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Protein kinetics of superoxide dismutase-1 in familial and sporadic amyotrophic lateral sclerosis.
Ly, Cindy V; Ireland, Margaret D; Self, Wade K; Bollinger, James; Jockel-Balsarotti, Jennifer; Herzog, Hillary; Allred, Peggy; Miller, Leah; Doyle, Michael; Anez-Bruzual, Isabel; Trikamji, Bhavesh; Hyman, Ted; Kung, Tyler; Nicholson, Katherine; Bucelli, Robert C; Patterson, Bruce W; Bateman, Randall J; Miller, Timothy M.
Afiliação
  • Ly CV; Department of Neurology, Washington University, Saint Louis, Missouri, USA.
  • Ireland MD; Department of Neurology, Washington University, Saint Louis, Missouri, USA.
  • Self WK; Department of Neurology, Washington University, Saint Louis, Missouri, USA.
  • Bollinger J; Department of Neurology, Washington University, Saint Louis, Missouri, USA.
  • Jockel-Balsarotti J; Department of Neurology, Washington University, Saint Louis, Missouri, USA.
  • Herzog H; Department of Neurology, Washington University, Saint Louis, Missouri, USA.
  • Allred P; Department of Neurology, Washington University, Saint Louis, Missouri, USA.
  • Miller L; Sean M. Healey & AMG Center for ALS, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.
  • Doyle M; Sean M. Healey & AMG Center for ALS, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.
  • Anez-Bruzual I; Sean M. Healey & AMG Center for ALS, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.
  • Trikamji B; Department of Neurology, Washington University, Saint Louis, Missouri, USA.
  • Hyman T; Department of Neurology, Washington University, Saint Louis, Missouri, USA.
  • Kung T; Department of Neurology, Washington University, Saint Louis, Missouri, USA.
  • Nicholson K; Sean M. Healey & AMG Center for ALS, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.
  • Bucelli RC; Department of Neurology, Washington University, Saint Louis, Missouri, USA.
  • Patterson BW; Department of Medicine, Washington University, Saint Louis, Missouri, USA.
  • Bateman RJ; Department of Neurology, Washington University, Saint Louis, Missouri, USA.
  • Miller TM; Hope Center for Neurological Disorders, Washington University, Saint Louis, Missouri, USA.
Ann Clin Transl Neurol ; 10(6): 1012-1024, 2023 06.
Article em En | MEDLINE | ID: mdl-37119480
OBJECTIVE: Accumulation of misfolded superoxide dismutase-1 (SOD1) is a pathological hallmark of SOD1-related amyotrophic lateral sclerosis (ALS) and is observed in sporadic ALS where its role in pathogenesis is controversial. Understanding in vivo protein kinetics may clarify how SOD1 influences neurodegeneration and inform optimal dosing for therapies that lower SOD1 transcripts. METHODS: We employed stable isotope labeling paired with mass spectrometry to evaluate in vivo protein kinetics and concentration of soluble SOD1 in cerebrospinal fluid (CSF) of SOD1 mutation carriers, sporadic ALS participants and controls. A deaminated SOD1 peptide, SDGPVKV, that correlates with protein stability was also measured. RESULTS: In participants with heterozygous SOD1A5V mutations, known to cause rapidly progressive ALS, mutant SOD1 protein exhibited ~twofold faster turnover and ~ 16-fold lower concentration compared to wild-type SOD1 protein. SDGPVKV levels were increased in SOD1A5V carriers relative to controls. Thus, SOD1 mutations impact protein kinetics and stability. We applied this approach to sporadic ALS participants and found that SOD1 turnover, concentration, and SDGPVKV levels are not significantly different compared to controls. INTERPRETATION: These results highlight the ability of stable isotope labeling approaches and peptide deamidation to discern the influence of disease mutations on protein kinetics and stability and support implementation of this method to optimize clinical trial design of gene and molecular therapies for neurological disorders. TRIAL REGISTRATION: Clinicaltrials.gov: NCT03449212.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Esclerose Lateral Amiotrófica Idioma: En Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Esclerose Lateral Amiotrófica Idioma: En Ano de publicação: 2023 Tipo de documento: Article