Genotype-property patient-phenotype relations suggest that proteome exhaustion can cause amyotrophic lateral sclerosis

PloS One
Kasper P Kepp

Abstract

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 (R2 = 0.31, p = 0.002), and this phenotype is further aggravated by charge (R2 = 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 misfold...Continue Reading

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Citations

Jan 13, 2016·Journal of Neurochemistry·Arun Kumar Somavarapu, Kasper P Kepp
Jul 28, 2016·British Medical Bulletin·Sarah Morgan, Richard W Orrell
Apr 9, 2017·Cellular and Molecular Life Sciences : CMLS·Pouria Dasmeh, Kasper P Kepp
Jul 7, 2020·Quarterly Reviews of Biophysics·Kasper P Kepp
Nov 3, 2016·Journal of Cell Science·Emma L BastowCampbell W Gourlay
Nov 22, 2019·Journal of Chemical Information and Modeling·Ning TangKasper P Kepp

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Methods Mentioned

BETA
transgenic

Software Mentioned

POPMUSIC
IMUTANT
MUTANT
POPMUSIC2

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