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An improved C. elegans model of Alzheimer’s Disease to monitor neuronal signalling activity

Project Description

Alzheimer’s Disease (AD) is one of the most common form of neurodegenerative diseases known today, affecting approximately 50 million people worldwide. The pathogenic mechanism is characterised by the formation of toxic Abeta oligomeric species and aggregates, that disrupt neuronal function. One of the neuronal cell types most affected by Abeta are glutamatergic neurons, which are required to receive and transmit sensory signals. For example, loss of the sense of smell (olfactory dysfunction) is one of the earliest symptoms of AD in humans. Similarly, in C. elegans, chemosensory deficits in behaviour mediated via glutamatergic neurons, occurs in already young animals expressing Abeta in the nervous system. We however do not know which glutamatergic neuronal subtype loses its signalling activity first as a consequence of Abeta-associated toxicity during AD progression and how neuronal function can be protected.

Using a C. elegans model of AD, we have shown that increased expression of the molecular chaperone Hsp90 in the C. elegans nervous system has two effects. Firstly, Hsp90 cell-autonomously protects neurons against the toxic effects of neuronally expressed Abeta(1-42) by suppressing the chemosensory behavioural deficit. Secondly, it cell-non-autonomously activates Hsp90 expression in other cell types via transcellular chaperone signalling (TCS), and so suppresses the formation of Abeta aggregates in distal cells. We found that neuron-induced TCS depends on glutamatergic neurotransmission (O’Brien et al., Cell Reports 2018). This is interesting, because Hsp90 is also known to regulate glutamate receptor function and neurotransmitter release. What we don’t know is whether this regulatory role of Hsp90 also extends to AD, by safeguarding glutamatergic neuronal signalling function during AD progression; and whether TCS can be harnessed to induce protective Hsp90 from one glutamatergic neuronal cell type to another.

We now want to determine which neuronal circuit succumbs first to Abeta expression during AD progression and how Hsp90 protects glutamatergic neuronal function. Therefore, we will establish an improved C. elegans model of Abeta-associated Alzheimer’s Disease (AD) that allows to monitor neuronal signalling activity throughout aging and progression of the disease; using a calcium reporter in combination with a glutamate sensor. The reporter would allow to determine when neuronal signalling activity declines, which neuronal subtypes are affected first and whether protective molecules (such as chaperones and pharmacological compounds) safeguard neuronal signaling activity. Identification of the exact neuronal subtype affected by Abeta expression and how Hsp90 preserves signalling function will provide novel insights into how AD develops. This will facilitate the development of new treatment options that can be applied early in the disease process to delay or even prevent further progression of the disease.
The improved C. elegans AD reporter will replace mouse neurodegenerative disease models such as AD, to investigate the protective effects of chaperones and pharmacological compounds at the level of neuronal signalling activity and correlated to behavioural output.

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Funding Notes

Fully funded PhD studentship with NC3Rs. Studentship covers UK/EU fees and stipend (c.£15,009) for 3 years to start in Oct 2020. Applicants should have/be expecting at least a 2.1 Hons. degree in a relevant subject. EU candidates require 3 years of UK residency in order to receive full studentship. Please apply online View Website and include CV and transcripts.


O’Brien, D., Jones, L., Good, S., Miles, J., Aston, R., Smith, C., Vijayabaskar, S., Westhead, D., and van Oosten-Hawle, P. (2018) A PQM-1-mediated response mediates transcellular chaperone signaling and organismal proteostasis. Cell Reports. 2018 Jun 26;23(13):3905-3919

Miles, J., Scherz-Shouval R., and van Oosten-Hawle, P. (2019) Expanding the organismal proteostasis network: Linking systemic stress signalling with the innate immune response. Trends in Biochemical Sciences, 2019 Jul 11. pii: S0968-0004(19)30142-2

van Oosten-Hawle, P., Porter, R.S., and Morimoto, R. I. (2013). Regulation of organismal proteostasis by transcellular chaperone signaling. Cell 153, 1366-1378

How good is research at University of Leeds in Biological Sciences?

FTE Category A staff submitted: 60.90

Research output data provided by the Research Excellence Framework (REF)

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