We report an apparently sporadic amyotrophic lateral sclerosis patient carrying a heterozygous novel frameshift SOD1 mutation (p.Ser108LeufsTer15), predicted to cause a premature protein truncation. RT-PCR analysis of SOD1 mRNA and SDS-PAGE/Western blot analysis of PBMC demonstrated that mRNA from the mutant allele is expressed at levels similar to those of the wild-type allele, but the truncated protein is undetectable also in the insoluble fraction and after proteasome inhibition. Accordingly, the dismutation activity in erythrocytes is halved. Thus, the pathogenic mechanism associated with this mutation might be based on an insufficient activity of SOD1 that would make motor neurons more vulnerable to oxidative injury. However, it cannot be excluded that p.Ser108LeufsTer15 SOD1 is present in the nervous tissue and, being less charged and hence having less repulsive forces than the wild-type protein, may trigger toxic mechanisms as a consequence of its propensity to aggregate.

A novel p.Ser108LeufsTer15 SOD1 mutation leading to the formation of a premature stop codon in an apparently sporadic ALS patient: insights into the underlying pathomechanisms

Canosa A.;De Marco G.;Lomartire A.;Rinaudo M. T.;Di Cunto F.;Turco E.;Barberis M.;Brunetti M.;Casale F.;Moglia C.;Calvo A.;Chio A.
2018-01-01

Abstract

We report an apparently sporadic amyotrophic lateral sclerosis patient carrying a heterozygous novel frameshift SOD1 mutation (p.Ser108LeufsTer15), predicted to cause a premature protein truncation. RT-PCR analysis of SOD1 mRNA and SDS-PAGE/Western blot analysis of PBMC demonstrated that mRNA from the mutant allele is expressed at levels similar to those of the wild-type allele, but the truncated protein is undetectable also in the insoluble fraction and after proteasome inhibition. Accordingly, the dismutation activity in erythrocytes is halved. Thus, the pathogenic mechanism associated with this mutation might be based on an insufficient activity of SOD1 that would make motor neurons more vulnerable to oxidative injury. However, it cannot be excluded that p.Ser108LeufsTer15 SOD1 is present in the nervous tissue and, being less charged and hence having less repulsive forces than the wild-type protein, may trigger toxic mechanisms as a consequence of its propensity to aggregate.
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189
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www.elsevier.com/locate/neuaging
Amyotrophic lateral sclerosis; Frameshift mutation; Oxidative stress; Protein aggregation; SOD1; Truncated protein; Aged; Amyotrophic Lateral Sclerosis; Female; Frameshift Mutation; Humans; Superoxide Dismutase-1
Canosa A.; De Marco G.; Lomartire A.; Rinaudo M.T.; Di Cunto F.; Turco E.; Barberis M.; Brunetti M.; Casale F.; Moglia C.; Calvo A.; Marklund S.L.; Andersen P.M.; Mora G.; Chio A.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1720183
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