Therapeutic Strategies for Restoring Palmitoylation and Autophagy in Neurodegeneration
The cellular clearance pathway autophagy is required for degrading toxic proteins and damaged organelles, but is disrupted in many neurodegenerative diseases. During induction many autophagy regulators quickly localise to membranes from the cytosol. The Martin lab has identified palmitoylation, which involves the addition of the fatty acid palmitate to cysteine residues, as a potential regulator to direct autophagy proteins to membranes. The Martin lab has confirmed that several regulators of autophagy are palmitoylated, including the key autophagy receptor p62 that tags and delivers toxic substrates to lysosomes for degradation. p62 palmitoylation was significantly decreased in brains of Huntington disease (HD) patients and an HD mouse model suggesting that decreased p62 palmitoylation may lead to the impaired cargo loading seen in HD cells. Therefore, rescuing p62 palmitoylation may represent a therapeutic target for HD.