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The mechanism of the C9ORF72 repeat expansion pathology in Amyotrophic Lateral Sclerosis and Frontotemporal dementia

Hildering, A.A. (2017) The mechanism of the C9ORF72 repeat expansion pathology in Amyotrophic Lateral Sclerosis and Frontotemporal dementia. Bachelor's Thesis, Biology.

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Abstract

Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal dementia (FTD) are progressive neurodegenerative diseases and the exact causes are still unknown. The most common mutation in both ALS and FTD is an extended repeat in a non-coding area of the C9ORF72 gene. Here we discuss three mayor theories regarding the mechanism of this pathology. Loss of function, RNA toxicity and repeat associated non-AUG (RAN) translation. A loss of function mechanism seems unlikely since there are no definitive clues that C9ORF72 protein levels are reduced and the phenotype of C9ORF72 knock-out models is significantly different from the pathology seen in patients. RNA molecules transcribed from the repeat expansion form RNA foci in effected cells. These RNA foci attract DNA and RNA binding proteins, possibly depleting their presence in the cytosol. RAN translation does occur in C9ORF72 linked ALS and FTD and the translated product forms aggregates. These aggregates reduce the activity of proteins involved in nuclear transport. In summary, both RNA toxicity and RAN translation are likely to contribute to the pathological phenotype of C9ORF72 linked ALS and FTD.

Item Type: Thesis (Bachelor's Thesis)
Degree programme: Biology
Thesis type: Bachelor's Thesis
Language: English
Date Deposited: 15 Feb 2018 08:29
Last Modified: 15 Feb 2018 08:29
URI: http://fse.studenttheses.ub.rug.nl/id/eprint/15303

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