SUPR
Identification of protein biomarkers for C9ORF72 in ALD and FTD patients
Dnr:

sens2021513

Type:

SNIC SENS

Principal Investigator:

Fang Fang

Affiliation:

Karolinska Institutet

Start Date:

2021-02-22

End Date:

2025-05-01

Primary Classification:

20602: Medical Materials

Webpage:

Allocation

Abstract

Background: A repeat expansion in the C9orf72 gene is associated with both ALS and FTD. ALS is characterised by muscle weakness due to loss of motor neurons in the spinal cord and other sites whereas FTD is characterized by behavioural abnormalities, likely due to degeneration of cortical neurons in the frontal and temporal lobe. The phenotypic variability is high in both ALS and FTD. The ‘GGGGCC’ hexanucleotide repeat expansion within intron 1 in the C9orf72 gene is the most common mutation in both familial and sporadic forms of ALS/FTD although the exact mechanism by which the C9ORF72 repeat expansions (RE) contribute to disease risk is still not fully elucidated. The main pathological mechanisms proposed include a) a negative effect on gene transcription leading to reduction of C9orf72 protein levels, b) an effect on sense and antisense folding of RNA structures causing binding of RNA-regulating proteins and c) translation of repeat-associated transcripts into toxic dipeptide repeat proteins. An important step on the way towards therapeutics development for C9ORF72-associated ALS and FTD is identification of downstream biomarkers, which may both reveal disease-biology as well as be of clinical use in trials. Aim: To identify CSF and plasma biomarkers for C9ORF72-associated ALS and FTD Study cohorts: Plasma samples were collected from a total of 495 ALS cases and controls of which a subset of patients and controls carried C9ORF72 REs. In addition, CSF samples were collected from 303 ALS patients with/without C9ORF72 REs and from 201 symptomatic and pre-symptomatic FTD patients with C9ORF72 REs of familial variants in GRN, TBK1 and MAPT. Some ALS patients also have longitudinal samples. Methods: A total of 368 circulating proteins on the Olink PEA NEU-I, NEU-expl, CVD-III and inflammation panels were measured in both CSF and plasma. Samples were randomised across plates and a pooled CSF plasma sample was included on all plates. Genome-wide genotyping was performed using the Illumina GSA-MDA v2. Array, which captures 650,000 SNPs and indels across the genome plus 60,000 variants selected from ClinVar. The total number of variants is 694,945.