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

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, Timothy M. Miller, Robert Bowser, Jonathan K. Watts, Leonard Petrucelli, Robert H. Brown, Mark W. Kankel () and Fen-Biao Gao ()
Additional contact information
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
Fen-Biao Gao: University of Massachusetts Chan Medical School

Nature Communications, 2022, vol. 13, issue 1, 1-8

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-30387-4

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