Endolysosomal dysfunction and exosome secretion: implications for neurodegenerative disorders

Growing evidence suggests that endolysosomal and autophagic defects are key pathogenic processes in various neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The causal relationship between these defects and neurodegeneration is supported by human genetic studies identifying disease mutations in genes controlling endolysosomal function and autophagy. The canonical view is that defects in these processes lead to impaired lysosomal clearance of proteins prone to form toxic oligomeric assemblies and/or aggregates, ultimately resulting in cellular pathologies that define these disorders. Because lysosomes mediate the clearance of a large number of lipids, lipid storage is frequently associated with compromised endolysosomal and autophagic function. However, an emerging notion, supported by our recent study on class III phosphatidylinositol 3-kinase (PI3K) Vps34, is that neuronal endolysosomal and autophagic dysfunction can manifest itself with the occurrence of physically damaged endomembranes and with the release of exosomes enriched for Amyloid Precursor Protein COOH-terminal fragments (APP-CTFs) as well as atypical phospholipid bis(monoacylglycero)phosphate (BMP). Here, we summarize our recent findings and their potential implications in the context of lysosomal biology, lipid signaling and neurodegenerative diseases.