P4–162: LRRK2 in Lewy bodies of Parkinson's disease and dementia with Lewy bodies

Mutations in LRRK2 encoding leucine–rich repeat kinase 2 is thus far the most frequent cause associated with autosomal dominant and sporadic Parkinson's disease (PD). LRRK2 is a novel kinase belonging to the ROCO protein superfamily. This large complex protein of 280 kDa contains several functional domains including leucine–rich repeats, Ras–related GTPase, mitogen–activated protein kinase kinase kinase (MAPKKK) and WD40 repeats. We wish to examine whether LRRK2 is directly associated with neuropathology of PD and related neurological disorders. By Western blotting and immunohistochemistry, we analyzed LRRK2 in brains of patients affected by PD and other related disorders using a highly specific antibody to LRRK2. We found that LRRK2 was localized, both in situ and following isolation, to Lewy bodies, the pathological hallmark of PD and dementia with Lewy bodies. Therefore, our study, for the first time, has identified LRRK2 as a novel protein that is both genetically associated with PD and a constituent of its hallmark pathology. Since several other PD–related proteins such as alpha–synuclein and parkin are phosphoproteins found in Lewy bodies, the co–localization of a protein kinase such as LRRK2 in Lewy bodies may provide a molecular mechanism underlying aberrant protein phosphorylation and signal transduction cascades associated with Parkinsonism. Our study shows that LRRK2 is a component of Lewy bodies and it may play an important role in disease pathogenesis of PD and other related disorders.