Endosomal sorting drives the formation of axonal prion protein endoggresomes

Abstract

Mutant prion protein particles form axonal aggregates inside endolysosomes via axonal transport and endosomal fusion.

An mTOR-independent Macroautophagy Activator Ameliorates Tauopathy and Prionopathy Neurodegeneration Phenotypes

“…Figure 5B DMSO left panel to the DMSO right panel). (Chassefeyre et al, 2021) Expresion of PrP was under control of the mouse PrP promoter (MoPrP),(Borchelt et al, 1996) and contained the mouse endogenous PrP secretory signal sequence (SS) and a C-terminal GPI anchor sequence to ensure proper passage through the secretory pathway. (Chassefeyre et al ., 2021)The large PrP PG14 membrane-delimited aggregate structures formed inside axons are termed endoggresomes, and they accumulate at dystrophic swollen sites within axons (see DMSO panels in Figure 5B).…”

“…In the axon, HOPS-mediated homotypic fusion of PrP PG14 -containing vesicles generates enlarged aggregate-containing endolysosomes that disrupt calcium dynamics, impair the axonal transport of vesicular cargo, and reduce neuronal viability, and thus appear to be central to inherited prion disease etiology. (Chassefeyre et al ., 2021) This so-called axonal rapid endosomal sorting and transport-dependent aggregation (ARESTA) mechanism of endoggresome formation can be inhibited by genetic downregulation of the Arl8b/kinesin-1/Vps41(HOPS) axis, which reduces PrP PG14 endoggresomes and restores neuronal heatlh and viability. (Chassefeyre et al ., 2021) Importantly, expressing of PrP PG14 results in significantly impaired lysosomal clearance capacity in axons, thus endoggresomes form within endolysosomes that do not acidify and are not properly degraded and grow over time (Chassefeyre et al ., 2021) Figure 5E).…”

“…(Chassefeyre et al ., 2021) This so-called axonal rapid endosomal sorting and transport-dependent aggregation (ARESTA) mechanism of endoggresome formation can be inhibited by genetic downregulation of the Arl8b/kinesin-1/Vps41(HOPS) axis, which reduces PrP PG14 endoggresomes and restores neuronal heatlh and viability. (Chassefeyre et al ., 2021) Importantly, expressing of PrP PG14 results in significantly impaired lysosomal clearance capacity in axons, thus endoggresomes form within endolysosomes that do not acidify and are not properly degraded and grow over time (Chassefeyre et al ., 2021) Figure 5E).…”

“…(Chassefeyre et al, 2021) Expresion of PrP was under control of the mouse PrP promoter (MoPrP),(Borchelt et al, 1996) and contained the mouse endogenous PrP secretory signal sequence (SS) and a C-terminal GPI anchor sequence to ensure proper passage through the secretory pathway. (Chassefeyre et al ., 2021)The large PrP PG14 membrane-delimited aggregate structures formed inside axons are termed endoggresomes, and they accumulate at dystrophic swollen sites within axons (see DMSO panels in Figure 5B). Endoggresomes form following the active transport of smaller PrP PG14 -carrying Golgi-derived vesicles into the axon by their association with the small endolysosomal GTPase Arl8, which recruits kinesin-1 and Vps41(HOPS) onto PrP PG14 -carrying endosomes.…”

Mutant Prion Protein Endoggresomes are Hubs for Local Axonal Organelle-Cytoskeletal Remodeling

“…; https://doi.org/10.1101/2023.03. 19.533383 doi: bioRxiv preprint with human prion disease 9,[17][18][19][20][21] . The buildup of endosomes and organelles in axons suggest a breakdown of the axonal cytoskeletal and trafficking systems, but how the genesis of these putative pathological lesions relate to the presence of misfolded protein aggregates at localized regions in axons, remains unexplored.…”