There has been much interest raised by the recent discovery that different autosomal dominant point mutations within the gene encoding for the Leucine Rich Repeat protein Kinase-2 (LRRK2), predispose humans to develop late-onset Parkinson's disease (PD, OMIM accession number 609007), with a clinical appearance indistinguishable from idiopathic PD. The genetic analysis undertaken to date indicates that mutations in LRRK2 are relatively frequent, not only accounting for 5-10% of familial PD, but are also found in a significant proportion of sporadic PD cases. Little is known about how LRRK2 is regulated in cells, what are its physiological substrates and how mutations in LRRK2 cause or increase risk of PD. In mammals there are two isoforms of the LRRK protein kinase, LRRK1 (2038 residues) and LRRK2 (2527 residues). They belong to a protein family that has also been termed Roco. Thus far mutations in LRRK2, but not LRRK1 have been linked to PD.
The LRRK/Roco class of protein kinases was initially characterised in the slime mould Dictyostelium discoideum, as a protein termed GbpC (cGMP binding protein C), that comprised an unusual member of the Ras/GTPase superfamily, distinct from other small GTPase domains as it possesses other domains including a protein kinase. Subsequent studies suggested that GbpC regulates chemotaxis and cell polarity in Dictyostelium, but the physiological substrates for this enzyme have not been elucidated. The defining feature of the LRRK/Roco-proteins is that they possess Leucine Rich Repeat (LRR) motif, a Ras-like small GTPase, a region of high amino acid conservation that has been termed the C-terminal Of Ras of complex (COR) domain, and a protein kinase catalytic domain. The protein kinase domain of LRRK2 belongs to the tyrosine-like serine/threonine protein kinases and is most similar to the Rho-Interacting Protein kinases (RIPK), that play key roles in innate immunity signalling pathways. Other domains are also found on specific members of the LRRK kinases. For example, the GbpC possesses an additional DEP, cyclicGMP-binding and Ras-GEF domains that are not found in mammalian LRRK1 and LRRK2. Human LRRK1 possesses 3 ankyrin repeats at its N-terminus, whereas LRRK2 lacks these domains, but possesses a WD40 repeat located towards its C-terminus not found in LRRK1.
Human LRRK2 consists of leucine rich repeats (residues 1010-1287), a small GTPase domain (residues 1335-1504), a COR domain (residues 1517-1843), a serine/threonine protein kinase domain (residues 1875-2132) and a motif that has low resemblance to a WD40 repeat (2231-2276). To date approximately 20 single amino acid substitution mutations have been linked to autosomal-dominant PD, and these have been found within or in close proximity to conserved residues of the small GTPase, COR, protein kinase and WD40 domains.
The most prevalent mutant form of LRRK2 accounting for approximately 6% of familial PD and 3% of sporadic PD cases in Europe, comprises an amino acid substitution of Gly2019 located within the conserved DYG-Mg2+-binding motif, in subdomain-VII of the kinase domain, to a Ser residue. Recent reports suggest that this mutation moderately enhances, approximately 2-3-fold, the autophosphorylation of LRRK2, as well as its ability to phosphorylate myelin basic protein. These findings suggest that over-activation of LRRK2 predisposes humans to develop PD, implying that drugs which inhibited LRRK2, could be utilised to delay the onset or even treat some forms of PD. The study of LRRK2 has been hampered by the difficulty in expressing active recombinant enzyme and by the lack of a robust quantitative assay.
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USPTO Backgrounds
USPTO Backgrounds