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Exploring the pathogenic interaction between dRab39 and α-Synuclein in Drosophila melanogaster

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posted on 2021-12-01, 16:20 authored by Charlotte A. Smith
Parkinson’s disease is the second most common neurodegenerative disorder it is generally considered that a combination of the environment and genetics plays a role in the pathogenesis of the disease. Although the majority of cases (~90%) are sporadic, with no known cause, over 20 genetic loci have been found to directly cause familial Parkinson’s to date. The major pathological hallmark of the disease is the loss of dopaminergic neurons in the substantia nigra pars compacta, with the remaining neurons containing proteinaceous inclusions termed Lewy bodies. Insoluble and fibrillar α-synuclein aggregates are the main component of Lewy bodies and mutations in the gene encoding α-synuclein - SNCA have been associated with both idiopathic and familial forms of the disease. More recently mutations in RAB39B is a member of the Rab GTPase family - the core regulators of cellular membrane dynamics - has been directly linked to early onset Parkinson’s characterised by intellectual disability, Lewy body pathology and dopaminergic neuron loss.
This thesis utilised a previously established Drosophila model for Parkinson’s disease to overexpress wild-type human α-synuclein within the central nervous system alongside a variety of genetic manipulations of Rab39 to enable the investigation into the interplay between dRab39 and aSyn in Parkinson’s pathogenesis. The study reports a novel Rab39 deficient Drosophila disease model for Parkinson’s disease. Downregulation of Rab39 in the dopaminergic neurons is characterised by a loss of dopaminergic neurons and locomotor ability, accompanied by reduced lifespan. Typically, co-expression of Rab39 RNAi and α-synuclein neuronally exacerbated the observed phenotypes than when they were expressed alone indicating that there could be a genetic interaction. The function of RAB39B is not clear but it appears to be involved in trafficking of cargo to synaptic terminals with an important regulatory role of autophagy. The findings from this thesis suggest disease pathology is likely due to altered dopamine metabolism and increased oxidative stress related to defective autophagy and mitochondrial defects.
This study also aimed to investigate potential neuroprotective candidates of α-Synuclein that are involved in vesicular trafficking. Here I have found that a neuronal reduction of the Calcium/Calmodulin dependent kinase- CamkI - is protective of α-synuclein dependent toxicity in Drosophila. Overall this thesis has provided insights into both the relationships of Rab39 and CamkI with aSyn, which may ultimately provide novel therapeutic strategies for Parkinson’s disease.

History

Supervisor(s)

Flaviano Giorgini

Date of award

2021-08-23

Author affiliation

Department of Genetics and Genome Biology

Awarding institution

University of Leicester

Qualification level

  • Doctoral

Qualification name

  • PhD

Language

en

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