title: Protein aggregation and protein instability govern familial amyotrophic lateral sclerosis patient survival.
abstract: The nature of the "toxic gain of function" that results from amyotrophic lateral sclerosis (ALS)-, Parkinson-, and Alzheimer-related mutations is a matter of debate. As a result no adequate model of any neurodegenerative disease etiology exists. We demonstrate that two synergistic properties, namely, increased protein aggregation propensity (increased likelihood that an unfolded protein will aggregate) and decreased protein stability (increased likelihood that a protein will unfold), are central to ALS etiology. Taken together these properties account for 69% of the variability in mutant Cu/Zn-superoxide-dismutase-linked familial ALS patient survival times. Aggregation is a concentration-dependent process, and spinal cord motor neurons have higher concentrations of Cu/Zn-superoxide dismutase than the surrounding cells. Protein aggregation therefore is expected to contribute to the selective vulnerability of motor neurons in familial ALS.
authors.affiliation: Department of Chemistry, Brandeis University, Waltham, Massachusetts, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Johnson
authors.forename: Nathalie Y R
authors.initials: NY
authors.lastname: Agar
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Agar
mesh_terms: D000328:Adult; D000368:Aged; D000465:Algorithms; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology / Q000235:genetics*; D004795:Enzyme Stability; D005192:Family Health; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009154:Mutation; D011489:Protein Denaturation; D017510:Protein Folding; D012307:Risk Factors; D013482:Superoxide Dismutase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D013482:Superoxide Dismutase