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Hypothalamic and other brain dysfunction by expression of C9orf72 hexanucleotide expansion in a transgenic zebrafish model of Motor neurone disease/Frontotemporal dementia (MND/FTD)

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  • Full or part time
    Dr Tennore Ramesh
    Prof Marysia Placzek
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Neurodegenerative disorders such as ALS, AD/FTD and Parkinson’s disease (PD) include other CNS changes in addition to the degeneration of motor systems and the cortex. One of the common systems affected in many of these patients is the sleep/wake cycle. Despite these observations, relatively little is known on the causal reasons for circadian pathology. Artificially induced sleep/wake disturbances in the sod1G93A mouse model accelerates disease onset and aggravated neuronal loss and glial activation in this model.

Recently, mutation in the C9orf72 gene was identified as a cause of ALS/FTD in human patients. This mutation show varying phenotype ranging from ALS to the FTD symptoms. The mutation results in the expansion of the hexanucleotide repeat GGGGCC (HRE) in the intronic region of the C9orf72 gene. C9orf72 function is not well understood, but recent data suggest that the protein play an important role in autophagy. Three potential mechanisms of toxicity is thought to lead to neurodegeneration and/or neuronal dysfunction. The loss of C9orf72 by methylation of the HRE, the gain of function toxicity by nuclear HRE RNA and the synthesis of dipeptide repeat proteins (DPR) such as GA,GR,GP,PA and PR through a non-canonical protein translation, also called as the repeat associated non-AUG (RAN) translation. Current data from studies in drosophila and in vitro cell models suggest that DPRs may drive a dominant portion of the cellular toxicity.

A recent paper by Dedeene et. al, 2019 demonstrated significant DPR accumulation in the hypothalamic region in nuclei involved in modulating the circadian rhythm. Strong DPR expression was observed in the pineal gland and suprachiasmatic nucleus (SCN) but none in other parts of the hypothalamus uninvolved in the circadian rhythm (neuro endocrine cells of the supraoptic nucleus:SON and the paraventricular nucleus:PVN). However, it is unclear whether this pathology drives the alteration in the circadian rhythm.

Zebrafish are excellent model systems to study vertebrate CNS function and pathology. We recently developed a zebrafish model of C9orf72 mutation and these zebrafish show all of the classical pathology and behavioural changes observed in human ALS[5]. These zebrafish show molecular pathology of RNA foci, DPR expression, muscle atrophy and age dependent locomotor dysfunction. Preliminary data in zebrafish larvae suggest a circadian rhythm dependent differences in the locomotor function between the zebrafish larvae carrying G4C2 expansion Vs the C4G2 expansion. The toxicity of individual DPRs is still unclear.

Funding Notes

RCUK equivalent home stipend rate per annum for 3.5 years
Home tuition fees for 3.5 years*
£6500 for consumables
* Overseas students may apply but need to fund the difference in tuition fees between the home and overseas rate.
A first class or upper second class honours degree in a biological sciences subject or a related discipline, or a merit or distinction in a suitable MSc. Experience working in a research laboratory is desirable.
You should be applying to start on a full-time or part-time PhD in October 2020.

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