Impaired Autophagic-Lysosomal Fusion in Parkinson’s Patient Midbrain Neurons Occurs through Loss of ykt6 and Is Rescued by Farnesyltransferase Inhibition

Caleb Pitcairn, Naomi Murata, Annie J. Zalon, Iva Stojkovska, Joseph R. Mazzulli*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Macroautophagy is a catabolic process that coordinates with lysosomes to degrade aggregation-prone proteins and damaged organelles. Loss of macroautophagy preferentially affects neuron viability and is associated with age-related neurodegeneration. We previously found that α-synuclein (α-syn) inhibits lysosomal function by blocking ykt6, a farnesyl-regulated soluble NSF attachment protein receptor (SNARE) protein that is essential for hydrolase trafficking in midbrain neurons. Using Parkinson’s disease (PD) patient iPSC-derived midbrain cultures, we find that chronic, endogenous accumulation of a-syn directly inhibits autophagosome-lysosome fusion by impairing ykt6-SNAP-29 complexes. In wild-type (WT) cultures, ykt6 depletion caused a near-complete block of autophagic flux, highlighting its critical role for autophagy in human iPSC-derived neurons. In PD, macroautophagy impairment was associated with increased farnesyltransferase (FTase) activity, and FTase inhibitors restored macroautophagic flux through promoting active forms of ykt6 in human cultures, and male and female mice. Our findings indicate that ykt6 mediates cellular clearance by coordinating autophagic-lysosomal fusion and hydrolase trafficking, and that macroautophagy impairment in PD can be rescued by FTase inhibitors.

Original languageEnglish (US)
Pages (from-to)2615-2629
Number of pages15
JournalJournal of Neuroscience
Volume43
Issue number14
DOIs
StatePublished - Apr 5 2023

Keywords

  • farnesyltransferase
  • iPSC
  • macroautophagy
  • midbrain neurons
  • protein aggregation
  • α-synuclein

ASJC Scopus subject areas

  • General Medicine

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