LRRK2: Genetic mechanisms vs genetic subtypes

Ignacio Mata, Philippe Salles, Mario Cornejo-Olivas, Paula Saffie, Owen A. Ross, Xylena Reed, Sara Bandres-Ciga

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

In 2004, the identification of pathogenic variants in the LRRK2 gene across several families with autosomal dominant late-onset Parkinson's disease (PD) revolutionized our understanding of the role of genetics in PD. Previous beliefs that genetics in PD was limited to rare early-onset or familial forms of the disease were quickly dispelled. Currently, we recognize LRRK2 p.G2019S as the most common genetic cause of both sporadic and familial PD, with more than 100,000 affected carriers across the globe. The frequency of LRRK2 p.G2019S is also highly variable across populations, with some regions of Asian or Latin America reporting close to 0%, contrasting to Ashkenazi Jews or North African Berbers reporting up to 13% and 40%, respectively. Patients with LRRK2 pathogenic variants are clinically and pathologically heterogeneous, highlighting the age-related variable penetrance that also characterizes LRRK2-related disease. Indeed, the majority of patients with LRRK2-related disease are characterized by a relatively mild Parkinsonism with less motor symptoms with variable presence of α-synuclein and/or tau aggregates, with pathologic pleomorphism widely described. At a functional cellular level, it is likely that pathogenic variants mediate a toxic gain-of-function of the LRRK2 protein resulting in increased kinase activity perhaps in a cell-specific manner; by contrast, some LRRK2 variants appear to be protective reducing PD risk by decreasing the kinase activity.

Original languageEnglish (US)
Title of host publicationHandbook of Clinical Neurology
PublisherElsevier B.V.
Pages133-154
Number of pages22
DOIs
StatePublished - Jan 2023

Publication series

NameHandbook of Clinical Neurology
Volume193
ISSN (Print)0072-9752
ISSN (Electronic)2212-4152

Keywords

  • Genetics
  • Heterogeneity
  • Kinase
  • LRRK2
  • Parkinson
  • Synuclein
  • Tauopathies
  • Therapy

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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