We did not observe monomeric LRRK2 in blue native gel or gel-filtration chromatography, indicating that LRRK2 may exist as constitutive dimer. Our observations correlating the loss of the LRRK2 dimer and suppression of neurotoxicity raise the possibility that strategies that prevent LRRK2 dimerization may interfere with its function and ability to cause neuron death. Experiments SB225002 utilizing fragments of mammalian or bacterial LRRK2 suggest that the pathogenic R1441C LRRK2 mutation disrupts LRRK2 dimerization. In our studies of full length human LRRK2, we did not observe isolated monomeric LRRK2 when studying the wild type, DWD40 or R1441C forms of the protein. Moreover, we find that Ferulic Acid R1441C-LRRK2 distributes between the a and b complexes similarly to the wild type protein. While our experiments employed LRRK2 overexpression, and may therefore not accurately reflect the behavior of endogenous levels of protein, they suggest that if, in the context of the intact protein, the R1441C mutation disrupts dimerization of the ROC domain, other LRRK2-LRRK2 interaction points maintain the dimeric LRRK2 complex. The fact that R1441C-LRRK2 remains dimeric is further consistent with a potential role for this form of LRRK2 in its neurotoxicity. Previous work on LRRK2 has focused almost exclusively on how functional changes in its GTPase and kinase domains may affect neurotoxicity. However, LRRK2 is a large multi-domain protein and the potential role of other domains in LRRK2 function and ability to cause neurodegeneration is much less well explored. Similar to our findings, previous work demonstrates that deletion of the WD40 domain almost entirely prevents autophosphorylation. In addition, the G2385R polymorphism in the WD40 domain is over-represented in ethnic Chinese patients with PD, and this polymorphism increases the sensitivity of cells to hydrogen peroxide. Our structural studies indicate that the carboxyl-terminal regions of LRRK1 and LRRK2 differ considerably, and these differences may contribute to an explanation of previous work demonstrating the failure of LRRK2 PD mutations to cause neurotoxicity when placed in the context of the LRRK1 protein. While one study suggests that LRRK1 contains a WD40 domain, this putative WD40 domain, if it exists, is divergent from a canonical WD40 domain. Homology modeling of the LRRK2 carboyxl-terminus strongly supports the notion that this region forms a WD40 domain,including the presence of a welldefined patch of positively charged residues.