Rab32 directly interacts with LRRK2 and mediates its transport to and from the pericentriolar endosome

LRRK2 is a multi-domain protein of 280 kDa. Mutations especially in the GTPase and kinase domains of LRRK2 are the most common causes of heritable and sometimes sporadic forms of Parkinson’s disease (PD) [1]. At least some of these mutations, including the most frequent one, G2019S, lead to an increased LRRK2 kinase activity and subsequently to PD pathogenesis [2 - 4]. Here, we demonstrate a novel mechanism of LRRK2 binding and transport, which involves the small GTPase Rab32. Rab32 and its closest homologue Rab38 are known to organize the trans Golgi network and thereby the transport of key enzymes in melanogenesis [5 - 6]. Here, we demonstrate that Rab32 interacts directly with LRRK2. In yeast 2 hybrid experiments we identified a coiled-coil motif containing region within the N-terminus of LRRK2 as possible interaction domain. GST pulldown experiments confirmed the interaction. Microscopic analyses displayed a colocalization of Rab32 and LRRK2 at pericentriolar endosomes, in perinuclear aggregates and in transport vesicles. In contrast, no colocalization of LRRK2 and Rab32 was detectable at the Golgi apparatus. Live cell imaging shows co-transport of Rab32 and LRRK2 to and from pericentriolar endosomes. Further investigation is needed how Rab32 influences LRRK2 function in the cell. We are currently focusing on the aspect how LRRK2 membrane recruitment, dimerization and kinase activity are modulated by Rab32.