Project Title: In vivo investigations of mitochondrial dynamics in genetic models of ALS

Supervisor: Dr Alex Whitworth and Dr Andrew Grierson

Project Description:

Amyotrophic lateral sclerosis (ALS) is still incurable, partly due to our lack of understanding of the mechanisms that lead to neuronal death. Insight into the pathogenic mechanisms has been greatly boosted recently by the identification of additional genes linked to rare inherited forms of ALS such as TARDBP, FUS and VCP. Moreover, the discovery that TDP-43 (encoded by TARDBP) is a key component of inclusions seen in sporadic forms of ALS (and other disorders) suggests it plays a central role in pathogenesis, but the mechanisms remain to be elucidated. Mitochondrial dysfunction has long been implicated in pathogenesis, largely informed by the association of SOD1 mutations with the disease. We have recently identified various markers of mitochondrial dysfunction in samples from patients with TARDBP mutations and sporadic patients.

We hypothesise that pathogenic forms of TDP-43, FUS and VCP may cause these defects by aberrantly influencing mitochondrial dynamics. This term encompasses local mitochondrial fusion and fission events, and also long-range transportation along neuronal processes. Neurons, especially long motor neurons, are known to be particularly susceptible to disturbances in these processes. The project use powerful genetic approaches in Drosophila coupled with cutting edge live-imaging techniques to interrogate the effect of normal and pathogenic TDP-43, FUS and VCP on mitochondrial dynamics, and determine the contribution to pathogenesis.

References:

• Duffy LM, Chapman AL, Shaw PJ, Grierson AJ.
  The role of mitochondria in the pathogenesis of Amyotrophic Lateral Sclerosis.
  Neuropathol Appl Neurobiol 2011.
• Lanson NA, Jr., Maltare A, King H, et al.
  A Drosophila model of FUS-related neurodegeneration reveals genetic interaction between FUS and TDP-43.
  Hum Mol Genet 2011.
• Ritson GP, Custer SK, Freibaum BD, et al.
  TDP-43 mediates degeneration in a novel Drosophila model of disease caused by mutations in VCP/p97.
  J Neurosci 2010;30:7729-39.
• Baqri RM, Turner BA, Rheuben MB, et al.
  Disruption of mitochondrial DNA replication in Drosophila increases mitochondrial fast axonal transport in vivo.
  PLoS One. 2009;4(11):e7874.

Contact Details:

Dr Alex Whitworth

http://www.shef.ac.uk/bms/research/whitworth

Email: a.whitworth@sheffield.ac.uk