Macquarie University
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Gene expression profiling of peripheral blood in sporadic and C9orf72-associated amyotrophic lateral sclerosis

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posted on 2022-03-29, 02:28 authored by Owen T. Watson
Amyotrophic lateral sclerosis (ALS) is a fatal neuro-degenerative disease characterised by the progressive loss of motor neurons. Progressive paralysis leads to death within 2-5 years of symptom onset. Currently there is no effective treatment for ALS as there is a lack of understanding regarding the cellular mechanisms of disease pathogenesis and progression. Approximately 10% of ALS patients have a family history of ALS (fALS), 90% of cases occur sporadically (sALS) and have an unknown disease aetiology. Causal ALS gene mutations only account for a small proportion of cases. Two individual projects were completed as part of this study. The first project sought to elucidate the altered molecular pathways that occur in ALS using unbiased transcriptome-wide analysis of a blood-derived RNA-Seq dataset, comprising 95 sALS patients and 69 controls. There was differential expression of 1,151 between sALS cases and controls. Functional analysis identified up-regulation of antiviral pathways in early-onset sALS. Targeted analysis found that three ALS-associated genes were significantly differentially expressed in sALS. Statistical analysis of clinical traits amongst sALS cases, uncovered that early-onset cases had slower disease progression than late-onset cases (p<0.001). The finding that antiviral activation occurs in asubset of sALS cases indicates that gene expression profiling of peripheral blood samples from large sALS cohorts will be essential for understanding disease pathogenesis and directing the targeted development of therapeutics for ALS. The second project sought to determine if expression of mRNA transcripts is altered in carriers of the ALS gene, C9orf72, compared to non-carriers. A hexanucleotide repeat expansion in the C9orf72 gene is the most frequent ALS-associated gene mutation. Haploinsufficiency of C9orf72, due to presence of the repeat expansion, may be a mechanism of pathogenesis. A previous (unpublished) DNA methylation study, within our group, has identified that the upstream C9orf72 promoter is significantly more methylated in carriers of the C9orf72 pathogenic repeat compared to non-carriers. RT-qPCR was conducted to determine the relative abundance of C9orf72 mRNA transcripts between carriers of the C9orf72 expansion (n=11) and age/sex matched controls (n=11). C9orf72 transcript 1 (NM 145005) was significantly reduced in C9orf72 repeat carriers compared to controls.


Table of Contents

1. Introduction -- 2. Subjects and materials-- 3. Methods -- 4. Results -- 5. Discussion -- Appendix -- List of symbols -- References.


Empirical thesis. Bibliography: pages 161-189

Awarding Institution

Macquarie University

Degree Type

Thesis MRes


MRes, Macquarie University, Faculty of Medicine and Health Sciences, Department of Biomedical Sciences

Department, Centre or School

Department of Biomedical Sciences

Year of Award


Principal Supervisor

Kelly Williams

Additional Supervisor 1

Ian Blair


Copyright Owen T. Watson 2019. Copyright disclaimer:




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