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

• DOI: 10.1038/s41467-022-30387-4
• Publication Date: 2022-05-19T10:04:29Z
• Authors: Gopinath Krishnan; Denitza Raitcheva; Daniel Bartlett; Mercedes Prudencio; Diane M. McKenna-...; Catherine Douthwr...; 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; Fen-Biao Gao
• Keywords: 0303 health sciences; C9orf72 Protein; Science; Q; Amyotrophic Lateral Sclerosis; 500; Proteins; Dipeptides; Amyotrophic lateral sclerosis; Predictive markers; Article; 3. Good health; 03 medical and health sciences; Frontotemporal Dementia; Medicine and Health Sciences; Humans; Biomarkers

AbstractGGGGCC repeat expansion inC9ORF72, 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 withC9ORF72mutations. 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 withC9ORF72mutations. However, in a patient withC9ORF72-ALS who was treated with antisense oligonucleotide (ASO) targeting the aberrantC9ORF72transcript, 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.