Neuronal lysosomal dysfunction releases exosomes harboring APP C-terminal fragments and unique lipid signatures

Abstract

Defects in endolysosomal and autophagic functions are increasingly viewed as key pathological features of neurodegenerative disorders. A master regulator of these functions is phosphatidylinositol-3-phosphate (PI3P), a phospholipid synthesized primarily by class III PI 3-kinase Vps34. Here we report that disruption of neuronal Vps34 function in vitro and in vivo impairs autophagy, lysosomal degradation as well as lipid metabolism, causing endolysosomal membrane damage. PI3P deficiency also promotes secretion of unique exosomes enriched for undigested lysosomal substrates, including amyloid precursor protein C-terminal fragments (APP-CTFs), specific sphingolipids, and the phospholipid bis(monoacylglycero)phosphate (BMP), which normally resides in the internal vesicles of endolysosomes. Secretion of these exosomes requires neutral sphingomyelinase 2 and sphingolipid synthesis. Our results reveal a homeostatic response counteracting lysosomal dysfunction via secretion of atypical exosomes eliminating lysosomal waste and define exosomal APP-CTFs and BMP as candidate biomarkers for endolysosomal dysfunction associated with neurodegenerative disorders.

Dysregulated Autophagy and Lysosome Function Are Linked to Exosome Production by Micro‐RNA 155 in Alcoholic Liver Disease

“…Various studies have shown a causal relationship between lysosomal dysfunction and exosome secretion . Another study reported that increased secretion of atypical exosomes is a homeostatic response to counter lysosomal dysfunction to eliminate lysosomal waste . Our results confirm that lysosomal dysfunction results in significantly higher exosome release in ALD, suggesting a crosstalk between lysosomal dysfunction and the exosomal pathway.…”

“…(36,37) Another study reported that increased secretion of atypical exosomes is a homeostatic response to counter lysosomal dysfunction to eliminate lysosomal waste. (38) Our results confirm that lysosomal dysfunction results in significantly higher exosome release in ALD, suggesting a crosstalk between lysosomal dysfunction and the exosomal pathway. We found impaired autophagy and increased exosome production in the mouse model of ALD and also in patients with ALD.…”

Lysosomal membrane permeabilization and cell death

“…The cytosolic side of the lysosomal membrane also serves as a signaling platform where mTORC1 interacts with cofactors in response to stress and initiates downstream cell responses . Recently, it has been proposed that lysosomal stress can induce the release of extracellular vesicles, such as exosomes, as an alternative pathway mediating the elimination of cellular waste …”

Exosomes: Revisiting their role as “garbage bags”

“…Impaired degradation and misfolded protein accumulation in long lived post‐mitotic cells such as neurons could lead to the secretion and propagation of pathogenic proteins . Exosomes might be used as vectors to evacuate these components out of the cells . Alzheimer's disease (AD) is a neurological disorder characterized by extracellular deposits of amyloid‐β peptide (Aβ).…”

“…135 Exosomes might be used as vectors to evacuate these components out of the cells. 136 Alzheimer's disease (AD) is a neurological disorder characterized by extracellular deposits of amyloid-β peptide (Aβ). Aβ is derived from the processing of amyloid precursor protein (APP) by βand γ-secretases in the endosomal compartment.…”