Mitochondrial Dysfunction and Alpha-Synuclein Synaptic Pathology in Parkinson’s Disease: Who’s on First?

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder. Its characteristic neuropathological features encompass the loss of dopaminergic neurons of the nigrostriatal system and the presence of Lewy bodies and Lewy neurites. hese are intraneuronal and intraneuritic proteinaceous insoluble aggregates whose main constituent is the synaptic protein �-synuclein. Compelling lines of evidence indicate that mitochondrial dysfunction and�-synuclein synaptic deposition may play a primary role in the onset of this disorder. However, it is not yet clear which of these events may come irst in the sequel of processes leading to neurodegeneration. Here, we reviewed data supporting either that�-synuclein synaptic deposition precedes and indirectly triggers mitochondrial damage or that mitochondrial deicits lead to neuronal dysfunction and�-synuclein synaptic accumulation. he present overview shows that it is still diicult to establish the exact temporal sequence and contribution of these events to PD.