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Poly(GR) and poly(GA) in cerebrospinal fluid as potential biomarkers for C9ORF72-ALS/FTD

Author

Listed:
  • Gopinath Krishnan

    (University of Massachusetts Chan Medical School)

  • Denitza Raitcheva

    (Biomarkers, Clinical Sciences Biogen)

  • Daniel Bartlett

    (Biomarkers, Clinical Sciences Biogen)

  • Mercedes Prudencio

    (Mayo Clinic)

  • Diane M. McKenna-Yasek

    (University of Massachusetts Chan Medical School)

  • Catherine Douthwright

    (University of Massachusetts Chan Medical School)

  • Björn E. Oskarsson

    (Mayo Clinic)

  • Shafeeq Ladha

    (St. Joseph’s Hospital and Medical Center and Barrow Neurological Institute)

  • Oliver D. King

    (University of Massachusetts Chan Medical School)

  • Sami J. Barmada

    (University of Michigan, 4005 BSRB)

  • Timothy M. Miller

    (Washington University)

  • Robert Bowser

    (St. Joseph’s Hospital and Medical Center and Barrow Neurological Institute)

  • Jonathan K. Watts

    (UMass Chan Medical School)

  • Leonard Petrucelli

    (Mayo Clinic)

  • Robert H. Brown

    (University of Massachusetts Chan Medical School)

  • Mark W. Kankel

    (Neuromuscular & Movement Disorders, Biogen
    Apple Tree Partners (ATP) Research Labs)

  • Fen-Biao Gao

    (University of Massachusetts Chan Medical School)

Abstract

GGGGCC repeat expansion in C9ORF72, which can be translated in both sense and antisense directions into five dipeptide repeat (DPR) proteins, including poly(GP), poly(GR), and poly(GA), is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we developed sensitive assays that can detect poly(GA) and poly(GR) in the cerebrospinal fluid (CSF) of patients with C9ORF72 mutations. CSF poly(GA) and poly(GR) levels did not correlate with age at disease onset, disease duration, or rate of decline of ALS Functional Rating Scale, and the average levels of these DPR proteins were similar in symptomatic and pre-symptomatic patients with C9ORF72 mutations. However, in a patient with C9ORF72-ALS who was treated with antisense oligonucleotide (ASO) targeting the aberrant C9ORF72 transcript, CSF poly(GA) and poly(GR) levels decreased approximately 50% within 6 weeks, indicating they may serve as sensitive fluid-based biomarkers in studies directed against the production of GGGGCC repeat RNAs or DPR proteins.

Suggested Citation

  • Gopinath Krishnan & Denitza Raitcheva & Daniel Bartlett & Mercedes Prudencio & Diane M. McKenna-Yasek & Catherine Douthwright & Björn E. Oskarsson & Shafeeq Ladha & Oliver D. King & Sami J. Barmada & , 2022. "Poly(GR) and poly(GA) in cerebrospinal fluid as potential biomarkers for C9ORF72-ALS/FTD," Nature Communications, Nature, vol. 13(1), pages 1-8, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30387-4
    DOI: 10.1038/s41467-022-30387-4
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