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Funded Studies

The Glucosylceramide Pathway in Parkinson's Disease and other Synucleinopathies: Genetic defects, Neuropathological characterization and cell culture models

Mutations in the beta glucocerebrosidase (GBA) gene are associated with Parkinson’s disease. Only a small number of neuropathologically confirmed PD, multiple system atrophy (MSA) and lewy body dementia (LBD) cases have been screened. Our MJFF grant will allow us to carry out the largest study by far, examining the GBA gene in neuropathologically confirmed cases of PD, LBD and MSA and then carry out detailed neuropathology and cell culture work to assess the impact of these genetic defects in brain tissue and in-vitro models.
Project Description: 
Parkinson’s disease, Lewy body dementia and multiple system atrophy are synucleinopathies whose primary pathogenic event is alpha synuclein aggregation into inclusion bodies in the brain tissue. Mutations in the beta glucocerebrosidase gene are associated with PD but no detailed neuropathological studies have been carried out to investigate how these mutations affect the brain. We plan to screen the GBA gene in the largest neuropathological PD, MSA and LBD cohort so far analysed. We will then characterize these mutations in the brain tissue in detail, assess the GBA enzyme level and carry out tissue culture experiments to see how these genetic changes affect cell survival and their interaction with synuclein and other PD associated proteins.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:  We plan to assess the GBA mutation frequency in British PD cases that have been neuropathologically diagnosed. We will then assess clinically diagnosed PD cases and use this data to help with diagnostics. The characterization of brain tissue and cell culture models will give help elucidate the mechanism of GBA associated PD and indicate potential therapies.
Anticipated Outcome: 
The frequency of GBA mutations in UK neuropatholoically and clinically diagnosed PD, MSA and LBD cases. The neuropathological characterization of these mutant cases and the effect of GBA mutations on tissue culture models.

Final Outcome

The researchers confirmed the role of the glucocerebrosidase (GBA) gene in the largest series of patients with clinically and pathologically defined PD in the British population. They also analyzed the frequency of GBA mutations in a neuropathologically defined MSA series. Overall, this implies a critical role for lipid metabolism in neurodegeneration.


  • Henry Houlden, PhD

    London United Kingdom

  • Coro PaisÌÁn Ruiz, PhD

    London United Kingdom

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