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Alpha-synuclein and microRNA function in human dopamine neurons


Bristol Medical School

, Applications accepted all year round Self-Funded PhD Students Only

About the Project

Rationale
Parkinson’s is a neurodegenerative disorder that is characterised by the loss of dopamine neurons in the substantia nigra, leading to impairment of the motor system and other non-motor symptoms such as loss of smell, cognitive and sleep disorders. The majority of Parkinson’s cases are idiopathic and are associated with risk factors such as environmental toxins and age, however a minority of Parkinson’s cases are familial and are linked to known genetic factors.

The gene encoding for α-synuclein, SNCA, was the first gene with mutations to be found to cause autosomal dominant disease, with missense mutations of SNCA such as A53T, A30P and G51D as well as triplication of the SNCA locus reported in Parkinson’s patients. α-Synuclein is a presynaptic neuronal protein that regulates synaptic vesicle release and can contribute to neuronal dysfunction in ways including aggregate formation, perturbing cellular homeostasis and disrupting synaptic function (reviewed in 1). We have identified that neurons with elevated levels of either wild-type or mutant α-synuclein show increased levels of specific microRNAs (miRNAs); some of these miRNAs are also released by the degenerating dopamine neurons (2). This project aims to elucidate the interplay between α-synuclein function, miRNA effects and neuroinflammation in Parkinson’s neurons.

Aims and Objectives
Validate changes in intracellular and released miRNAs in human dopamine neurons expressing wild-type and mutant α-synuclein;
Investigate the effects of α-synuclein-mediated miRNA changes on target genes, thereby identifying potential novel mechanisms of α-synuclein toxicity in neurons;
Investigate how miRNAs released by the degenerating neurons can activate microglia, the immune surveillance cells of the brain, using in vitro neurons derived from human induced pluripotent cells and in vivo models of Parkinson’s (3).

Methods
A wide range variety of techniques will be used. This includes molecular and cell biology techniques such as quantitative PCR, neuronal differentiation from induced pluripotent stem cells, lentiviral vectors, Western blotting, immunocytochemistry and histological techniques.

References

1. Wong YC, Krainc D. (2017) α-synuclein toxicity in neurodegeneration: mechanism and therapeutic strategies. Nature Medicine 23(2):1-13

2. Leggio L, Vivarelli S, L'Episcopo F, Tirolo C, Caniglia S, Testa N, Marchetti B, Iraci N (2017) microRNAs in Parkinson's Disease: From Pathogenesis to Novel Diagnostic and Therapeutic Approaches. Int J Mol Sci. 18(12). pii: E2698

3. Sanchez-Guajardo, V., Tentillier, N. & Romero-Ramos, M. (2015) The relation between alpha-synuclein and microglia in Parkinson's disease: Recent developments. Neuroscience 302, 47-58

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