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

Gopinath Krishnan, Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Denitza Raitcheva, Biomarkers, Clinical Sciences Biogen, Cambridge, MA, 02142, USA.
Daniel Bartlett, Biomarkers, Clinical Sciences Biogen, Cambridge, MA, 02142, USA.
Mercedes Prudencio, Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
Diane M. McKenna-Yasek, Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Catherine Douthwright, Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Björn E. Oskarsson, Department of Neurology, Mayo Clinic, Jacksonville, FL, 32224, USA.
Shafeeq Ladha, Departments of Neurology and Translational Neuroscience, St. Joseph's Hospital and Medical Center and Barrow Neurological Institute, 350W Thomas Road, Phoenix, AZ, 85013, USA.Follow
Oliver D. King, Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Sami J. Barmada, Department of Neurology, University of Michigan, 4005 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI, 48109-2200, USA.
Timothy M. Miller, Department of Neurology, Washington University, Saint Louis, MI, 63110, USA.
Robert Bowser, Departments of Neurology and Translational Neuroscience, St. Joseph's Hospital and Medical Center and Barrow Neurological Institute, 350W Thomas Road, Phoenix, AZ, 85013, USA.Follow
Jonathan K. Watts, RNA Therapeutics Institute and Department of Biochemistry and Molecular Pharmacology, UMass Chan Medical School, Worcester, MA, 01605, USA.
Leonard Petrucelli, Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
Robert H. Brown, Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Mark W. Kankel, Neuromuscular & Movement Disorders, Biogen, Cambridge, MA, 02142, USA. mkankel@atpresearchlabs.com.
Fen-Biao Gao, Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA. fen-biao.gao@umassmed.edu.

Document Type

Article

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.

Medical Subject Headings

Amyotrophic Lateral Sclerosis (genetics, metabolism); Biomarkers; C9orf72 Protein (genetics, metabolism); Dipeptides (metabolism); Frontotemporal Dementia (genetics, metabolism); Humans; Proteins

Publication Date

5-19-2022

Publication Title

Nature communications

E-ISSN

2041-1723

Volume

13

Issue

1

First Page

2799

PubMed ID

35589711

Digital Object Identifier (DOI)

10.1038/s41467-022-30387-4

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