A protein linked to Parkinson's disease may cause neurodegeneration by inhibiting autophagy, Winslow et al. reveal.
The degradative autophagy pathway clears a variety of toxic waste from cells, including misfolded proteins and defective mitochondria. These two types of cellular trash accumulate in neurons from Parkinson's patients, suggesting that autophagy could be impaired in these cells. A commonly aggregated protein in Parkinson's disease is α-synuclein, whose gene is often mutated or overexpressed in familial forms of the illness. Winslow et al. found that excess α-synuclein inhibits autophagy by blocking formation of the autophagosome—the double-membraned vesicle that engulfs cytoplasmic garbage and delivers it to lysosomes for destruction.
A previous study showed that α-synuclein inhibits Rab1a, a small GTPase that controls secretory transport from the ER to the Golgi. Winslow et al. found that Rab1a knockdown also impaired autophagosome formation whereas overexpression of the GTPase reversed the inhibitory effects of α-synuclein on autophagy. Depleting other Rab proteins involved in ER to Golgi transport failed to block autophagy however, suggesting that Rab1a has a specialized role in autophagosome biogenesis. This function is important at an early step in the pathway: an abundance of α-synuclein or lack of Rab1a mislocalized an early acting part of the autophagy machinery called Atg9 and blocked the formation of putative autophagosome precursors known as omegasomes.
Compromising autophagy in this way could enhance the gradual accumulation of toxic proteins and dysfunctional mitochondria, sensitizing neurons to cell death. Senior author David Rubinsztein now wants to investigate how α-synuclein inhibits Rab1a and how this impairs autophagosome formation. BS
