Protein Trafficking

Protein trafficking likely plays an important role in the formation of alpha-synuclein aggregates common to PD, as well as in many normal cellular processes. PINK1 has also been shown to play an important role in mitochondrial trafficking, specifically affecting mitochondrial morphology (Weihofen et al., 2009).

Alpha-synuclein has been shown to bind negatively charged lipid bilayers, possibly playing a role in aggregation and neurotoxicity. Mutations to alpha-synuclein found in familial cases of PD (A53T, A30P, and E36K) increase bilayer affinity (Pandey et al., 2009; Perlmutter et al., 2009).

Alpha-synuclein aggregation has also been shown to affect microtubule-dependent trafficking, leading to neuritic degeneration, trafficking defects, and Golgi fragmentation. These features are common to PD, as well as other neurodegenerative disorders (Lee et al., 2006). Microtubules have also been shown to regulate dopamine transporter activity via a heteromeric complex with alpha-synuclein. Alpha-synuclein binds to DAT, inhibiting activity; microtubule inhibitors alleviated the decrease in dopamine uptake and increased cell surface expression of DAT (Wersinger and Sidhu, 2005).