Dissecting the signaling pathways in Parkinson's and their therapeutic potential

Dissecting the signaling pathways in Parkinson's and their therapeutic potential
Theme: Parkinson's disease and other neurodegenerative disorders

Part of the Parkinson’s UK Programme Stream
Monday 24th April, 09:30 – 11:10

Twenty five years of genetic research in Parkinson's have led to the identification of several monogenic forms of the disorder and of numerous genetic risk factors increasing the risk to develop Parkinson's. Monogenic forms, caused by a single mutation in a dominantly or recessively inherited gene, such as LRRK2, are well-established, albeit relatively rare types of Parkinson's. They collectively account for about 8% of all people diagnosed with Parkinson's. Additionally, mutations in the glucocerebrosidase (GBA) gene, which encodes the lysosomal enzyme that is deficient in Gaucher's disease, are important and common risk factors for Parkinson's and related disorders. Indeed, ~10% of sporadic Parkinson's cases carry a mutation in the GBA making this a significant risk factor. Patients with GBA-associated parkinsonism exhibit varying parkinsonian phenotypes but tend to have an earlier age of onset and more associated cognitive changes than patients with parkinsonism without GBA mutations. Whilst these gene mutations are relatively rare, the pathways that these genes regulate can give a very important insight into mechanisms which can cause neuronal loss leading to Parkinson's. Indeed, research over the past twenty five years have identified important areas of overlap between mechanisms by which specific gene mutations cause or increase Parkinson's risk and the mechanisms proposed to cause sporadic Parkinson's such as altered abnormal protein processing, mitochondrial dysfunction, neuroinflammation etc. Importantly, this research has led to the development of novel drugs to treat Parkinson's associated with specific gene mutations. However, since there is an extensive overlap in disease mechanisms between familial and sporadic Parkinson's it has been proposed that such drugs may also benefit both forms of Parkinson's, many of which are in clinical trials.

  • Claudia Manzoni, UCL School of Pharmacy, UK: Modelling the function of LRRK2 as controller of multiple pathways - a systems biology perspective
  • Dario Alessi, University of Dundee, UK: Pharmacological strategies targeting LRRK2
  • Matthew Gegg, University College London, UK: The effect of glucocerebrosidase deficiency on the endolysosomal pathway and identification of potential pharmacological treatments (co-chair)
  • Michela Deleidi, German Centre for Neurodegenerative Diseases (DZNE), Germany: Dissecting GBA1 Parkinson' s disease: from 2D to 3D iPSC models

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