Mitochondrial Import and Accumulation of α-Synuclein Impair Complex I in Human Dopaminergic Neuronal Cultures and Parkinson Disease Brain

Abstract

α-Synuclein, a protein implicated in the pathogenesis of Parkinson disease (PD), is thought to affect mitochondrial functions, although the mechanisms of its action remain unclear. In this study we show that the N-terminal 32 amino acids of human α-synuclein contain cryptic mitochondrial targeting signal, which is important for mitochondrial targeting of α-synuclein. Mitochondrial imported α-synuclein is predominantly associated with the inner membrane. Accumulation of wild-type α-synuclein in the mitochondria of human dopaminergic neurons caused reduced mitochondrial complex I activity and increased production of reactive oxygen species. However, these defects occurred at an early time point in dopaminergic neurons expressing familial α-synuclein with A53T mutation as compared with wild-type α-synuclein. Importantly, α-synuclein that lacks mitochondrial targeting signal failed to target to the mitochondria and showed no detectable effect on complex I function. The PD relevance of these results was investigated using mitochondria of substantia nigra, striatum, and cerebellum of postmortem late-onset PD and normal human brains. Results showed the constitutive presence of ∼14-kDa α-synuclein in the mitochondria of all three brain regions of normal subjects. Mitochondria of PD-vulnerable substantia nigra and striatum but not cerebellum from PD subjects showed significant accumulation of α-synuclein and decreased complex I activity. Analysis of mitochondria from PD brain and α-synuclein expressing dopaminergic neuronal cultures using blue native gel electrophoresis and immunocapture technique showed the association of α-synuclein with complex I. These results provide evidence that mitochondrial accumulated α-synuclein may interact with complex I and interfere with its functions. α-Synuclein, a protein implicated in the pathogenesis of Parkinson disease (PD), is thought to affect mitochondrial functions, although the mechanisms of its action remain unclear. In this study we show that the N-terminal 32 amino acids of human α-synuclein contain cryptic mitochondrial targeting signal, which is important for mitochondrial targeting of α-synuclein. Mitochondrial imported α-synuclein is predominantly associated with the inner membrane. Accumulation of wild-type α-synuclein in the mitochondria of human dopaminergic neurons caused reduced mitochondrial complex I activity and increased production of reactive oxygen species. However, these defects occurred at an early time point in dopaminergic neurons expressing familial α-synuclein with A53T mutation as compared with wild-type α-synuclein. Importantly, α-synuclein that lacks mitochondrial targeting signal failed to target to the mitochondria and showed no detectable effect on complex I function. The PD relevance of these results was investigated using mitochondria of substantia nigra, striatum, and cerebellum of postmortem late-onset PD and normal human brains. Results showed the constitutive presence of ∼14-kDa α-synuclein in the mitochondria of all three brain regions of normal subjects. Mitochondria of PD-vulnerable substantia nigra and striatum but not cerebellum from PD subjects showed significant accumulation of α-synuclein and decreased complex I activity. Analysis of mitochondria from PD brain and α-synuclein expressing dopaminergic neuronal cultures using blue native gel electrophoresis and immunocapture technique showed the association of α-synuclein with complex I. These results provide evidence that mitochondrial accumulated α-synuclein may interact with complex I and interfere with its functions. Parkinson disease (PD) 2The abbreviations used are: PDParkinson diseaseDANdopaminergic primary neuronalNDRINational Disease Resource InterchangeELISAenzyme-linked immunosorbent assayROSreactive oxygen speciessiRNAsmall interference RNA. is associated with the degeneration of dopaminergic neurons in the substantia nigra pars compacta. One of the pathological hallmarks of PD and related synucleinopathies is the presence of intracellular inclusions called Lewy bodies that consist of aggregates of the presynaptic soluble protein called α-synuclein.(1Bennett M.C. Pharmacol. Ther. 2005; 105: 311-331Crossref PubMed Scopus (153) Google Scholar, 2Dawson T.M. Dawson V.L. Science. 2003; 302: 819-822Crossref PubMed Scopus (1408) Google Scholar, 3Shults C.W. Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 1661-1668Crossref PubMed Scopus (363) Google Scholar). In addition, it is well known that mitochondrial dysfunction and oxidative stress are associated with the pathogenesis of PD (4Abou-Sleiman P.M. Muqit M.M. McDonald N.Q. Yang Y.X. Gandhi S. Healy D.G. Harvey K. Harvey R.J. Deas E. Bhatia K. Quinn N. Lees A. Latchman D.S. Wood N.W. Ann. Neurol. 2006; 60: 414-419Crossref PubMed Scopus (144) Google Scholar, 5Fiskum G. Starkov A. Polster B.M. Chinopoulos C. Ann. N. Y. Acad. Sci. 2003; 991: 111-119Crossref PubMed Scopus (220) Google Scholar, 6Greenamyre J.T. Betarbet R. Sherer T.B. Parkinsonism. Relat. Disord. 2003; 9: S59-S64Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar, 7Lin M.T. Beal M.F. Nature. 2006; 443: 787-795Crossref PubMed Scopus (4704) Google Scholar). Triplication of α-synuclein gene and point mutations in the coding region has been associated with early onset of familial forms of PD. The familial PD represents only a minor proportion of all PD cases, whereas the majority of cases belong to sporadic form of the disease. However, some forms of familial PD have also been linked to mutations in PINK1 and DJ1 (2Dawson T.M. Dawson V.L. Science. 2003; 302: 819-822Crossref PubMed Scopus (1408) Google Scholar, 3Shults C.W. Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 1661-1668Crossref PubMed Scopus (363) Google Scholar, 8Bonifati V. Rizzu P. Squitieri F. Krieger E. Vanacore N. van Swieten J.C. Brice A. van Duijn C.M. Oostra B. Meco G. Heutink P. Neurol. Sci. 2003; 24: 159-160Crossref PubMed Scopus (343) Google Scholar, 9Bonifati V. Rizzu P. van Baren M.J. Schaap O. Breedveld G.J. Krieger E. Dekker M.C. Squitieri F. Ibanez P. Joosse M. van Dongen J.W. Vanacore N. van Swieten J.C. Brice A. Meco G. van Duijn C.M. Oostra B.A. Heutink P. Science. 2003; 299: 256-259Crossref PubMed Scopus (2287) Google Scholar, 10Valente E.M. bou-Sleiman P.M. Caputo V. Muqit M.M. Harvey K. Gispert S. Ali Z. Del T.D. Bentivoglio A.R. Healy D.G. Albanese A. Nussbaum R. Gonzalez-Maldonado R. Deller T. Salvi S. Cortelli P. Gilks W.P. Latchman D.S. Harvey R.J. Dallapiccola B. Auburger G. Wood N.W. Science. 2004; 304: 1158-1160Crossref PubMed Scopus (2725) Google Scholar). Studies have shown that these proteins localize to mitochondria and gain toxic functions due to the mutations, which may lead to mitochondrial dysfunction (11Canet-Aviles R.M. Wilson M.A. Miller D.W. Ahmad R. McLendon C. Bandyopadhyay S. Baptista M.J. Ringe D. Petsko G.A. Cookson M.R. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 9103-9108Crossref PubMed Scopus (926) Google Scholar, 12Moore D.J. Zhang L. Troncoso N. Y. Dawson T.M. Dawson V.L. 2005; PubMed Scopus Google Scholar, L. Caputo V. E. L. Dallapiccola B. E.M. G. 2005; PubMed Scopus Google Scholar). on of wild-type and familial forms of α-synuclein in and have mitochondrial Y. A. E. A. M. T. M. E. Full Text Full Text PDF PubMed Scopus Google Scholar, Y. 2006; PubMed Scopus Google Scholar). However, the on mitochondrial of α-synuclein mechanisms mitochondrial functions in the normal and in PD human have not been in Parkinson disease dopaminergic primary neuronal Disease Resource immunosorbent reactive oxygen interference RNA. Studies from the mitochondrial targeting of and protein with a cryptic mitochondrial targeting signal G. L. D. PubMed Scopus Google Scholar, G. V. Full Text Full Text PDF PubMed Scopus Google Scholar, S. G. PubMed Scopus Google Scholar, M.A. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, G. M.A. 2003; PubMed Scopus Google Scholar). These protein using postmortem human and human neuronal we showed that the accumulation of protein mitochondrial was associated with the of mitochondrial L. B.M. 2006; PubMed Scopus Google Scholar). In the we the cryptic mitochondrial targeting at the of α-synuclein. Mitochondrial targeting of α-synuclein in and in and also mitochondrial defects in α-synuclein neuronal to that mitochondrial accumulation of α-synuclein may an important of mitochondrial dysfunction as in the pathogenesis of PD. was investigated in human PD. results show that mitochondria are of the of α-synuclein the pathogenesis of PD. of α-synuclein a and a was using from human brain N-terminal of the using the an and M. Full Text PDF PubMed Scopus Google for was using wild-type as a to contain and a and these α-synuclein a and a and these the from The of all the to and of dopaminergic primary neuronal cultures as to the at with wild-type and N-terminal α-synuclein using and in of using a The at for and the was at for to mitochondrial The mitochondrial was at to and The was in and and at for The was in and used for of mitochondrial with was investigated with to and of in of α-synuclein in was using α-synuclein from of human of three to and was to the the of to mitochondrial to complex In Mitochondrial mitochondria from as S. G. PubMed Scopus Google Scholar). the and N-terminal in a to the of the in proteins was in a as G. V. Full Text Full Text PDF PubMed Scopus Google Scholar, S. G. PubMed Scopus Google Scholar). The was to and mitochondria and at for Mitochondrial proteins and to The imported using the In of α-synuclein was in the presence of Mitochondrial of α-synuclein was as and the mitochondrial was to using to α-synuclein. on with and for and for as G. M.A. 2003; PubMed Scopus Google Scholar). with with to the and to The with and to brain to from the Disease Resource of which with PD and normal with no These subjects a postmortem time and from to and to used to postmortem human from the The PD cases used in the study on the and the for and a of from region was for in and PD subjects used in the study for the presence of Lewy whereas showed no Lewy of from of brain was in of and at for and from the as L. B.M. 2006; PubMed Scopus Google Scholar). to was the R.J. Full Text PDF PubMed Google Scholar). of mitochondrial with was investigated with to mitochondrial and and in and to and as S. G. PubMed Scopus Google Scholar). Mitochondrial proteins and to with α-synuclein mitochondrial I and The with primary and and the using the and a with One of α-synuclein in and mitochondria in from PD and was using the as the was in the at the of as G. M.A. 2003; PubMed Scopus Google Scholar, L. B.M. 2006; PubMed Scopus Google Scholar). from with primary to α-synuclein at for The with for and with The and using an of Mitochondrial complex and as Pharmacol. 2006; PubMed Scopus Google Scholar). The activity of complex I in the mitochondria was the in due to the of at using of activity was the of at in the presence of activity was the in of at of and was as F. Nussbaum 2005; PubMed Scopus Google Scholar). In of from substantia nigra of normal was in and with of human α-synuclein at for and of α-synuclein and at for the the for mitochondrial complex as Pharmacol. 2006; PubMed Scopus Google Scholar, F. Nussbaum 2005; PubMed Scopus Google Scholar). of in was in the mitochondrial from with wild-type and α-synuclein using Mitochondria with in of a and and at for in the was using a at and at mitochondrial in and to blue native gel electrophoresis as L. B.M. 2006; PubMed Scopus Google Scholar). The with to of complex I and α-synuclein. of of complex I was using I from to the from of mitochondrial The of complex I was using complex I was to using to α-synuclein and using The mitochondrial α-synuclein and complex I activity was using and the of of In some was Mitochondrial of from the of α-synuclein is in amino acids this region also form an A. 2005; Full Text Full Text PDF PubMed Scopus Google the of mitochondrial targeting G. PubMed Scopus Google Scholar, P. K. N. 2004; PubMed Scopus Google Scholar). also used the which the signal targeting of The a of mitochondria The of α-synuclein to mitochondria was the protein was used for the mitochondrial of α-synuclein increased to the N-terminal was used for that the of human α-synuclein may as mitochondrial targeting These results a on the mitochondrial of human α-synuclein using in mitochondrial and in in neuronal of of α-synuclein of protein used for amino acids used for in a Mitochondrial of and investigated the α-synuclein protein to the mitochondria using an in mitochondrial in which was used as a for the of The in the presence of using the and with of in wild-type α-synuclein with mitochondria in the of the ∼14-kDa a of this protein to In α-synuclein in mitochondria was not of the mitochondrial of α-synuclein is shown in Results showed that of which the mitochondrial no effect on mitochondrial of α-synuclein protein the of α-synuclein. 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In of results from in the showed that of the mitochondrial in to the inner the association of imported α-synuclein predominantly with inner of to α-synuclein failed to show in the mitochondria the of α-synuclein used in the study at for Mitochondrial of we the for the targeting of α-synuclein to the mitochondria N-terminal of amino acids not the mitochondrial of α-synuclein However, the of 32 amino acids reduced the mitochondrial of α-synuclein as no detectable protein was in mitochondria In of signal in these results provide evidence that the N-terminal is a also the mitochondrial of familial mutation of α-synuclein. the A53T mutation on this mutation has been shown to wild-type α-synuclein Z. Y. A. Dawson V.L. Dawson T.M. 2005; PubMed Scopus Google Scholar). in the showed that was imported in to of α-synuclein showed that was imported in to mitochondria with as compared with Accumulation of in the Mitochondria of in targeting of α-synuclein to mitochondria was in human which are in the pathogenesis of PD. The has been to provide a to study human B.A. PubMed Scopus Google Scholar). the mitochondrial functions in with wild-type and α-synuclein but detectable of intracellular α-synuclein. the interference from we α-synuclein in a with a at the with and mitochondria and and the of proteins The results showed protein accumulated in the mitochondrial In of in mitochondrial the protein showed reduced mitochondrial that the 32 amino acids of α-synuclein are important for mitochondrial targeting in and in The of mitochondrial and in with and and and was detectable only in whereas was in These results that mitochondrial and used in this study not contain significant and of Results from showed that the mitochondrial accumulation of which from to of mitochondrial protein at time the with time However, the of and the at all three time The of α-synuclein in mitochondria was also investigated of the protein in with and to with and to the mitochondrial with showed a intracellular α-synuclein that and mitochondria that of the α-synuclein with However, the of predominantly α-synuclein and mitochondrial which not with These results that α-synuclein is to mitochondria and that the N-terminal 32 are important for mitochondrial Mitochondrial Accumulation of and I of α-synuclein in cultures is associated with mitochondrial dysfunction and oxidative stress Y. A. E. A. M. T. M. E. Full Text Full Text PDF PubMed Scopus Google Scholar). In addition, complex I activity is of the mitochondrial in PD P.M. 2006; PubMed Scopus Google Scholar, D. M.T. Ann. Neurol. PubMed Scopus Google Scholar). investigated the effect of mitochondrial accumulation of α-synuclein on mitochondrial complex I activity. The mitochondrial of with and for complex I activity. accumulation of wild-type α-synuclein in mitochondria was a significant in complex I activity and an in reactive oxygen as compared with with the familial showed significant mitochondrial accumulation as early as as compared with showed a significant in complex I activity and at an time point the However, the of mitochondrial which as a Mitochondrial accumulation of α-synuclein showed no significant in complex and not with which showed no detectable mitochondrial not in significant effect on mitochondrial complex I activity the production of results with α-synuclein not These results show for the time that accumulation of α-synuclein in the mitochondrial may mitochondrial functions and oxidative of on Mitochondrial study showed the of mitochondrial complex I and in α-synuclein F. Nussbaum 2005; PubMed Scopus Google Scholar). investigated the of the constitutive presence of α-synuclein on complex I activity in human of α-synuclein. Results showed but detectable of α-synuclein in the mitochondrial of the of with the protein of α-synuclein in the as well as in mitochondrial as compared with was of α-synuclein However, the of no effect on the of and mitochondrial In with F. Nussbaum 2005; PubMed Scopus Google was a significant in the which the complex I and complex in the mitochondria from α-synuclein I activity in these showed a but These results an important for the α-synuclein in the of mitochondrial in the Mitochondria of and of investigated the PD relevance of mitochondrial targeting and accumulation of α-synuclein in in and neuronal using human postmortem PD and normal brains. 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However, the of α-synuclein in the mitochondria of cerebellum from PD and normal subjects and Importantly, mitochondrial in all cases of PD and normal subjects I and These results the accumulation of α-synuclein in the mitochondria of substantia nigra and striatum of in PD subjects. mitochondrial accumulation of α-synuclein in substantia nigra and striatum of PD subjects was not associated with postmortem not with of Mitochondria in PD and of α-synuclein in PD brain investigated with and also The showed that the which the mitochondrial proteins as well as proteins to the mitochondria ∼14-kDa α-synuclein mitochondrial and inner but not the However, the α-synuclein in the Results also showed that of which the reduced the of but not of ∼14-kDa α-synuclein the association of α-synuclein with the inner of mitochondria with in of mitochondrial in the soluble However, α-synuclein and an inner protein in the In of results from in and these a association of α-synuclein with the inner of mitochondria of PD the we of substantia nigra of PD and normal subjects using α-synuclein and with In of in of α-synuclein and and and results of the of PD showed the associated with the mitochondrial inner of whereas normal subjects showed of α-synuclein in the mitochondria However, we the association of on the of a mitochondria of PD and normal subjects the α-synuclein in PD and normal subjects was associated with and and Mitochondrial in PD accumulation of α-synuclein in mitochondria was associated with complex I activity and oxidative stress in the we the accumulation of α-synuclein in the mitochondria of of PD subjects was with complex I Results showed in the mitochondrial complex I in the substantia nigra of PD subjects as compared with the of normal subjects from PD subjects also showed results not the mitochondrial complex I in the cerebellum of PD to the of normal subjects we the the of α-synuclein in the mitochondria of substantia nigra from PD subjects and mitochondrial complex I using which showed significant the the cerebellum of which not show the accumulation of α-synuclein in the mitochondrial no significant mitochondrial α-synuclein and complex I of Mitochondrial with the of α-synuclein on complex I α-synuclein was predominantly associated with the mitochondrial inner In the of we from substantia nigra of normal brain and with of α-synuclein and the complex I activity as and Results in showed that complex I activity was α-synuclein in a we the of α-synuclein in as and with the of α-synuclein of mitochondrial which complex I activity with in the significant of of and These results the of of α-synuclein with complex I. this in we the blue native electrophoresis of mitochondrial of from striatum of PD subjects and normal subjects as well as expressing wild-type and α-synuclein The to and with to α-synuclein the of complex I which the of and the complex of C. R. R. L. 2004; PubMed Scopus Google Scholar). showed that to three and in mitochondria from PD brain and with wild-type for to α-synuclein and However, to the complex I from mitochondria of normal striatum, and and although these not with to α-synuclein the association of mitochondrial accumulated we the immunocapture of complex I from mitochondria from striatum of PD and normal as well as expressing α-synuclein. complex I was to with to α-synuclein and Results showed the presence of of α-synuclein in the complex I from PD brain and wild-type α-synuclein expressing mitochondria the I from mitochondria from and expressing wild-type and of complex protein These results provide evidence that accumulated α-synuclein in human dopaminergic neuronal cultures and PD may interact with complex which is mitochondrial In this study we show for the time that human α-synuclein is imported mitochondria in and in in human Mitochondrial of α-synuclein is on mitochondrial and mitochondrial that the mitochondrial of α-synuclein is and mitochondrial we also show that α-synuclein in the mitochondrial of and substantia from from PD we have the mitochondrial targeting signal of α-synuclein. The N-terminal that the N-terminal region of which is for mitochondrial the mitochondrial targeting signal of α-synuclein is In of results from in we show that α-synuclein is to mitochondria of dopaminergic neurons and postmortem human brains. the and in this study provide evidence that α-synuclein is predominantly associated with inner in the human showed the constitutive presence of of α-synuclein on the mitochondrial of brain Yang R. J.C. PubMed Scopus Google Scholar). In of we have also a of α-synuclein on the mitochondrial of human However, the for the association of α-synuclein with mitochondrial inner in the human of in the is not The functions of α-synuclein in the mitochondrial and are not Results from of α-synuclein in the human and and α-synuclein F. Nussbaum 2005; PubMed Scopus Google showed I and using α-synuclein F. Nussbaum 2005; PubMed Scopus Google a for α-synuclein in the of of a mitochondrial inner has been is thought to for the of mitochondrial in oxidative PubMed Scopus Google Scholar). of evidence that constitutive α-synuclein may a protein and also to C.W. Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 1661-1668Crossref PubMed Scopus (363) Google Scholar, T.D. Yang Sci. 9: PubMed Scopus Google Scholar, M. S. M. Y. T.D. 2006; PubMed Scopus Google Scholar, M. D. 2003; PubMed Scopus Google Scholar). The study that mitochondria α-synuclein is in association with complex I and the mitochondrial may complex I and in human may also related to a for mitochondrial constitutive α-synuclein in the functions of mitochondrial and F. Nussbaum 2005; PubMed Scopus Google an important for α-synuclein in the normal functions of mitochondrial in the oxidative in using human and PD that accumulation of α-synuclein in the mitochondria complex I and increased oxidative is that of that lacks the mitochondrial targeting signal not only failed to localize to mitochondria but also not mitochondrial Accumulation of α-synuclein in the mitochondria from striatum and substantia nigra of PD subjects from to as compared with normal subjects. However, the for mitochondrial accumulation of α-synuclein in the in the PD subjects is not One is that is an increased mitochondrial targeting of α-synuclein protein the pathogenesis of PD. In a of we have an important for in the mitochondrial targeting of a of important proteins G. L. D. PubMed Scopus Google Scholar, G. V. Full Text Full Text PDF PubMed Scopus Google Scholar, M.A. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). showed that mitochondrial targeting of and protein of at G. L. D. PubMed Scopus Google Scholar, G. V. Full Text Full Text PDF PubMed Scopus Google Scholar). However, in the of of a protein target to the is for the of the mitochondrial targeting signal M.A. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). has been shown that α-synuclein a of and normal and disease A. P. A. D. P. 2004; PubMed Scopus Google Scholar, M. A. S. M. T. L. C. Full Text Full Text PDF PubMed Scopus Google Scholar). is that these to increased mitochondrial accumulation the of mitochondrial The is that α-synuclein is at the pathogenesis of PD. However, at the of mitochondrial in the of α-synuclein normal and disease is not is in to the of on mitochondrial targeting of α-synuclein as well as the in the of α-synuclein normal and disease results also showed a significant the accumulation of α-synuclein and decreased complex I in human PD in complex I activity in PD brain is in with that showed and in complex I and complex in the substantia nigra D. P. PubMed Scopus Google and in the of PD P.M. 2006; PubMed Scopus Google Scholar). have also the of mitochondrial complex I activity as the of mitochondrial dysfunction in PD (4Abou-Sleiman P.M. Muqit M.M. McDonald N.Q. Yang Y.X. Gandhi S. Healy D.G. Harvey K. Harvey R.J. Deas E. Bhatia K. Quinn N. Lees A. Latchman D.S. Wood N.W. Ann. Neurol. 2006; 60: 414-419Crossref PubMed Scopus (144) Google Scholar, M. M.T. Quinn Disord. PubMed Scopus Google Scholar, D.S. Ann. Neurol. PubMed Scopus Google Scholar). of evidence for the of decreased complex I activity in the pathogenesis of PD from complex I as and to which showed mitochondrial dysfunction as well as the of dopaminergic neurons R. Sherer T.B. G. M. J.T. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). results also show the of complex I activity α-synuclein in important of this study is that α-synuclein was in association with complex I in mitochondria of PD and dopaminergic neurons with mitochondrial of α-synuclein was These results that α-synuclein may target the complex I. results that association of mitochondrial accumulated α-synuclein with complex I may a to complex I dysfunction and increased oxidative In association of α-synuclein with the of complex I is that α-synuclein to that are in the of a of complex I C. R. R. L. 2004; PubMed Scopus Google Scholar, R.J. C. M. R.J. van L. M. 2005; PubMed Scopus Google Scholar, I. T. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). α-synuclein may the of complex I to In mitochondria from normal striatum and with α-synuclein for which showed of mitochondrial α-synuclein not show detectable association of α-synuclein with complex I. accumulated N-terminal α-synuclein protein associated with complex I its activity results that of mitochondrial dysfunction may from its action on and with complex I. Results from in and in that the mitochondrial accumulation of familial occurred at and showed the mitochondrial at an time in an in the mitochondrial targeting of it is that in this mutation may also the of α-synuclein in the mitochondrial mutations as and are also known to in the familial PD M.R. 2005; PubMed Scopus Google Scholar, T. Neurol. PubMed Scopus Google Scholar). However, the of these familial mutations on mitochondrial and its functions in the pathogenesis of PD are a of In using human we show for the time that constitutive of mitochondrial α-synuclein may important for the normal functions of mitochondrial whereas mitochondrial accumulation of α-synuclein may to the of complex I function. the and of mitochondrial α-synuclein may an important in the of mitochondrial dysfunction as in PD. of for and for postmortem human brains.