Genotype-Property Patient-Phenotype Relations Suggest that Proteome Exhaustion Can Cause Amyotrophic Lateral Sclerosis

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Late-onset neurodegenerative diseases remain poorly understood as search continues for the perceived pathogenic protein species. Previously, variants in Superoxide Dismutase 1 (SOD1) causing Amyotrophic Lateral Sclerosis (ALS) were found to destabilize and reduce net charge, suggesting a pathogenic aggregation mechanism. This paper reports analysis of compiled patient data and experimental and computed protein properties for variants of human SOD1, a major risk factor of ALS. Both stability and reduced net charge correlate significantly with disease, with larger significance than previously observed. Using two independent methods and two data sets, a probability <3% (t-statistical test) is found that ALS-causing mutations share average stability with all possible 2907 SOD1 mutations. Most importantly, un-weighted patient survival times correlate strongly with the misfolded/unfolded protein copy number, expressed as an exponential function of the experimental stabilities (R-2 = 0.31, p = 0.002), and this phenotype is further aggravated by charge (R-2 = 0.51, p = 1.8 x 10-5). This finding suggests that disease relates to the copy number of misfolded proteins. Exhaustion of motor neurons due to expensive protein turnover of misfolded protein copies is consistent with the data but can further explain e. g. the expression-dependence of SOD1 pathogenicity, the lack of identification of a molecular toxic mode, elevated SOD1 mRNA levels in sporadic ALS, bioenergetic effects and increased resting energy expenditure in ALS patients, genetic risk factors affecting RNA metabolism, and recent findings that a SOD1 mutant becomes toxic when proteasome activity is recovered after washout of a proteasome inhibitor. Proteome exhaustion is also consistent with energy-producing mitochondria accumulating at the neuromuscular junctions where ALS often initiates. If true, this exhaustion mechanism implies a complete change of focus in treatment of ALS towards actively nursing the energy state and protein turnover of the motor neurons.
Original languageEnglish
Issue number3
Number of pages19
Publication statusPublished - 2015

Bibliographical note

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


  • Primates Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Humans, Mammals, Primates, Vertebrates) - Hominidae [86215] human common middle age female, male
  • Human SOD1 gene [Hominidae]
  • mRNA
  • Proteasome 140879-24-9 EC
  • RNA metabolism
  • SOD1 expression mutation
  • 02506, Cytology - Animal
  • 02508, Cytology - Human
  • 03502, Genetics - General
  • 03506, Genetics - Animal
  • 03508, Genetics - Human
  • 10062, Biochemistry studies - Nucleic acids, purines and pyrimidines
  • 10064, Biochemistry studies - Proteins, peptides and amino acids
  • 10802, Enzymes - General and comparative studies: coenzymes
  • 12502, Pathology - General
  • 17506, Muscle - Pathology
  • 20504, Nervous system - Physiology and biochemistry
  • 20506, Nervous system - Pathology
  • 34508, Immunology - Immunopathology, tissue immunology
  • Clinical Immunology
  • Molecular Genetics
  • Neurology
  • Amyotrophic lateral sclerosis Amyotrophic Lateral Sclerosis (MeSH) nervous system disease, muscle disease pathology
  • Genotype-property
  • Protein copy number
  • Proteome
  • Resting energy expendi- ture
  • Biochemistry and Molecular Biophysics
  • Human Medicine, Medical Sciences
  • Motor neuron nervous system
  • Neuromuscular junction nervous system
  • 2C9V Protein Data Bank amino acid sequence
  • Multidisciplinary
  • Human Superoxide-dismutase
  • Wild-type Sod1
  • Mutant Sod1
  • Stability changes
  • Motor-neurons
  • Mouse model
  • Mutations

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