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Rotenone-Dependent Changes of Anterograde Motor Protein Expression and Mitochondrial Mobility in Brain Areas Related to Neurodegenerative Diseases

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Abstract

The presence of protein aggregates is common in neurodegenerative disorders; however, the real cause and effect of these aggregates during neurodegeneration is still a matter of investigation. We hypothesize that impairment of intracellular traffic may appear in the absence of protein inclusions and might trigger protein aggregation. In the present study, we aimed to evaluate mitochondria mobility as well as protein and messenger RNA expression of KIF1B and KIF5 that are molecular motors for neuronal anterograde traffic, in hippocampus, substantia nigra, and locus coeruleus of 10-month-old Lewis rats and cultured cells, from these same areas, following exposure to low doses of rotenone that do not lead to protein inclusions. The present study showed alteration in KIF1B and KIF5 expression, as well as in mitochondria mobility prior to protein aggregation involved in neurodegenerative disorders. These findings suggest that change in intracellular trafficking might be critical and one of the primary events for impairment of cell physiology during neurodegeneration associated with protein inclusions.

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References

  • Alam M, Schmidt WJ (2004) Mitochondrial complex I inhibition depletes plasma testosterone in the rotenone model of Parkinson’s disease. Physiol Behav 83(3):395–400. doi:10.1016/j.physbeh.2004.08.010

    Article  PubMed  CAS  Google Scholar 

  • Amadoro G, Corsetti V, Ciotti MT, Florenzano F, Capsoni S, Amato G, Calissano P (2011) Endogenous abeta causes cell death via early tau hyper phosphorylation. Neurobiol Aging 32(6):969–990. doi:10.1016/j.neurobiolaging.2009.06.005

    Article  PubMed  CAS  Google Scholar 

  • Amiri M, Hollenbeck PJ (2008) Mitochondrial biogenesis in the axons of vertebrate peripheral neurons. Dev Neurobiol 68(11):1348–1361. doi:10.1002/dneu.20668

    Article  PubMed  CAS  Google Scholar 

  • Arendt T, Bruckner MK, Bigl V, Marcova L (1995) Dendritic reorganisation in the basal forebrain under degenerative conditions and its defects in Alzheimer’s disease. II. Ageing, Korsakoff’s disease, Parkinson’s disease, and Alzheimer’s disease. J Comp Neurol 351(2):189–222. doi:10.1002/cne.903510203

    Article  PubMed  CAS  Google Scholar 

  • Arnold B, Cassady SJ, VanLaar VS, Berman SB (2011) Integrating multiple aspects of mitochondrial dynamics in neurons: age-related differences and dynamic changes in a chronic rotenone model. Neurobiol Dis 41(1):189–200. doi:10.1016/j.nbd.2010.09.006

    Article  PubMed  CAS  Google Scholar 

  • Ballatore C, Lee VM, Trojanowski JQ (2007) Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci 8(9):663–672. doi:10.1038/nrn2194

    Article  PubMed  CAS  Google Scholar 

  • Bilsland LG, Sahai E, Kelly G, Golding M, Greensmith L, Schiavo G (2010) Deficits in axonal transport precede ALS symptoms in vivo. Proc Natl Acad Sci USA 107(47):20523–20528. doi:10.1073/pnas.1006869107

    Article  PubMed  CAS  Google Scholar 

  • Brunnstrom H, Friberg N, Lindberg E, Englund E (2011) Differential degeneration of the locus coeruleus in dementia subtypes. Clin Neuropathol 30(3):104–110. doi:10.5414/NPP30104

    PubMed  CAS  Google Scholar 

  • Buckman JF, Hernandez H, Kress GJ, Votyakova TV, Pal S, Reynolds IJ (2001) MitoTracker labeling in primary neuronal and astrocytic cultures: influence of mitochondrial membrane potential and oxidants. J Neurosci Methods 104(2):165–176. doi:10.1016/S0165-0270(00)00340-X

    Article  PubMed  CAS  Google Scholar 

  • Chaves RS, Melo TQ, Martins SA, Ferrari MF (2010) Protein aggregation containing beta-amyloid, alpha-synuclein and hyperphosphorylated tau in cultured cells of hippocampus, substantia nigra and locus coeruleus after rotenone exposure. BMC Neurosci 11:144. doi:10.1186/1471-2202-11-144

    Article  PubMed  Google Scholar 

  • Cleveland TALAWaDE (1999) Slowing of axonal transport is a very early event in the toxicity of ALS−linked SOD1 mutants to motor neurons. Nat Neurosci 2:50–56. doi:10.1038/4553

    Article  Google Scholar 

  • Demers G, Griffin G, De Vroey G, Haywood JR, Zurlo J, Bedard M (2006) Animal research. Harmonization of animal care and use guidance. Science 312(5774):700–701. doi:10.1126/science.1124036

    Article  PubMed  CAS  Google Scholar 

  • Falzone TL, Gunawardena S, McCleary D, Reis GF, Goldstein LS (2010) Kinesin-1 transport reductions enhance human tau hyper phosphorylation, aggregation and neurodegeneration in animal models of tauopathies. Hum Mol Genet 19(22):4399–4408. doi:10.1093/hmg/ddq363

    Article  PubMed  CAS  Google Scholar 

  • Gentile A, Amadoro G, Corsetti V, Ciotti MT, Serafino A, Calissano P (2008) Spontaneous aggregation and altered intracellular distribution of endogenous alpha-synuclein during neuronal apoptosis. J Alzheimers Dis 13(2):151–160

    PubMed  CAS  Google Scholar 

  • Goedert M (2001) Alpha-synuclein and neurodegenerative diseases. Nat Rev Neurosci 2(7):492–501. doi:10.1038/35081564

    Article  PubMed  CAS  Google Scholar 

  • Goldstein LS (2003) Do disorders of movement cause movement disorders and dementia? Neuron 40(2):415–425. doi:10.1016/S0896-6273(03)00630-5

    Article  PubMed  CAS  Google Scholar 

  • Green ML, Singh AV, Ruest LB, Pisano MM, Prough RA, Knudsen TB (2011) Differential programming of p53-deficient embryonic cells during rotenone block. Toxicology 290(1):31–41. doi:10.1016/j.tox.2011.08.013

    Article  PubMed  CAS  Google Scholar 

  • Gunawardena S, Goldstein LS (2001) Disruption of axonal transport and neuronal viability by amyloid precursor protein mutations in drosophila. Neuron 32(3):389–401. doi:10.1016/S0896-6273(01)00496-2

    Article  PubMed  CAS  Google Scholar 

  • Guo X, Macleod GT, Wellington A, Hu F, Panchumarthi S, Schoenfield M, Marin L, Charlton MP, Atwood HL, Zinsmaier KE (2005) The GTPase dMiro is required for axonal transport of mitochondria to drosophila synapses. Neuron 47(3):379–393. doi:10.1016/j.neuron.2005.06.027

    Article  PubMed  CAS  Google Scholar 

  • Henchcliffe C, Beal MF (2008) Mitochondrial biology and oxidative stress in Parkinson disease pathogenesis. Nat Clin Pract Neurol 4(11):600–609. doi:10.1038/ncpneuro0924

    Article  PubMed  CAS  Google Scholar 

  • Hirokawa N, Noda Y (2008) Intracellular transport and kinesin superfamily proteins, KIFs: structure, function, and dynamics. Physiol Rev 88(3):1089–1118. doi:10.1152/physrev.00023.2007

    Article  PubMed  CAS  Google Scholar 

  • Hirokawa N, Takemura R (2005) Molecular motors and mechanisms of directional transport in neurons. Nat Rev Neurosci 6(3):201–214. doi:10.1038/nrn1624

    Article  PubMed  CAS  Google Scholar 

  • Hirokawa N, Niwa S, Tanaka Y (2010) Molecular motors in neurons: transport mechanisms and roles in brain function, development, and disease. Neuron 68(4):610–638. doi:10.1016/j.neuron.2010.09.039

    Article  PubMed  CAS  Google Scholar 

  • Hollenbeck PJ, Saxton WM (2005) The axonal transport of mitochondria. J Cell Sci 118(Pt 23):5411–5419. doi:10.1242/jcs.02745

    Article  PubMed  CAS  Google Scholar 

  • Kamal A, Stokin GB, Yang Z, Xia CH, Goldstein LS (2000) Axonal transport of amyloid precursor protein is mediated by direct binding to the kinesin light chain subunit of kinesin-I. Neuron 28(2):449–459. doi:10.1016/S0896-6273(00)00124-0

    Article  PubMed  CAS  Google Scholar 

  • Kamal A, Almenar-Queralt A, LeBlanc JF, Roberts EA, Goldstein LS (2001) Kinesin-mediated axonal transport of a membrane compartment containing beta-secretase and presenilin-1 requires APP. Nature 414(6864):643–648. doi:10.1038/414643a

    Article  PubMed  CAS  Google Scholar 

  • Kanaan NM, Morfini GA, LaPointe NE, Pigino GF, Patterson KR, Song Y, Andreadis A, Fu Y, Brady ST, Binder LI (2011) Pathogenic forms of tau inhibit kinesin-dependent axonal transport through a mechanism involving activation of axonal phosphotransferases. J Neurosci 31(27):9858–9868. doi:10.1523/JNEUROSCI.0560-11.2011

    Article  PubMed  CAS  Google Scholar 

  • Kivell BM, McDonald FJ, Miller JH (2001) Method for serum-free culture of late fetal and early postnatal rat brainstem neurons. Brain Res 6(3):91–99. doi:10.1016/S1385-299X(00)00037-4

    CAS  Google Scholar 

  • Lyons DA, Naylor SG, Scholze A, Talbot WS (2009) Kif1b is essential for mRNA localization in oligo dendrocytes and development of myelinated axons. Nat Genet 41(7):854–858. doi:10.1038/ng.376

    Article  PubMed  CAS  Google Scholar 

  • Mandal M, Wei J, Zhong P, Cheng J, Duffney LJ, Liu W, Yuen EY, Twelvetrees AE, Li S, Li XJ, Kittler JT, Yan Z (2011) Impaired alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor trafficking and function by mutant huntingtin. J Biol Chem 286(39):33719–33728. doi:10.1074/jbc.M111.236521

    Article  PubMed  CAS  Google Scholar 

  • Martin LJ (2007) Transgenic mice with human mutant genes causing Parkinson’s disease and amyotrophic lateral sclerosis provide common insight into mechanisms of motor neuron selective vulnerability to degeneration. Rev Neurosci 18(2):115–136

    PubMed  CAS  Google Scholar 

  • Orr AL, Li S, Wang CE, Li H, Wang J, Rong J, Xu X, Mastroberardino PG, Greenamyre JT, Li XJ (2008) N-terminal mutant huntingtin associates with mitochondria and impairs mitochondrial trafficking. J Neurosci 28(11):2783–2792. doi:10.1523/JNEUROSCI.0106-08.2008

    Article  PubMed  CAS  Google Scholar 

  • Owen DJ, Collins BM (2010) Vesicle transport: a new player in APP trafficking. Curr Biol 20(9):R413–R415. doi:10.1016/j.cub.2010.03.017

    Article  PubMed  CAS  Google Scholar 

  • Phinney AL, Andringa G, Bol JG, Wolters E, van Muiswinkel FL, van Dam AM, Drukarch B (2006) Enhanced sensitivity of dopaminergic neurons to rotenone-induced toxicity with aging. Parkinsonism Relat Disord 12(4):228–238. doi:10.1016/j.parkreldis.2005.12.002

    Article  PubMed  Google Scholar 

  • Ross CA, Poirier MA (2005) Opinion: what is the role of protein aggregation in neurodegeneration? Nat Rev 6(11):891–898. doi:10.1038/nrm1742

    Article  CAS  Google Scholar 

  • Sheng ZH, Cai Q (2012) Mitochondrial transport in neurons: impact on synaptic homeostasis and neurodegeneration. Nat Rev Neurosci 13(2):77–93. doi:10.1038/nrn3156

    Article  PubMed  CAS  Google Scholar 

  • Sherer TB, Betarbet R, Testa CM, Seo BB, Richardson JR, Kim JH, Miller GW, Yagi T, Matsuno-Yagi A, Greenamyre JT (2003) Mechanism of toxicity in rotenone models of Parkinson’s disease. J Neurosci 23(34):10756–10764. doi:23/34/10756

    PubMed  CAS  Google Scholar 

  • Soane L, Kahraman S, Kristian T, Fiskum G (2007) Mechanisms of impaired mitochondrial energy metabolism in acute and chronic neurodegenerative disorders. J Neurosci Res 85(15):3407–3415. doi:10.1002/jnr.21498

    Article  PubMed  CAS  Google Scholar 

  • Stamer K, Vogel R, Thies E, Mandelkow E, Mandelkow EM (2002) Tau blocks traffic of organelles, neurofilaments, and APP vesicles in neurons and enhances oxidative stress. J Cell Biol 156(6):1051–1063. doi:10.1083/jcb.200108057

    Article  PubMed  CAS  Google Scholar 

  • Stokin GB, Lillo C, Falzone TL, Brusch RG, Rockenstein E, Mount SL, Raman R, Davies P, Masliah E, Williams DS, Goldstein LS (2005) Axonopathy and transport deficits early in the pathogenesis of Alzheimer’s disease. Science 307(5713):1282–1288. doi:10.1126/science.1105681

    Article  PubMed  CAS  Google Scholar 

  • Tanaka Y, Kanai Y, Okada Y, Nonaka S, Takeda S, Harada A, Hirokawa N (1998) Targeted disruption of mouse conventional kinesin heavy chain, KIF5B, results in abnormal perinuclear clustering of mitochondria. Cell 93(7):1147–1158. doi:10.1016/S0092-8674(00)81459-2

    Article  PubMed  CAS  Google Scholar 

  • Uchida A, Alami NH, Brown A (2009) Tight functional coupling of kinesin-1A and dynein motors in the bidirectional transport of neurofilaments. Mol Biol Cell 20(23):4997–5006. doi:10.1091/mbc.E09-04-0304

    Article  PubMed  CAS  Google Scholar 

  • Xia CH, Roberts EA, Her LS, Liu X, Williams DS, Cleveland DW, Goldstein LS (2003) Abnormal neurofilament transport caused by targeted disruption of neuronal kinesin heavy chain KIF5A. J Cell Biol 161(1):55–66. doi:10.1083/jcb.200301026

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors are grateful to Professors Luciana Amaral Haddad, Regina Celia Mingroni Netto, Angela Maria Vianna Morgante, and Luis Eduardo Soares Netto for their kind assistance in providing infrastructure to perform some of the experiments presented herein. This study was supported by research grants from Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) (2008/04480-9; 2011/06434-7) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (472042/2008-4; 471779/2010-5). T.Q.M., S.A.M., and R.S.C. received scholarships from FAPESP (2009/12200-9; 2011/05576-2; 2011/00478-2, respectively); A.M.D. received scholarship from CNPq (PIBIC 124062/2010-5); and K.L.G.F. received a scholarship from Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES).

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The authors declare that they have no conflict of interest.

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Correspondence to Merari F. R. Ferrari.

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Melo, T.Q., D’unhao, A.M., Martins, S.A. et al. Rotenone-Dependent Changes of Anterograde Motor Protein Expression and Mitochondrial Mobility in Brain Areas Related to Neurodegenerative Diseases. Cell Mol Neurobiol 33, 327–335 (2013). https://doi.org/10.1007/s10571-012-9898-z

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