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

University of Sheffield - Neuroscience Department

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 amyotrophic lateral sclerosis (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. Our previous studies showed that Arfaptin 2 regulates the aggregation of mutant huntingtin protein (Nature Cell Biology 2002). A dominant inhibitory mutant of arfaptin 2 (HC-AIP2) inhibits aggregation of mutant huntingtin by impairing proteasome function. Our recent data also showed that overexpression of HC-AIP2 significantly increases cell survival in NSC34 SOD1 G93A and primary cultured SOD1 G93A motor neurons. Therefore, we hypothesis that HC-AIP2 would improve motor neuron survival in ALS. In order to elucidate arfaptin 2 as a therapeutic target for ALS, we propose to further investigate the involvement of arfaptin 2 in post-mortem brain tissues, in ALS iPS-derived motor neurons and in mouse models of ALS.

The Faculty of Medicine, Dentistry & Health Doctoral Academy Scholarships cover Home/EU fee and RCUK rate stipend for three years. Overseas students may apply but will need to fund the difference between the Home and Overseas fee from another source.

Proposed start date: October 2017

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Northern England