Aberrant Stress Granule Dynamics and Aggrephagy in ALS Pathogenesis.

Jiayu Gu,Qiming Sun,Yi Zhang

doi:10.3390/cells10092247

Abstract

Stress granules are conserved cytosolic ribonucleoprotein (RNP) compartments that undergo dynamic assembly and disassembly by phase separation in response to stressful conditions. Gene mutations may lead to aberrant phase separation of stress granules eliciting irreversible protein aggregations. A selective autophagy pathway called aggrephagy may partially alleviate the cytotoxicity mediated by these protein aggregates. Cells must perceive when and where the stress granules are transformed into toxic protein aggregates to initiate autophagosomal engulfment for subsequent autolysosomal degradation, therefore, maintaining cellular homeostasis. Indeed, defective aggrephagy has been causally linked to various neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). In this review, we discuss stress granules at the intersection of autophagy and ALS pathogenesis.

Highlights

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive degeneration of the upper and lower motor neurons, resulting in a loss of motor function and eventually death
Mutant superoxide dismutase 1 (SOD1) interacts with TIA-1, one of the core components of stress granules associated with ALS
Transactive Response DNA-Binding Protein 43 (TDP-43) has been detected as abnormal cytoplasmic aggregates in neurons and glia of more than 90% of ALS and 45% of frontotemporal dementia (FTD)

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive degeneration of the upper and lower motor neurons, resulting in a loss of motor function and eventually death. SOD1 is not a resident protein of SGs. mutant SOD1 interacts with TIA-1, one of the core components of stress granules associated with ALS. ALS-associated FUS mutants can bind and sequester wild type (WT) FUS into cytoplasmic SGs [66], accelerating aberrant liquid to solid phase transition of stress granules [67]. The chromosome 9 open reading frame 72 gene consists of 11 exons with three main transcripts formed through a complex process of alternative splicing and produces two protein isoforms It is found in almost 40% of familial ALS and FTD cases [76,77]. The above-mentioned autophagy activities of C9orf appear to be altered in ALS-associated C9orf mutations It is unclear whether the protein aggregates of C9orf mutants are substrates of autophagy

Future Perspectives

Findings

Methods