Alphasynuclein Mutations Mislocalize Cytoplasmic P300 Compromising Autophagy Which Is Rescued By Acly Inhibition Sung Min Son Farah H Siddiqi Ana Lopez Rizwan Ansari Sylwia D Tyrkalska So Jung Park Tilo Kunath Emmanouil Metzakopian Angeleen Fleming David C Rubinsztein by Sung Min Son & Farah H. Siddiqi & Ana Lopez & Rizwan Ansari & Sylwia D. Tyrkalska & So Jung Park & Tilo Kunath & Emmanouil Metzakopian & Angeleen Fleming & David C. Rubinsztein 101016/JNEURON202503028 instant download after payment.

SUMMARYTriplications and certain point mutations in the SNCA gene, encoding alpha-synuclein (a-Syn), cause Parkinson’s disease (PD). Here, we demonstrate that the PD-causing A53T a-Syn mutation and elevated a-Synexpression perturb acetyl-coenzyme A (CoA) and p300 biology in human neurons and in the CNS of zebrafishand mice. This dysregulation is mediated by activation of ATP-citrate lyase (ACLY), a key enzyme that generates acetyl-CoA in the cytoplasm, via two mechanisms. First, ACLY activity increases acetyl-CoA levels,which activate p300. Second, ACLY activation increases LKB1 acetylation, which inhibits AMPK, leadingto increased cytoplasmic and decreased nuclear p300. This lowers histone acetylation and increases acetylation of cytoplasmic p300 substrates, like raptor, which causes mechanistic target of rapamycin complex 1(mTORC1) hyperactivation, thereby impairing autophagy. ACLY inhibitors rescue pathological phenotypes inPD neurons, organoids, zebrafish, and mouse models, suggesting that this pathway is a core feature of a-Syntoxicity and that ACLY may be a suitable therapeutic target.