Understanding the role of the interruptions in repeat expansion diseases
A number of ataxias are caused by DNA repeat expansions. For example, Freidreich's ataxia is caused by expansion of a non-coding GAA repeat, whilst some spinocerebellar ataxias such as SCA1, SCA2, SCA3 and SCA17 are caused by a CAG repeat expansion encoding polyglutamine at the protein level. Our research aims to further understand how these unstable repeat expansions cause the disease phenotype and how interruptions in the repeat sequence modify this. Additionally, we are investigating how the repeat length changes with and between tissues and whether factors such as intrerruptions and DNA repair pathway components play a role in influencing this. This research may help understand why certain areas of the brain degenerate first and why pateints with the same repeat length have varying phenotypes.
- Menon, R. P., Nethisinghe, S., Faggiano, S., Vannocci, T., Rezaei, H., Pemble, S., et al. (2013). The role of interruptions in polyQ in the pathology of SCA1. PLoS Genet. 9, e1003648. doi:10.1371/journal.pgen.1003648.
- Nethisinghe, S., Pigazzini, M. L., Pemble, S., Sweeney, M. G., Labrum, R., Manso, K., et al. (2018). PolyQ Tract Toxicity in SCA1 is Length Dependent in the Absence of CAG Repeat Interruption. Front. Cell. Neurosci. 12, 200. doi:10.3389/fncel.2018.00200.
- Nethisinghe, S., Lim, W. N., Ging, H., Zeitlberger, A., Abeti, R., Pemble, S., et al. (2018). Complexity of the Genetics and Clinical Presentation of Spinocerebellar Ataxia 17. Front. Cell. Neurosci. 12, 429. doi:10.3389/fncel.2018.00429.
- Al-Mahdawi, S., Ging, H., Bayot, A., Cavalcanti, F., La Cognata, V., Cavallaro, S., et al. (2018). Large Interruptions of GAA Repeat Expansion Mutations in Friedreich Ataxia Are Very Rare. Front. Cell. Neurosci. 12, 443. doi:10.3389/fncel.2018.00443.
Preclinical testing of ataxia therapies
The Centre is involved in testing a number of potential therapies for ataxia in a laboratory setting using patients cells. These cells include fibroblasts from skin biopsies and more disease-relevant cell types such as nerve and heart cells that can be derived from induced pluripotent stem cells (iPSCs). Assays for assessing therapeutic efficacy include correction of mRNA and protein expression, improvements to the cellular phenotype including cell health, structure and viability.
- Abeti, R., Baccaro, A., Esteras, N., and Giunti, P. (2018). Novel Nrf2-Inducer Prevents Mitochondrial Defects and Oxidative Stress in Friedreich’s Ataxia Models. Front. Cell. Neurosci. 12, 188. doi:10.3389/fncel.2018.00188
Mitochondrial pathophysiology in rare disorders
Our research studies focus on pathologies involving mitochondrial defects. By using sophisticated physiological assays, we can distinguish mitochondrial dysfunction present in disease models compared to healthy controls. We already succeeded in identifying underlying cellular impairments in Friedreich's ataxia (FRDA), and we aim to identify them in: Spinocerebellar ataxias (SCAs), Dentatorubral-pallidoluysian atrophy (DRPLA), and Xeroderma pigmentosum (XP).
In FRDA, in particular, we uncovered the involvement of cerebellar granule neurons in the pathology. By assessing intracellular lipid peroxidation, reactive oxygen species (ROS), mitochondrial complex activity, and cell death, we revealed the deuterated polyunsaturated fatty acids (PUFAs) were recovering the pathological phentoype in cellular models. Besides, we hilghlighted that in patients fibroblasts, Complex I deficiency is prominent, and Omaveloxalone, can restore the complex activity and overcome FRDA phenotype. We are also involved in understanding calcium dysregulation and cell signalling responsible for the recurrent cardiomyopathies, and the most common cause of death, in FRDA patients.
- Abeti R, Parkinson MH, Hargreaves IP, Angelova PR, Sandi C, Pook MA, Giunti P, Abramov AY. 'Mitochondrial energy imbalance and lipid peroxidation cause cell death in Friedreich's ataxia'. Cell Death Dis. 2016 May 26;7(5):e2237. doi: 10.1038/cddis.2016.111. PMID: 27228352; PMCID: PMC4917650.
- Abeti R, Baccaro A, Esteras N, Giunti P. Novel Nrf2-Inducer Prevents Mitochondrial Defects and Oxidative Stress in Friedreich's Ataxia Models. Front Cell Neurosci. 2018 Jul 17;12:188. doi: 10.3389/fncel.2018.00188. PMID: 30065630; PMCID: PMC6056642.
- Abeti R, Brown AF, Maiolino M, Patel S, Giunti P. Calcium Deregulation: Novel Insights to Understand Friedreich's Ataxia Pathophysiology. Front Cell Neurosci. 2018 Oct 2;12:264. doi: 10.3389/fncel.2018.00264. PMID: 30333728; PMCID: PMC6176067.
- Abeti R, Zeitlberger A, Peelo C, Fassihi H, Sarkany RPE, Lehmann AR, Giunti P. Xeroderma pigmentosum: overview of pharmacology and novel therapeutic strategies for neurological symptoms. Br J Pharmacol. 2019 Nov;176(22):4293-4301. doi: 10.1111/bph.14557. Epub 2019 Jan 23. PMID: 30499105; PMCID: PMC6887903.