Objective:

This study investigates new roles for alpha-synuclein in regulating lysosomal and mitochondrial function and their potential crosstalk at mitochondria-lysosome contact sites.

Background:

Parkinson’s disease (PD) is the second most common neurodegenerative disease and a highly devastating movement disorder. Its etiology has been linked to both mitochondrial and lysosomal dysfunction, but the mechanisms underlying this are still not completely understood. Recent studies have shown that mitochondria and lysosomes directly interact at mitochondria-lysosome contact sites, which may be critical in PD pathophysiology. Alpha-synuclein (α-syn) is a lipid-binding protein whose accumulation is a hallmark of PD, and α-syn mutations can also directly cause familial forms of PD. However, the dynamic role of α-syn in regulating the crosstalk between mitochondria and lysosomes remains to be further investigated.

Design/Methods:

Live Super-Resolution microscopy was used to study mitochondrial and lysosomal dynamics and to assess α-syn’s role in regulating their crosstalk and function. In addition, the effects of α-syn’s post-translational modifications, PD-associated mutant α-syn, and the role of specific α-syn domains were examined for their ability to modulate mitochondrial and lysosomal homeostasis.

Results:

α-syn was found to regulate a novel mechanistic crosstalk between mitochondria and lysosomes, with this regulation modulated by post-translational modifications in a-syn. Importantly, PD-associated α-syn mutants were further able to disrupt this pathway. Furthermore, α-syn domains were also able to regulate this crosstalk, thus demonstrating a key role for α-syn in regulating both lysosomal and mitochondrial function.

Conclusions:

Disruptions in α-synuclein’s normal function impair the crosstalk between mitochondria and lysosome and may be a key driver of PD pathogenesis. These findings highlight potential therapeutic targets aimed at restoring organelle communication in PD.