Autophagic stress activates two distinct compensatory secretory pathways in neurons

ABSTRACT: Neurons are reliant on autophagy to constitutively degrade damaged proteins and organelles in order to maintain cellular homeostasis. Autophagic dysfunction is associated with neurodegenerative diseases including Parkinson Disease. Mutations in the kinase LRRK2 are one of the most common causes of familial Parkinson disease; neurons expressing pathogenic LRRK2 mutations exhibit impaired autophagosome maturation. Here, we use biochemical, live cell imaging and unbiased proteomic approaches to demonstrate that LRRK2 mutant neurons engage two distinct secretory autophagy pathways as compensatory quality control mechanisms. First, we find that LRRK2 mutant neurons upregulate secretory autophagy, releasing cargos usually degraded by basal autophagy such as synaptic proteins and mitochondria. Second, we find that LRRK2 mutant neurons exhibit increased release of MVB-derived exosomes. We propose that these two secretory pathways act in tandem to dispose of cellular waste and to induce transcellular communication, respectively. We demonstrate that both pathways are upregulated in a knockin mouse model expressing pathogenic LRRK2 and that exosomal release prevents the apoptosis-mediated cell death of neurons from this mouse. These findings identify compensatory pathways that are upregulated by expression of pathogenic mutations disrupting neuronal autophagy. These pathways contribute to the maintenance of cellular homeostasis and thus may delay neurodegenerative disease progression over the short term, but have the potential to exacerbate degeneration over the longer term through the release of proinflammatory components such as mitochondrial DNA.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Erika Holzbaur, Ph.D.  

PROVIDER: MSV000095428 | MassIVE | Wed Jul 24 07:11:00 BST 2024

SECONDARY ACCESSION(S): PXD054181

REPOSITORIES: MassIVE