α-synuclein, LRRK2 and their interplay in Parkinson's disease

Of the various genetic factors contributing to the pathogenesis of Parkinson's disease (PD), only mutations in a-synuclein (alpha-syn) and LRRK2 genes cause clinical and neuropathological phenotypes closely resembling the sporadic cases. Therefore, studying the pathophysiological functions of these two PD-related genes is particularly informative in understanding the underlying molecular pathogenic mechanism of the disease. PD-related missense and multiplication mutations in alpha-syn may cause both early-and late-onset PD, whereas various PD-related LRRK2 missense mutations may contribute to the more common late-onset PD. While intensive studies have been carried out to elucidate the pathogenic properties of PD-related mutant a-syn and LRRK2, our knowledge of their normal functions and their potential genetic interplay remains rudimental. In this review, we summarize the progress made regarding the pathophysiological functions of alpha-syn, LRRK2 and their interaction in PD, based on the available literature and our unpublished observations.