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

By L. Devi, V. Raghavendran, B. M. Prabhu, N. Avadhani, H. Anandatheerthavarada. Journal of Biological Chemistry, 2008

1,051 citations recorded by the source corpus.

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.

Subfields: Cellular and Molecular Neuroscience, Neurology

View Paper: https://www.semanticscholar.org/paper/fe8b5ef6b4ddc0dbd33a40d81476d81a167827ec

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In Cellular and Molecular Neuroscience

1. P. Jenner
2. R. Youle
3. A. Abramov
4. S. Gandhi
5. A. Schapira
6. M. Mouradian
7. Mark Hallett
8. V. Dias

In Neurology

1. P. Jenner
2. R. Youle
3. Edward A. Fon
4. H. McBride
5. Gian-Luca McLelland
6. M. Mouradian
7. V. Dias
8. E. Junn

Citations in the corpus

• The Roles of PINK1, Parkin and Mitochondrial Fidelity in Parkinson's Disease (2015, background): “The a-synuclein aggregates can localize to mitochondria and may cause mitochondrial dysfunction (Devi et al., 2008; Dryanovski et al., 2013).”
• α-Synuclein in Parkinson's disease. (2012, background): “Many studies now have confirmed that a proportion of a-synuclein, endogenous or overexpressed, resides within mitochondria, and that it causes down-regulation of complex I activity, thus linking a-synuclein with the effects of mitochondrial toxins, and potentially, sporadic PD (Li et al. 2007; Devi ”
• The Role of Oxidative Stress in Parkinson’s Disease (2013, result): “This interaction is supported by in vivo studies demonstrating alpha-synuclein in the mitochondrial membrane of dopaminergic neurons of the mouse brain [254], and in the mitochondrial fraction of human dopaminergic neurons, whereby levels in the SN and striatum are higher in postmortem PD brains tha”
• Role of Oxidative Stress in Parkinson's Disease (2013, background): “In addition, α-synuclein, although mostly cytosolic, seems to interact with mitochondrial membranes and to inhibit Complex I [32].”
• Genetic Animal Models of Parkinson’s Disease (2010, neutral): “Moreover, the substantia nigra and striatum, but not the cerebellum, of PD patients accumulate a-synuclein in the setting of decreased mitochondrial complex I activity (Devi et al., 2008), and patients with mitochondrial mutations have Lewy bodies (Betts-Henderson et al., 2009).”
• Pathological roles of MAPK signaling pathways in human diseases. (2010, background): “mitochondria and mitochondrial oxidative stress appears to contribute to the regulation of neuronal apoptosis by α-synuclein [69,70]”
• A new pathway for mitochondrial quality control: mitochondrial‐derived vesicles (2014, background): “A number of studies have identified a-synuclein as present either within mitochondria (Cole et al, 2008; Devi et al, 2008), or localized to mitochondrial-associated membranes of the ER (Guardia-Laguarta et al, 2014) and have implicated it in binding to anionic and cardiolipin-containing membranes…”
• The cerebellum in Parkinson’s disease (2013, background): “Devi et al. (2008) showed that accumulation of”
• Etiology and pathogenesis of Parkinson's disease (2011, background): “Alpha-synuclein has been reported to inhibit complex I in a dose-dependent manner.(63,64) Mitochondrial abnormalities of structure and function have been observed in transgenic mice overexpressing mutant alpha-synuclein.”
• Mechanism of Oxidative Stress in Neurodegeneration (2012, background): “Expression of mutant α-synuclein in mouse models or neurons results in mitochondrial dysfunction and increased ROS production [33, 34].”