Coexpression of DVL1 increased LRRK2 steady-state protein levels, an effect that was dependent on the DEP domain.
LRRK2-DVL1-3 interactions were disrupted by the LRRK2 Y1699C mutation (609007.0002), whereas pathogenic mutations at residues arg1441 (see, e.g., 609007.0001) and arg1728 strengthened LRRK2-DVL1 interactions.
Phosphorylation of tubulin was enhanced 3-fold by the LRRK2 G2019S mutation (609007.0006), which suggested that mutant LRRK2-induced neurodegeneration in PD may be partly mediated by increased phosphorylation of tubulin-beta, which may interfere with neurite outgrowth, axonal transport, and synapse formation. (2009) reported interaction of LRRK2 with the dishevelled family of phosphoproteins, DVL1 (601365), DVL2 (602151), and DVL3 (601368), key regulators of Wnt (Wingless/Int; 164820) signaling pathways important for axon guidance, synapse formation, and neuronal maintenance.
The LRRK2 Roc-COR domain and the DVL1 (601365) DEP domain were necessary and sufficient for LRRK2-DVL1 interaction.
However, LRRK2 did not appear to be integrated into membranes.
Further studies showed that LRRK2 dimerizes, shows kinase activity, and is able to phosphorylate itself. (2008) found that the ROC, or GTPase-like, domain of LRRK2 interacted with alpha (see TUBA1A; 602529)/beta (see TUBB2B; 612850)-tubulin heterodimers that form microtubules.
Similar studies on rodent brain showed Lrrk2 expression in the striatum and absence of Lrrk2 expression in the midbrain.Expression of mutant LRRK2 induced apoptotic cell death in human SH-SY5Y neuroblastoma cells and in mouse cortical neurons in vitro. (2006) detected LRRK2 expression in medium-sized spiny neurons of the caudate and putamen.Larger, presumably cholinergic neurons and dopamine neurons were devoid of LRRK2 signal.LRRK2 interacted preferentially with the C-terminal R2 RING finger domain of parkin, and parkin interacted with the COR domain of LRRK2.Coexpression of LRRK2 and parkin increased cytoplasmic protein aggregates that contained LRRK2 and enhanced the ubiquitination of these aggregates.(2004) identified a putative disease-causing transcript (DKFZp434H2111) within a 2.6-Mb region encompassing a locus for Parkinson disease-8 (PARK8; 607060).The predicted transcript encodes a deduced 2,482-amino acid protein with a leucine-rich repeat, a kinase domain, a RAS domain, and a WD40 domain.Northern blot analysis detected a 9-kb m RNA transcript in all tissues tested, including brain.The authors named the protein product dardarin, derived from the Basque word dardara, meaning tremor. (2004) cloned LRRK2 from a human brain c DNA library and found that it encodes a 2,527-amino acid protein with a molecular mass of approximately 250-k D.Coexpression of DVL1 with LRRK2 in mammalian cells resulted in the redistribution of LRRK2 to typical cytoplasmic DVL1 aggregates in HEK293 and SH-SY5Y cells and colocalization in neurites and growth cones of differentiated dopaminergic SH-SY5Y cells.Since the DVL1 DEP domain is known to be involved in the regulation of small GTPases, 19625296, images] [Full Text]" pmid="19625296"Gehrke et al.