Genetic and Environmental Factors Influence Pleomorphy of lRRK2 Parkinsonism

Abstract

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.Gly2019Ser (rs34637584), was described, and it is now estimated that there are approximately 100,000 people worldwide that carry 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. These differences may result from interactions between 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 developing disease-modifying therapies for PD and LRRK2-related neurodegeneration.