Distinctive features of the D101N and D101G variants of superoxide dismutase 1; Two mutations that produce rapidly progressing motor neuron disease

Jacob Ayers, Herman Lelie, Aron Workman, Mercedes Prudencio, Hilda Brown, Susan Fromholt, Joan Valentine, Julian Whitelegge, David Borchelt

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Mutations in superoxide dismutase 1 (SOD1) associated with familial amyotrophic lateral sclerosis induce misfolding and aggregation of the protein with the inherent propensity of mutant SOD1 to aggregate generally correlating, with a few exceptions, to the duration of illness in patients with the same mutation. One notable exception was the D101N variant, which has been described as wild-type-like. The D101N mutation is associated with rapidly progressing motor neuron degeneration but shows a low propensity to aggregate. By assaying the kinetics of aggregation in a well-characterized cultured cell model, we show that the D101N mutant is slower to initiate aggregation than the D101G mutant. In this cell system of protein over-expression, both mutants were equally less able to acquire Zn than WT SOD1. In addition, both of these mutants were equivalently less able to fold into the trypsin-resistant conformation that characterizes WT SOD1. A second major difference between the two mutants was that the D101N variant more efficiently formed a normal intramolecular disulfide bond. Overall, our findings demonstrate that the D101N and D101G variants exhibit clearly distinctive features, including a different rate of aggregation, and yet both are associated with rapidly progressing disease. We sought to better characterize the biochemical features of two SOD1 mutants associated with rapidly progressing disease, the D101G and wild-type like D101N mutants. We observed using our cell model that that although similarities were observed when comparing the ability to bind metals and resist trypsin digestion, these mutants differed in their ability to initiate aggregation and to form the normal intramolecular disulfide bond. We conclude that these mutants exhibit distinct properties despite producing similar disease phenotypes in patients. We sought to better characterize the biochemical features of two SOD1 mutants associated with rapidly progressing disease, the D101G and wild-type like D101N mutants. We observed using our cell model that that although similarities were observed when comparing the ability to bind metals and resist trypsin digestion, these mutants differed in their ability to initiate aggregation and to form the normal intramolecular disulfide bond. We conclude that these mutants exhibit distinct properties despite producing similar disease phenotypes in patients.

Original languageEnglish (US)
Pages (from-to)305-314
Number of pages10
JournalJournal of Neurochemistry
Volume128
Issue number2
DOIs
StatePublished - Jan 2014

Fingerprint

Motor Neuron Disease
Neurons
Superoxide Dismutase
Agglomeration
Mutation
Disulfides
Trypsin
Digestion
Metals
Phenotype
Nerve Degeneration
Motor Neurons
Conformations
Superoxide Dismutase-1
Cultured Cells
Proteins
Cells
Kinetics

Keywords

  • aggregation
  • ALS
  • oxidation
  • SOD1
  • stability

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Distinctive features of the D101N and D101G variants of superoxide dismutase 1; Two mutations that produce rapidly progressing motor neuron disease. / Ayers, Jacob; Lelie, Herman; Workman, Aron; Prudencio, Mercedes; Brown, Hilda; Fromholt, Susan; Valentine, Joan; Whitelegge, Julian; Borchelt, David.

In: Journal of Neurochemistry, Vol. 128, No. 2, 01.2014, p. 305-314.

Research output: Contribution to journalArticle

Ayers, Jacob ; Lelie, Herman ; Workman, Aron ; Prudencio, Mercedes ; Brown, Hilda ; Fromholt, Susan ; Valentine, Joan ; Whitelegge, Julian ; Borchelt, David. / Distinctive features of the D101N and D101G variants of superoxide dismutase 1; Two mutations that produce rapidly progressing motor neuron disease. In: Journal of Neurochemistry. 2014 ; Vol. 128, No. 2. pp. 305-314.
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