Diminished Neuronal ESCRT-0 Function Exacerbates AMPA Receptor Derangement and Accelerates Prion-Induced...

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Biology

Background:

• Endolysosomal pathway defects are implicated in prion and other neurodegenerative diseases.
• Prion diseases involve prion oligomer trafficking through the multivesicular body (MVB) and subsequent lysosomal degradation or exosomal release.
• The impact of prion disease on cellular proteostatic pathways, particularly the ESCRT machinery, remains unclear.

Purpose of the Study:

• To investigate the role of Hrs and STAM1 (ESCRT-0) in prion pathogenesis.
• To determine how reduced ESCRT-0 impacts prion conversion, cellular toxicity, and disease progression in vivo.
• To elucidate the mechanism by which neuronal Hrs depletion exacerbates prion disease.

Main Methods:

• Analysis of Hrs and STAM1 levels in prion-affected human and mouse brains.
• Generation and prion-challenge of conditional knockout mice with neuronal, astrocytic, or microglial Hrs deletion.
• Assessment of survival, synaptic derangements, protein ubiquitination, receptor deregulation, and PrP^C surface levels in experimental models.

Main Results:

• Prion-affected brains showed a significant reduction in Hrs and STAM1 (ESCRT-0).
• Neuronal Hrs depletion in mice led to shortened survival, accelerated synaptic derangements, and accumulation of ubiquitinated proteins.
• Neuronal Hrs depletion increased surface levels of the cellular prion protein (PrP^C), potentially enhancing neurotoxic signaling.

Conclusions:

• Reduced Hrs in prion-affected brains impairs synaptic clearance of ubiquitinated proteins and exacerbates neurodegeneration.
• Loss of neuronal Hrs significantly accelerates prion disease progression and associated synaptic pathology.
• Enhanced PrP^C surface distribution due to Hrs depletion may contribute to accelerated neurotoxicity in prion disease.