Biochemical, genetic, and translational studies of LRRK2 in Parkinson disease:
Our research on Parkinson’s disease (PD) was inspired by the new genetic discovery in 2004 that mutations in LRRK2 (leucine-rich repeats kinase 2) are the most frequent cause of familial PD. We found that LRRK2 was localized to the Lewy bodies in many non-LRRK2 carriers of PD and dementia with Lewy bodies (Zhu et al., 2006). This was the first study implicating LRRK2 in the pathogenesis of not only familial PD, but also sporadic PD and related Parkinsonism disorders. Through detailed biochemical studies on the enzymatic activities of LRRK2, we showed that LRRK2 is both a protein kinase and an authentic GTPase, the latter self-regulates the intrinsic kinase activity of LRRK2 (Guo et al., 2007). To elucidate the pathogenic role of LRRK2 in vivo, we have established transgenic C. elegans models of PD caused by LRRK2 clinical mutations (R1441C and G2019S) (Yao et al., 2010). We have utilized these C. elegans transgenic LRRK2 models to characterize and validate the efficacy of small molecule inhibitors of LRRK2 (Yao et al., 2013). We have also uncovered a neuroprotective role of glutaredoxin 1 in LRRK2-associated neurodegeneration, revealing a mechanism by which oxidative protein modification contribute to the pathogenesis of PD (Johnson et al., 2015; Johnson et al., 2016).
Genetic and biomarker studies of PD, AD and AD-related dementias:
The Chen lab takes a collaborative and multidisciplinary approach to better understand the core mechanisms that drive neurodegeneration and to translate bench science into clinical practice. Our collaboration with the big data experts has resulted in a NIH funded multi-PI R01 award to identify new genetic and druggable targets impacting AD pathogenesis. More recently, we have worked closely with basic scientists and clinical faculty in order to develop patient-oriented projects that potentially impact molecular diagnosis of PD, AD, and AD-related dementias. These translational projects are currently supported by NIH multi-PI grant awards including a U01 award to identify skin biomarkers for PD, a R01 award to develop novel biomarker assays for Lewy body dementia using peripheral tissue biopsies from the skin, olfactory mucosa, and colon, and a R01 award to translate skin biomarker assays into novel diagnostic platforms for AD and other tauopathies.