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

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…

• UO
  University of Pennsylvania
• NI
  National Institutes of Health
• NI
  National Institute on Aging