Human loss-of-function variants suggest that partial LRRK2 inhibition is a safe therapeutic strategy for Parkinson’s disease

Abstract

Human genetic variants predicted to cause loss-of-function of protein-coding genes (pLoF variants) provide natural in vivo models of human gene inactivation, and can be valuable indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes 1,2 . Gain-of-kinase-function variants in LRRK2 are known to significantly increase the risk of Parkinson's disease 3,4 , suggesting that inhibition of LRRK2 kinase activity is a promising therapeutic strategy. While preclinical studies in model organisms have raised some on-target toxicity concerns 5-8 , the biological consequences of LRRK2 inhibition have not been wellcharacterized in humans. Here we systematically analyse pLoF variants in LRRK2 observed across 141,456 individuals sequenced in the Genome Aggregation Database (gnomAD) 9 , 49,960 exome sequenced individuals from the UK Biobank, and over 4 million participants in the 23andMe genotyped dataset. After stringent variant curation, we identify 1,455 individuals with high-confidence pLoF variants in LRRK2, 82.5% with experimental validation. We show that heterozygous pLoF variants in LRRK2 reduce LRRK2 protein levels but are not strongly associated with reduced life expectancy, or with any specific phenotype or disease state. These data suggest that therapeutics that partially downregulate LRRK2 levels or kinase activity are unlikely to have major on-target safety liabilities. Our results demonstrate the value of largescale genomic databases and phenotyping of human LoF carriers for target validation in drug discovery.

Combined knockout ofLrrk2andRab29does not result in behavioral abnormalitiesin vivo

“…However, the lack of a robust brain phenotype precludes us from answering the question of the directional relationship between LRRK2 and RAB29 with the data presented here. There are peripheral phenotypes in models of LRRK2 deficiency, such as accumulation of lysosomal markers in the kidney and invasion of the alveolar space by type-II pneumocytes in the lung (Baptista et al, 2013;Kuwahara et al, 2016;Whiffin et al, 2019). Further studies on the peripheral phenotypes in the Rab29 -/and Lrrk2 -/-/Rab29 -/animals will be required to clarify whether LRRK2 is upstream or downstream of RAB29 in vivo.…”

Penetrance of Parkinson’s disease in LRRK2 p.G2019S carriers is modified by a polygenic risk score

“…10 The underlying pathogenic mechanism of LRRK2-linked PD is currently unknown, but a great deal of focus has been placed on the ability of the p.G2019S mutation to increase LRRK2 kinase activity, especially since loss-of-function mutations do not seem to be contributing to disease. 11,12 In the last several years, genome-wide association studies (GWAS) have identified an everincreasing number of risk loci for PD. Individually, each of these loci confers modest effects on risk for disease.…”

Penetrance of Parkinson's Disease in LRRK2 p.G2019S Carriers Is Modified by a Polygenic Risk Score

“…However, other reports have not replicated this finding and instead nominated variants in SNCA as modifiers of LRRK2 mutation penetrance . The underlying pathogenic mechanism of LRRK2‐ linked PD is currently unknown, but a great deal of focus has been placed on the ability of the p.G2019S mutation to increase LRRK2 kinase activity, especially given that loss‐of‐function mutations do not seem to be contributing to disease …”