Original Paper

Neurochemical Research

, Volume 32, Issue 10, pp 1700-1708

First online:

Open Access This content is freely available online to anyone, anywhere at any time.

LRRK2 Low-penetrance Mutations (Gly2019Ser) and Risk Alleles (Gly2385Arg)—Linking Familial and Sporadic Parkinson’s Disease

  • Vincenzo BonifatiAffiliated withDepartment of Clinical Genetics, Erasmus MC Email author 


The identification of mutations in the leucine-rich repeat kinase 2 (LRRK2) gene as a cause of autosomal dominant Parkinson’s disease (PD) was a major step forward in the genetic dissection of this disorder. However, what makes LRRK2 unique among the known PD-causing genes is that a low-penetrance mutation, Gly2019Ser, is a frequent determinant not only of familial, but also of sporadic PD in several populations from South Europe, North Africa and Middle East. Moreover, a different polymorphic variant, Gly2385Arg, is a frequent risk factor for PD among Chinese and Japanese populations. Currently, the Gly2019Ser and Gly2385Arg variants represent the most relevant PD-causing mutation and risk allele, respectively, linking the etiology of the familial and the sporadic forms of this disease. Understanding how the dysfunction of LRRK2 protein leads to neurodegeneration might provide crucial insights for unraveling the molecular mechanisms of PD and for developing disease-modifying therapies.


Parkinson’s disease Familial Sporadic LRRK2 Mutation Risk allele