Endosomal Sorting Drives the Formation of Mutant Prion Endoggresomes

Abstract

Intra-axonal misfolded protein aggregates are a pathological feature of neurodegenerative diseases. How aggregates are formed and cleared is key to maintaining proteostasis. By systematically analyzing the trafficking itinerary of a misfolded GPI-anchored prion protein (PrP) mutant, we unveil endocytic pathways that drive its immediate degradation in the soma, versus its aggregation in axons inside endosomal structures we termed endoggresomes. Axonal sorting occurs post-Golgi, by association of mutant PrP vesicles with Arl8b/kinesin-1/HOPS, a complex that earmarks them for axonal entry, fusion, and aggregation via a mechanism of axonal rapid endosomal sorting and transport-dependent aggregation (ARESTA). Endoggresomes persist in axons due to transport and lysosomal deficits, impairing calcium dynamics and accelerating neuronal death. Reducing ARESTA inhibits endoggresome formation and circumvents these defects. These data identify the endo-lysosomal system as critical for the sorting of misfolded PrP, and ARESTA as an actionable anti-aggregation target that can ameliorate axonal dysfunction in the prionopathies.

Influence of metabolic stress and metformin on synaptic protein profile in SH‐SY5Y‐derived neurons

“…These authors suggested that, when paired with cognitive data, these neurite enlargements seen with AD brains suggest a compensatory increase in size to maintain equivalent synaptic transmission rates despite a significant loss in the number of synaptic contacts (Bertoni-Freddari et al, 1993;Scheff et al, 1990). A second observation, that has also been reported in AD patients, suggests that abnormal neurite swelling likely occurs because of aberrant accumulation of axonal cargo and cytoskeletal proteins (Argueti-Ostrovsky et al, 2021;Chassefeyre et al, 2021;Stokin et al, 2005) driven by defects in axonal transport and autophagic clearance mechanisms (Argueti-Ostrovsky et al, 2021;Kobro-Flatmoen et al, 2021). Given the association between metabolic dysregulation and intracellular impairments such as cellular transport and autophagy, it is likely that the neurite enlargements observed both by us and with previous AD reports implicate a strong metabolic component in the progression of cognitive decline.…”

“…Given the known off-target effects of MET, it is not unusual for differences in outcomes to be observed when comparing results between types of AMPK activators (MET vs. A-769662 (Yang et al, 2022) vs. AICAR (Amato et al, 2011)). However, one explanation for these differences may be that METinduced enlargements in neurite size and length are a response to cellular stress and reductions in synaptic protein content similar to those observed with IR treatments (Argueti-Ostrovsky et al, 2021;Chassefeyre et al, 2021;Stokin et al, 2005). This would be despite MET and IR clearly inducing the activation of separate pathways where the underlying driver might be related to a perturbed metabolic state.…”