Dissecting endolysosomal trafficking defects in Parkinson's disease (360G-Wellcome-214589_Z_18_Z)

£1,016,853

Endolysosomal trafficking defects are increasingly being implicated in Parkinson's disease (PD). In particular, a number of genes associated with lysosomal storage disorders (LSDs) have been identified as risk factors for developing PD. The precise mechanisms linking endolysosomal genes to PD are not fully understood, but are likely to involve common pathogenic mechanisms. Therefore, through developing a greater understanding of these pathogenic processes, we aim to discover new therapeutic targets in PD. To do this we will study a number of PD-linked genes, including LSD-genes (GBA1, SMPD1, NAGLU, SLC17A5 and ARSB) and Rab39B, encoding an endosomal Rab GTPase. Specifically, we will create novel knockout models of these genes using Drosophila and human PD neuronal cultures, in addition to performing advanced genetic studies. The latter will include a genome-wide association study on the Drosophila Genetic Reference Panel of > 200 inbred fly lines harbouring LSD gene loss-of-function. The common biological pathways and genes associated with protection against PD will be identified and compared to those detected by transcriptomic analysis using RNA-sequencing. Targeted genetic and therapeutic drug screening will also be performed on the PD flies. Novel therapies and therapeutic targets will be validated in iPSC-derived dopaminergic neurones and brain tissue from PD patients.

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Grant Details

Amount Awarded 1016853
Applicant Surname Kinghorn
Approval Committee Clinical Interview Committee
Award Date 2018-12-05T00:00:00+00:00
Financial Year 2018/19
Grant Programme: Title Clinical Research Career Development Fellowship
Internal ID 214589/Z/18/Z
Lead Applicant Dr Kerri Kinghorn
Partnership Value 1016853
Planned Dates: End Date 2024-08-31T00:00:00+00:00
Planned Dates: Start Date 2019-01-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region Greater London
Sponsor(s) Prof Linda Partridge