Protein Aggregation and Protein Instability Govern Familial Amyotrophic Lateral Sclerosis Patient Survival

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. : Amyotrophic lateral sclerosis (ALS), also known in America as Lou Gehrig's disease, is a fatal neurodegenerative disease with no effective treatment. Paralysis occurs as the result of the death of cells that connect the brain to various muscles, namely, the motor neurons of the brain and spinal cord. Ninety percent of ALS is sporadic and of unknown cause. A landmark discovery in ALS research was that mutations in the gene coding for Cu/Zn-superoxide dismutase cause at least 2% of ALS, and researchers have since discovered at least 119 such mutations. Neurologists also discovered that different mutations have remarkably different prognoses. For example, patients with the A4V mutation survive an average of 1 year after diagnosis, whereas patients with the H46R mutation survive an average of 18 years. Biochemists discovered that different mutations result in remarkably different physical properties, for example, stability of Cu/Zn-superoxide dismutase. In this article we apply an algorithm that predicts how fast a given Cu/Zn-superoxide dismutase will aggregate (stick to other proteins) and demonstrate that faster aggregation relates to faster death of ALS patients. We also demonstrate that loss of Cu/Zn-superoxide dismutase stability relates to faster ALS patient death. Our findings imply that aggregation of unfolded SOD1 is toxic for ALS patients, and in fact accounts for 69% of the variability in mutant Cu/Zn-superoxide-dismutase-linked familial ALS patient survival times. Increased protein aggregation and decreased protein stability are shown to be central to familial amyotrophic lateral sclerosis etiology.