dnj-14: a new C. elegans model for neurodegenerative diseases


Kashyap, Sudhanva dnj-14: a new C. elegans model for neurodegenerative diseases. PhD thesis, University of Liverpool.

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Abstract

Human neurodegenerative diseases are becoming an increasing burden on society as populations age. However, the underlying mechanisms that cause age-dependent neurodegeneration still remain unclear. Consequently, therapies for these debilitating and eventually fatal disorders are lacking. Simple model organisms have great potential for uncovering conserved mechanisms of neurodegeneration and thus for identifying neuroprotective drugs. In this study we describe a new C. elegans model of age-dependent neurodegeneration caused by mutation of the dnj-14 gene. DNJ-14 is the worm homologue of cysteine string protein (CSP), a neuronal chaperone protein that prevents the misfolding of presynaptic proteins. Previously it has been shown that CSP knockout mice have a short lifespan and exhibit progressive age-related neurotransmission defects, sensorimotor dysfunction and pre-synaptic neurodegeneration. We show in this study that mutations in C. elegans dnj-14 also result in a significant reduction of lifespan. In addition, dnj-14 mutants exhibit age-dependent reductions in locomotion and sensitivity to aldicarb - a behavioural read-out of cholinergic neurotransmission. The above phenotypes correlate to an age-dependent loss of neurons as indicated by the punctate/abnormal expression of the GFP marker in dnj-14 worms. This loss of neurons in the head region corresponds with a reduced ability of the dnj-14 mutants to reach a food source or a volatile attractant indicating the loss of chemosensory neurons. Treatment with resveratrol, a polyphenol with a neuroprotective role in several neurodegenerative disease models, rescues the phenotypes of the dnj-14 mutant worms. This suggests that the dnj-14 model can be used to identify generic neuroprotective interventions rather than drug targets that are disease specific. CSP is thought to prevent neurodegeneration by chaperoning the synaptic SNARE protein, SNAP-25. In this study we have shown that the mutation of ric-4, worm SNAP-25 homologue, produced phenotypes similar to those seen in dnj-14 mutants, suggesting a functional interaction between the two presynaptic proteins. The dnj-14;ric-4 double mutant showed no further deterioration of lifespan and locomotion phenotype. This suggested genetic epistasis in C. elegans similar to CSP knock out mice. Moreover, treatment with resveratrol rescued the lifespan phenotype of the ric-4 worms and also the ric-4;dnj-14 double mutant. Overexpression of ric-4 in dnj-14 mutants rescued the lifespan and chemosensory defects as seen in the food race assays. This further suggests that the dnj-14 model is similar to the CSP knock out model in mice. More importantly, mutations in CSP cause Adult-onset Neuronal Ceroid Lipofuscinosis (ANCL), a human neurodegenerative disease. Hence, characterisation of dnj-14 mutants could well act as a model to study ANCL.

Item Type: Thesis (PhD)
Additional Information: Date: 2013-12 (completed)
Subjects: ?? QP ??
Depositing User: Symplectic Admin
Date Deposited: 09 Mar 2015 13:21
Last Modified: 16 Dec 2022 04:42
DOI: 10.17638/00017393
Supervisors:
URI: https://livrepository.liverpool.ac.uk/id/eprint/17393
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