Aviva Tolkovsky
Emeritus Reader in Biochemistry
Our research is focused on understanding the causes of neurodegeneration at the cellular level. Neuro-degeneration affects people of all ages and leads to irreversible loss of cognitive and/or physical functions. In the majority of cases, the mechanisms of degeneration are still unknown, limiting the scope of neuroprotective therapies. In addition to studying ischaemic- and diabetes-related degeneration, we are studying death imposed by the environmental toxin arsenite and inclusion bodies made of protein containing polyglutamine (polyQ) repeats, as in Huntington’s disease. Arsenite imposes a very complex dominant death mechanism because sequential waves of new death signals are recruited continuously over time. Our main objective is to delineate how many death signal motifs there are (i.e. can death signalling be exhausted) and to complete the description of the ‘wiring’ diagram that connects the signals to their respective death proteins using genomic and pharmacological manipulation. With regard to PolyQ proteins, our data suggest that the inclusions they form cause a novel mechanism of death. We are therefore trying to understand how death is governed and whether we can harness autophagy, a dormant protein clearance and cell nutritive pathway, to reduce toxic inclusion size. We are also pursuing a form of cell death we discovered a few years ago, which we termed limoktonia (meaning death by famine). Most especially we are concentrating on understanding what induces mitochondria – the power factories of the cell – to disappear during this death and what can be done to preserve these vital organelles. We hope our studies will highlight possible therapeutic targets and contribute to the development of useful long-term neuroprotective therapies.
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C Goemans
Mitochondrial changes during limoktonia: from normal to clustered to eliminated visualised after delivery of a red fluorescent protein to mitochondria of sympathetic neurons |
Recent publications
- Gumy LF, Bampton ETW, Tolkovsky AM. (2008) Hyperglycaemia inhibits Schwann cell proliferation and migration and restricts regeneration of axons and Schwann cells from adult murine DRG. Mol Cell Neurosci. 37(2):298-311.
- Goemans CG, Boya P, Skirrow CJ, Tolkovsky AM. (2008) Intra-mitochondrial degradation of Tim23 curtails the survival of cells rescued from apoptosis by caspase inhibitors. Cell Death Differ. 15(3):545-54.
- King MA, Goemans CG, Hafiz F, Prehn JH, Wyttenbach A, Tolkovsky AM. (2008) Cytoplasmic inclusions of Htt exon1 containing an expanded polyglutamine tract suppress execution of apoptosis in sympathetic neurons. J Neurosci. 28(53):14401-15.
- Ciechomska IA, Goemans GC, Skepper JN, Tolkovsky AM. (2009) Bcl-2 complexed with Beclin-1 maintains full anti-apoptotic function. Oncogene. 28(21):2128-41.
- Tolkovsky AM. (2009) Mitophagy. Biochim Biophys Acta. 1793(9):1508-15. Review.