Investigating the role of TDP-43 in ALS

About the project

We aim to elucidate the cellular mechanisms that cause the motor neurone disease amyotrophic lateral sclerosis (ALS). It is established that in >95% of ALS cases, the RNA/DNA-binding protein TDP-43 mislocalises to the cytoplasm and forms insoluble protein aggregates in affected neurons. It is unclear how TDP-43 relates to the onset and progression of disease. Our lab strives to identify pathways that control TDP-43 mislocalisation, aggregation and disease progression. To do this, we use a variety of approaches including genetics of the fruit fly, in vitro biochemical techniques, mammalian cell and neuronal culture systems with neuropathology of the human spinal cord.

Currently, we are focused on understanding how the poly(ADP-ribose) polymerases and various stress-related proteins control TDP-43 and whether pharmacological strategies that target these pathways could have therapeutic potential in ALS.

Funder(s)

Academy of Medical Sciences Springboard Fellowship, Dundee University start-up grant

Publication(s)

McGurk L, Rifai OM, Bonini NM
TDP-43, a protein central to amyotrophic lateral sclerosis, is destabilized by tankyrase-1 and -2.
J Cell Sci
2020 Jun 23
McGurk L, Mojsilovic-Petrovic J, Van Deerlin VM, Shorter J, Kalb RG, Lee VM, et al.
Nuclear poly(ADP-ribose) activity is a therapeutic target in amyotrophic lateral sclerosis.
Acta Neuropathologica Communications
2018 Aug 29
McGurk L, Gomes E, Guo L, Mojsilovic-Petrovic J, Tran V, Kalb RG, et al.
Poly(ADP-Ribose) Prevents Pathological Phase Separation of TDP-43 by Promoting Liquid Demixing and Stress Granule Localization.
Molecular Cell
2018 Sep 06

Primary location

Dundee

Principal Investigator

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