PXD054181

PXD054181 is an original dataset announced via ProteomeXchange.

Title	Autophagic stress activates two distinct compensatory secretory pathways in neurons
Description	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.
HostingRepository	MassIVE
AnnounceDate	2025-06-27
AnnouncementXML	Submission_2025-06-27_10:13:29.332.xml
DigitalObjectIdentifier
ReviewLevel	Non peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Hossein
SpeciesList	scientific name: Mus musculus; common name: house mouse; NCBI TaxID: 10090;
ModificationList	Oxidation; Acetyl; Carbamidomethyl
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2024-07-24 07:11:56	ID requested
⏵ 1	2025-06-27 10:13:29	announced

no publication

submitter keyword: Neuron, Homeostasis, Neurodegenerative diseases, LRRK2, Mitochondria

Erika Holzbaur, Ph.D.
contact affiliation	University of Pennsylvania
contact email	holzbaur@pennmedicine.upenn.edu
lab head
Hossein
contact affiliation	CHOP
contact email	fazeliniah@email.chop.edu
dataset submitter

MassIVE dataset URI

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