Objective: To review and examine the most current identified modifiers of Parkinsonism in the LRRK2 population.

Background: LRRK2 is a protein with multiple domains and proposed functions whose full purpose has yet to be defined. Certain mutations typically found in the kinase-coding region are associated with an increased risk in developing Parkinsonism. The phenotype is essentially identical to iPD, however, age of onset can range from 30’s to past 80’s. Pathology is typically Lewy-body. Penetrance is incomplete and age-dependent; ranging from 28 % at age 59 to 74 % at age 79 years in the G2019S LRRK2 population. It is thought that studying the environmental and or genetic factors that could modify the course of the disease could both reveal LRRK2’s pathophysiology and provide novel molecular targets to slow or halt disease progression. For the purposes of this review, the term modifier may reference any co-mutation which either alters severity of disease or age of onset.

Methods: PubMed database was searched to identify relevant literature (published between January 2000 – February 2018). Search terms used included “LRRK2 modifier,” “LRRK2 Penetrance,” “LRRK2,” and “LRRK2 Age of Onset.” Studies were categorized by human vs animal model. They were further categorized by which LRRK2 mutation was studied.

Results: Out of all articles captured with the search terms above, the majority referenced the LRRK2 G2019S mutation, which is the most common variant in the North American and European population, and is particularly prevalent in the North African and Ashkenazi Jewish population. A total of five unique mutations were designated as LRRK2 G2019S modifiers in the human population. Modifiers investigated in drosophila models typically concurred with the molecular pathways implicated in human counterparts. Many of these modifiers were investigated initially as they are also associated with iPD, however some novel markers were identified using genome-wide linkage and association studies. Several of these mutations have also been identified as modifiers in other neurodegenerative diseases.

Conclusions: There are several novel LRRK2 modifiers listed in recent literature. Evaluating the molecular pathways relevant to these modifiers may provide both insight into LRRK2 PD pathophysiology and therapeutic targets to slow and or halt the progression of Parkinsonism in this population.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-review-of-modifiers-of-parkinsonism-in-the-leucine-rich-repeat-kinase-2-lrrk2-population/