How alpha-synuclein mutations cause Parkinson’s pathology
SNCA gene mutations that encode for alpha-synuclein (α-Syn) protein has been implicated in Parkinson’s disease (PD).
The researchers in this study describe how Parkinson’s disease mutations in alpha-synuclein compromise autophagy, a major route for alpha-synuclein degradation.
A53T and triplication a-Syn mutations activate ATP-citrate lyase (ACLY), which enhances cytoplasmic p300 activity. This in turn stimulates mTORC1 to inhibit autophagy.
Importantly, ACLY inhibitors restores autophagy and reduces α-Syn aggregates in neuronal models and in zebrafish, and mouse a-synucleinopathy models.
