Genetic and Environmental Factors Influence the Pleomorphy of LRRK2 Parkinsonism.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Disease Susceptibility* ; Environment* ; Gene-Environment Interaction* ; Phenotype*; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/*genetics ; Parkinsonian Disorders/*diagnosis ; Parkinsonian Disorders/*etiology; Age Factors ; Alleles ; Animals ; Genetic Predisposition to Disease ; Humans ; Incidence ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism ; Multifactorial Inheritance ; Mutation ; Neurodegenerative Diseases/etiology ; Neurodegenerative Diseases/metabolism ; Neurodegenerative Diseases/pathology ; Parkinsonian Disorders/epidemiology ; Parkinsonian Disorders/metabolism ; Penetrance

Missense mutations in the LRRK2 gene were first identified as a pathogenic cause of Parkinson's disease (PD) in 2004. Soon thereafter, a founder mutation in LRRK2 , p.G2019S (rs34637584), was described, and it is now estimated that there are approximately 100,000 people worldwide carrying this risk variant. While the clinical presentation of LRRK2 parkinsonism has been largely indistinguishable from sporadic PD, disease penetrance and age at onset can be quite variable. In addition, its neuropathological features span a wide range from nigrostriatal loss with Lewy body pathology, lack thereof, or atypical neuropathology, including a large proportion of cases with concomitant Alzheimer's pathology, hailing LRRK2 parkinsonism as the "Rosetta stone" of parkinsonian disorders, which provides clues to an understanding of the different neuropathological trajectories. These differences may result from interactions between the LRRK2 mutant protein and other proteins or environmental factors that modify LRRK2 function and, thereby, influence pathobiology. This review explores how potential genetic and biochemical modifiers of LRRK2 function may contribute to the onset and clinical presentation of LRRK2 parkinsonism. We review which genetic modifiers of LRRK2 influence clinical symptoms, age at onset, and penetrance, what LRRK2 mutations are associated with pleomorphic LRRK2 neuropathology, and which environmental modifiers can augment LRRK2 mutant pathophysiology. Understanding how LRRK2 function is influenced and modulated by other interactors and environmental factors-either increasing toxicity or providing resilience-will inform targeted therapeutic development in the years to come. This will allow the development of disease-modifying therapies for PD- and LRRK2 -related neurodegeneration.
Competing Interests: The authors declare no conflict of interest.

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N/A Farmer Family Foundation Parkinson's Research Initiative; P30 AG066515 United States AG NIA NIH HHS; N/A Alexander and Eva Nemeth Foundation; P30AG066515-01 United States NH NIH HHS; N/A Michael J. Fox Foundation; N/A Sergey Brin Family Foundation

Keywords: GWAS; LRRK2; Parkinson’s disease; environmental risk factors; genetics; modifier; neuropathology; parkinsonism; polygenic risk score

EC 2.7.11.1 (Leucine-Rich Repeat Serine-Threonine Protein Kinase-2)

Date Created: 20210126 Date Completed: 20210906 Latest Revision: 20231110

20250114

PMC7864502

10.3390/ijms22031045

33494262