title: Compartmentalization of superoxide dismutase 1 (SOD1G93A) aggregates determines their toxicity.
abstract: Neurodegenerative diseases constitute a class of illnesses marked by pathological protein aggregation in the brains of affected individuals. Although these disorders are invariably characterized by the degeneration of highly specific subpopulations of neurons, protein aggregation occurs in all cells, which indicates that toxicity arises only in particular cell biological contexts. Aggregation-associated disorders are unified by a common cell biological feature: the deposition of the culprit proteins in inclusion bodies. The precise function of these inclusions remains unclear. The starting point for uncovering the origins of disease pathology must therefore be a thorough understanding of the general cell biological function of inclusions and their potential role in modulating the consequences of aggregation. Here, we show that in human cells certain aggregate inclusions are active compartments. We find that toxic aggregates localize to one of these compartments, the juxtanuclear quality control compartment (JUNQ), and interfere with its quality control function. The accumulation of SOD1G93A aggregates sequesters Hsp70, preventing the delivery of misfolded proteins to the proteasome. Preventing the accumulation of SOD1G93A in the JUNQ by enhancing its sequestration in an insoluble inclusion reduces the harmful effects of aggregation on cell viability.
authors.affiliation: Department of Biological Chemistry,  Weizmann Institute of Science, Rehovot 76100,  Israel.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Weisberg
authors.forename: Roman
authors.initials: R
authors.lastname: Lyakhovetsky
authors.forename: Ayelet-chen
authors.initials: AC
authors.lastname: Werdiger
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Gitler
authors.forename: Yoav
authors.initials: Y
authors.lastname: Soen
authors.forename: Daniel
authors.initials: D
authors.lastname: Kaganovich
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D002479:Inclusion Bodies / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D017510:Protein Folding; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
chemical_list: D018840:HSP70 Heat-Shock Proteins; C000606290:SOD1 protein, human; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D046988:Proteasome Endopeptidase Complex