New therapeutic approaches to Parkinson's disease targeting GBA, LRRK2 and Parkin

Konstantin Senkevich; Uladzislau Rudakou; Ziv Gan-Or

doi:10.1016/j.neuropharm.2021.108822

New therapeutic approaches to Parkinson's disease targeting GBA, LRRK2 and Parkin

Neuropharmacology. 2022 Jan 1:202:108822. doi: 10.1016/j.neuropharm.2021.108822. Epub 2021 Oct 7.

Authors

Konstantin Senkevich¹, Uladzislau Rudakou², Ziv Gan-Or³

Affiliations

¹ The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montréal, QC, Canada; Department of Neurology and neurosurgery, McGill University, Montréal, QC, Canada; First Pavlov State Medical University of St. Petersburg, Saint-Petersburg, Russia.
² The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montréal, QC, Canada; Department of Neurology and neurosurgery, McGill University, Montréal, QC, Canada; Department of Human Genetics, McGill University, Montréal, QC, Canada.
³ The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montréal, QC, Canada; Department of Neurology and neurosurgery, McGill University, Montréal, QC, Canada; Department of Human Genetics, McGill University, Montréal, QC, Canada. Electronic address: ziv.gan-or@mcgill.ca.

PMID: 34626666
DOI: 10.1016/j.neuropharm.2021.108822

Abstract

Parkinson's disease (PD) is defined as a complex disorder with multifactorial pathogenesis, yet a more accurate definition could be that PD is not a single entity, but rather a mixture of different diseases with similar phenotypes. Attempts to classify subtypes of PD have been made based on clinical phenotypes or biomarkers. However, the most practical approach, at least for a portion of the patients, could be to classify patients based on genes involved in PD. GBA and LRRK2 mutations are the most common genetic causes or risk factors of PD, and PRKN is the most common cause of autosomal recessive form of PD. Patients carrying variants in GBA, LRRK2 or PRKN differ in some of their clinical characteristics, pathology and biochemical parameters. Thus, these three PD-associated genes are of special interest for drug development. Existing therapeutic approaches in PD are strictly symptomatic, as numerous clinical trials aimed at modifying PD progression or providing neuroprotection have failed over the last few decades. The lack of precision medicine approach in most of these trials could be one of the reasons why they were not successful. In the current review we discuss novel therapeutic approaches targeting GBA, LRRK2 and PRKN and discuss different aspects related to these genes and clinical trials.

Keywords: Clinical trials; GBA; Genetic targets; LRRK2; PRKN; Parkinson's disease.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

Antiparkinson Agents / pharmacology
Antiparkinson Agents / therapeutic use*
Genes, Recessive / genetics
Genetic Association Studies
Glucosylceramidase / genetics*
Humans
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics*
Molecular Targeted Therapy / methods*
Mutation
Parkinson Disease / classification
Parkinson Disease / drug therapy*
Parkinson Disease / genetics*
Phenotype
Precision Medicine
Ubiquitin-Protein Ligases / genetics*

Substances

Antiparkinson Agents
Ubiquitin-Protein Ligases
parkin protein
LRRK2 protein, human
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
GBA protein, human
Glucosylceramidase