Research

Amyotrophic lateral sclerosis (ALS) is a debilitating and fatal degenerative disorder of motor neurones in human, which is manifested by progressive muscle weakness, wasting and spasticity. It causes the death of over 100,000 individuals worldwide every year, mainly striking in mid-life (50s - 60s) and killing within 1-5 years following diagnosis. There is no cure for ALS. About 10% of all cases are familial, mostly with a dominant pattern of inheritance. Mutations in Cu/Zn superoxide dismutase 1 (SOD1) have been found to account for 20-25% of familial ALS cases, and mutations in TAR DNA-binding protein 43 (TDP-43) and fused in sarcoma/translated in liposarcoma (FUS/TLS) have been identified in both familial and sporadic cases of ALS. Evidence suggests that defects in axonal transport play an important role in neurodegeneration and we have shown that retrograde axonal transport defects exist in motor neurones of the SOD1G93A transgenic mouse model for ALS even in the embryonic stages of development [Kieran et al., J. Cell Biol., 2005]. In addition, in the Legs at odd angles (Loa) mouse, we have identified a point mutation in cytoplasmic dynein, which causes motor neurone degeneration in homozygous mice as a result of impaired dynein-dynactin interaction and consequently impaired retrograde axonal transport [Deng et al, J. Biol. Chem., 2010; Hafezparast et al, Science, 2003]. Our research is currently focused on elucidating (1) the molecular mechanisms of motor neurone degeneration caused by impaired dynein-dynactin interactions in Loa mouse; (2) the effects of the Loa mutation on receptor tyrosine kinase signalling and trafficking `signalling endosomes¿ in motor neurones; (3) the link between Loa mutation and the unexpected protection of the mitochondria from toxic mutant SOD1G93A [El-Kadi et al, J. Biol. Chem., 2010]; (4) the roles of TDP-43 and FUS/TLS in transcription, RNA splicing, and DNA repair in motor neurones.

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The Hafezparast Lab

Neurodegenerative Disease and Ageing Research Centre