10.1007/s11515-016-1416-0
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DOI: https://doi.org/10.1007/s11515-016-1416-0