Lewy Body-like α-Synuclein Aggregates Resist Degradation and Impair Macroautophagy

Abstract

Background: ␣-Synuclein aggregates and macroautophagy are associated with neurodegeneration. Results: Modulation of macroautophagic activity does not affect ␣-synuclein aggregate levels, although these aggregates cause accumulation of immature autophagosomes. Conclusion: ␣-Synuclein aggregates are resistant to degradation and impair autophagy by delaying autophagosome maturation. Significance: Understanding the impact of ␣-synuclein aggregates on autophagy may help elucidate therapies for ␣-synucleinmediated neurodegeneration.

α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner

“…Understanding the underlying toxicity of different αS species in the aggregation pathway has been a major goal in the field. Although current theories suggest that oligomeric species might constitute the most toxic species (Karpinar et al, 2009;Outeiro et al, 2008;Winner et al, 2011), consensus is still lacking (El-Agnaf et al, 1998;Tanik et al, 2013). An undisputable fact, obtained from the clinical research, is that intracellular aggregates are found in the surviving neurons of PD patients indicating that their presence can, perhaps, have a beneficial effect in cell survival (Forno, 1996).…”

Autophagosome dynamics in neurodegeneration at a glance

“…In Parkinson's disease, wild-type a-synuclein aggregates impair autophagy by delaying autophagosome maturation (Tanik et al, 2013) and mutant a-synuclein A53T causes accumulation of autophagic-vesicular structures and impaired lysosomal hydrolysis (Stefanis et al, 2001). Parkinson's-diseaselinked mutations in another gene, ATP13A2 (PARK9) that encode a lysosomal P-type ATPase, also lead to defects in lysosomal acidification, the processing of lysosomal enzymes and the clearance of autophagic substrates (Dehay et al, 2012;Usenovic et al, 2012).…”

Endothelial Degeneration of Parkinson's Disease is Related to Alpha-Synuclein Aggregation

“…Aggregation of p62 was observed in the LBs by showing co-localisation with pα-synuclein but not in the Lewy neurites. The co-expression of autophagosomes and α-synuclein has been previously reported in an in vitro study [8]. Some large LBlike p62 aggregates were not associated with the LBs (Figures 3F).…”

“…Because p62 itself is also a substrate of autophagy, impairment of autophagy leads to p62 accumulation [12,13]. LBs were recently reported to be associated with p62 that accumulates in cell culture, implying that the α-synuclein aggregates resist degradation and impair autophagy [8].…”