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; Fen Biao Gao

doi:10.1038/s41467-022-30387-4

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, Fen Biao Gao

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	2799
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-30387-4
State	Published - Dec 2022

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Krishnan, G., Raitcheva, D., Bartlett, D., Prudencio, M., McKenna-Yasek, D. M., Douthwright, C., Oskarsson, B. E., Ladha, S., King, O. D., Barmada, S. J., Miller, T. M., Bowser, R., Watts, J. K., Petrucelli, L., Brown, R. H., Kankel, M. W., & Gao, F. B. (2022). Poly(GR) and poly(GA) in cerebrospinal fluid as potential biomarkers for C9ORF72-ALS/FTD. Nature communications, 13(1), Article 2799. https://doi.org/10.1038/s41467-022-30387-4

Krishnan, G, Raitcheva, D, Bartlett, D, Prudencio, M, McKenna-Yasek, DM, Douthwright, C, Oskarsson, BE, Ladha, S, King, OD, Barmada, SJ, Miller, TM, Bowser, R, Watts, JK, Petrucelli, L, Brown, RH, Kankel, MW & Gao, FB 2022, 'Poly(GR) and poly(GA) in cerebrospinal fluid as potential biomarkers for C9ORF72-ALS/FTD', Nature communications, vol. 13, no. 1, 2799. https://doi.org/10.1038/s41467-022-30387-4

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

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.",

author = "Gopinath Krishnan and Denitza Raitcheva and Daniel Bartlett and Mercedes Prudencio and McKenna-Yasek, {Diane M.} and Catherine Douthwright and Oskarsson, {Bj{\"o}rn E.} and Shafeeq Ladha and King, {Oliver D.} and Barmada, {Sami J.} and Miller, {Timothy M.} and Robert Bowser and Watts, {Jonathan K.} and Leonard Petrucelli and Brown, {Robert H.} and Kankel, {Mark W.} and Gao, {Fen Biao}",

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AU - Krishnan, Gopinath

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AU - Bartlett, Daniel

AU - Prudencio, Mercedes

AU - McKenna-Yasek, Diane M.

AU - Douthwright, Catherine

AU - Oskarsson, Björn E.

AU - Ladha, Shafeeq

AU - King, Oliver D.

AU - Barmada, Sami J.

AU - Miller, Timothy M.

AU - Bowser, Robert

AU - Watts, Jonathan K.

AU - Petrucelli, Leonard

AU - Brown, Robert H.

AU - Kankel, Mark W.

AU - Gao, Fen Biao

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

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

Abstract

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