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Do oxidatively modified proteins cause ALS?
1Department of Chemistry and Biochemistry, University of California at Los Angeles, Los Angeles, CA 90095-1569, USA. jsv@chem.ucla.edu
Abstract:
Over 90 individual mutations in SOD1 are known to cause familial amyotrophic lateral sclerosis (FALS). It is widely accepted that these mutations exert their toxic effects by a gain of function mechanism, but the nature of these toxic effects is as yet unknown. It has been proposed by several laboratories that reactions of FALS-mutant CuZnSOD are the source of elevated oxidative stress in CuZnSOD-linked FALS. It has also been proposed that aggregates of CuZnSOD are somehow involved in the disease. The hypothesis that aggregates of CuZnSOD cause ALS is particularly attractive because protein aggregates are frequently associated with other neurodegenerative diseases. Recent evidence increasingly suggests that protein aggregates containing CuZnSOD protein play a role in CuZnSOD-linked ALS, but it is not yet know why the aggregates form nor if the CuZnSOD proteins in the aggregates are cleaved, oxidized, demetallated, or otherwise covalently modified.
Insights
Over 90 mutations in SOD1 cause familial ALS (FALS). While a gain-of-function mechanism is accepted, the exact toxic effects and the role of SOD1 protein aggregates remain unclear, hindering FALS understanding.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Familial amyotrophic lateral sclerosis (FALS) is linked to over 90 mutations in the SOD1 gene.
- The toxic mechanism of FALS-mutant SOD1 is thought to involve a gain-of-function, but remains poorly understood.
- Protein aggregates are implicated in neurodegenerative diseases, and their role in SOD1-linked FALS is under investigation.
Purpose of the Study:
- To investigate the nature of toxic effects caused by FALS-mutant CuZnSOD.
- To explore the potential role of CuZnSOD protein aggregates in the pathogenesis of FALS.
- To determine the reasons for aggregate formation and modifications within aggregates.
Main Methods:
- The study reviews existing literature and proposes hypotheses regarding FALS mechanisms.
- It focuses on the biochemical properties of mutant CuZnSOD and aggregate formation.
- Further research is suggested to analyze aggregate composition and formation triggers.
Main Results:
- Evidence increasingly suggests that protein aggregates containing CuZnSOD play a role in FALS.
- The precise reasons for the formation of these aggregates are not yet known.
- It remains undetermined if CuZnSOD proteins within aggregates undergo cleavage, oxidation, or demetallation.
Conclusions:
- While SOD1 mutations are known to cause FALS, the exact gain-of-function toxic effects are unknown.
- Protein aggregates of CuZnSOD are increasingly suspected to be involved in FALS.
- Further research is needed to elucidate the formation and modification of these aggregates in FALS.