PhD Studentship: Arfaptin 2 as a therapeutic target for amyotrophic lateral sclerosis (ALS)

The cause of motor neuron (MN) degeneration is unknown in the majority of cases of ALS, although a number of pathogenic processes, including protein aggregation, mitochondrial dysfunction, oxidative stress, excitotoxicity and neurofilament dysfunction, are thought to play important roles in ALS. It has been reported that the capacity of the proteasome system to degrade proteins may be a limiting factor in the vulnerability of neurons to the degenerative process. Arfaptin-2, a downstream effector of ADP-ribosylation factors (ARFs), was identified as a novel protein as a target protein for GTP-ARFs and for GDP- Rac1. Humbert and colleagues showed that phosphorylation of Arfaptin-2 at Ser260 by Akt inhibits polyQ-huntingtin- induced toxicity by rescuing proteasome impairment (Rangone H et al, J Biol Chem 2005).

Our previous studies showed that Arfaptin 2 regulates the aggregation of mutant huntingtin protein and that a dominant inhibitory mutant of arfaptin 2 (HC-AIP2) inhibits aggregation of mutant huntingtin by activating and rescuing proteasome function (Peters PJ and Ning K et al, Nat Cell Biol, 2002). Our recent data also showed that overexpression of HC-AIP2 significantly increases cell survival in primary cultured SOD1 G93A motor neurons. Therefore, we hypothesize that arfaptin-2 plays a modulatory role in ALS and expression of a dominant inhibitory mutant of arfaptin-2 (HC-AIP2) would improve motor neuron survival via activation of proteasome activities in the sod1 and C9orf72 zebrafish model of ALS.

The specific aims are:

1. To investigate expression and distribution of arfaptin-2 in control and ALS Brains;
2. To assess whether depletion of arfaptin 2 affects disease pathogenesis in the sod1 and C9orf72 zebrafish model of ALS;
3. To study the effects of HC-AIP2 on motor neuron survival and lifespan in models of ALS.

The outcome of the above specific aims would gain valuble evidence that arfaptin 2 is a therapeutic target for ALS. The next logical step is to devolop preclincal and clinical treatment of gene therapy for ALS patients.

This is a high profile project to investigate arfaptin 2 as a neuro-protective target for ALS. Apart from molecular and cell biology, the student will receive training on how to handle zebrafish and assess behavioural analysis, histological analysis of pathology. The work described here will be achieved in the state-of- the-art Translational Neuroscience Laboratory under the supervision of Dr. Ke Ning (primary supervisor, http://sitran.org/people/ning/ ) and Dr Tennore Ramesh (secondary supervisor, http://sitran.org/people/ramesh/ ).

Funding Notes

We encourage excellent students to apply for a PhD studentship within the Department of Neuroscience at the University of Sheffield. The project involves a multidisciplinary approach to explore the role of Arfaptin 2 in motor neuron diseases, in particular Amyotrophic lateral sclerosis (ALS).
 

Eligibility Requirements

Candidates are expected to have a first or upper second class honours degree in Biological Sciences or a similar discipline. We offer our PhD students advanced, interdisciplinary training in neuroscience.