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The findings demonstrated LRRK2 expression in brain dopaminoceptive areas, suggesting to the authors that LRRK2 dysfunction in these areas may diminish trophic support of dopamine neurons. (2006) detected Lrrk2 in multiple areas throughout rat brain.Lrrk2 localization was neuron-specific, detected in microsomal, synaptic vesicle-enriched and synaptosomal cytosolic fractions, as well as the mitochondrial outer membrane. Further studies in human and rat brain showed LRRK2 in punctate structures within neuronal perikarya, dendrites, and axons.
The findings suggested that stabilization of microtubules by tubulin-beta phosphorylation may represent a physiologic function of LRRK2 in neurons.The LRRK2 gene encodes a protein with 5 putative functional domains: an N-terminal leucine-rich repeat (LRR) domain, a Roc (Ras of complex protein) domain that shares sequence homology to the Ras-related GTPase superfamily, a COR (C-terminal of Roc) domain, a mitogen-activated protein kinase kinase kinase (MAPKKK) domain, and a C-terminal WD40 repeat domain.Mutation in this gene is one of the most common causes of inherited Parkinson disease (PARK8; 607060) (summary by 18214993, images] [Full Text]" pmid="18214993"Paisan-Ruiz et al.No differences were observed between normal brains and those from individuals with Parkinson disease.Similar studies on rodent brain showed Lrrk2 expression in the striatum and absence of Lrrk2 expression in the midbrain.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.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.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.(2004) identified a putative disease-causing transcript (DKFZp434H2111) within a 2.6-Mb region encompassing a locus for Parkinson disease-8 (PARK8; 607060).