Neuronal death signaling pathways triggered by mutant LRRK2.

Autosomal dominantly inherited mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease. While considerable progress has been made in understanding its function and the many different cellular activities in which it participates, a clear understanding of the mechanism(s) of the induction of neuronal death by mutant forms of LRRK2 remains elusive. Although several models have documented the progressive loss of dopaminergic neurons of the substantia nigra, more complete interrogations of the modality of neuronal death have been gained from cellular models. Overexpression of mutant LRRK2 in neuronal-like cell lines or in primary neurons induces an apoptotic type of cell death involving components of the extrinsic as well as intrinsic death pathways. While informative, these studies are limited by their reliance upon isolated neuronal cells; and the pathways triggered by mutant LRRK2 in neurons may be further refined or modulated by extracellular signals. Nevertheless, the identification of specific cell death-associated signaling events set in motion by the dominant action of mutant LRRK2, the loss of an inhibitory function of wild-type LRRK2, or a combination of the two, expands the landscape of potential therapeutic targets for future intervention in the clinic.