Progress and Prospects in Parkinson's Research/Causes/Inheritance/LRRK2

"The LRRK2 gene has been implicated in the onset of some types of familial Parkinson’s Disease."

General data
The full official name of LRRK2 is Leucine-Rich Repeat Kinase 2.

Like many other genes, LRRK2 is known by more than one name. Alternative names are:-
 * PARK8
 * ROCO2

In the human genome LRRK2 is to be found on the long arm of chromosome 12.

The cytogenetic location is 12q12.

The molecular base pairs are from 40,618,812 to 40,763,086.

The PD Gene database (2011) lists 50 Polymorphisms for this gene, of which 38 are termed ‘Significant’. It also cites 102 Caucasian gene association studies, 21 Asian gene association studies and 4 Caucasian Family-based studies.

What does LRRK2 do?
The LRRK2 gene provides instructions for making a protein called dardarin. It is active in the brain and other tissues throughout the body, but overall little is known about this gene or the dardarin protein. One common mutation occurs in the Basque region of Spain and the name is derived from 'dardara' the Basque word for tremor.

Studies of the gene's instructions have revealed some clues about its function. Part of the LRRK2 gene provides instructions for making a protein segment (LRR domain, see the image, below) that is rich in a protein building block (an amino acid) called leucine.

Proteins with leucine-rich regions appear to play a role in activities that require protein to protein interactions, such as transmitting signals or helping to assemble the cell's structural framework (cytoskeleton). Other parts of the LRRK2 gene provide instructions for protein regions called the ROC-COR domain and the WD40 domain. These domains also suggest that dardarin is capable of multiple protein to protein interactions.

Additional research findings indicate that dardarin has an enzyme activity known as a kinase. Proteins with kinase activity assist in the transfer of a phosphate group (a cluster of oxygen and phosphorus atoms) from the energy molecule ATP to amino acids in certain proteins. This phosphate transfer is called phosphorylation, and it is an essential step in turning on and off many cell activities. Dardarin has a second enzyme activity referred to as a GTPase activity. This activity is associated with a region of the protein called the ROC domain. The ROC domain may act as a molecular switch that controls the overall shape of the dardarin protein. In one model the Y1699C pathogenic mutation in the COR domain is proposed to enhance interaction between the GTPase and COR domains and cause both a reduction in LRRK2 GTPase activity and alter the shape of the LRRK2 protein in such a way as to disrupt LRRK2 dimerization.

 Purified LRRK2 forms homodimers.

The effect of mutation
Toft et al 2005 linked a heterozygous mutation in the LRRK2 gene with PD. It is Gly2019Ser.

They observed that related incidence of the disease was age–dependant, increasing from 21% at the age of 50 years to 81% at 70 years. The late onset of disease observed for G2019S LRRK2 mutation is similar to that seen in most cases of Parkinsonism (idiopathic) and differs from the earlier disease onset seen for other forms of inherited Parkinsonism. G2019S LRRK2 mutation is associated with Lewy body formation which is also characteristic of most cases of Parkinson disease

The Basque mutation referred to above replaces the amino acid Arginine with the amino acid Glycine at protein position 1396 (written as Arg1396Gly or R1396G).

Studies in Chinese and Japanese populations have identified another LRRK2 mutation that replaces the amino acid Glycine with the amino acid Arginine at protein position 2385 (written as Gly2385Arg or G2385R).

Research
Justus Daeschel of Mayo University,Jacksonville is working on a project to generate LRRK2-specific antibodies in models devoid of the murine homologue of LRRK2. Their project description states:-

"The lack of endogenous LRRK2 protein renders the models much more susceptible to the antigen response caused by human LRRK2 fragments and stimulates the immune system to produce highly specific and sensitive antibodies. Our first experiment has been designed to test (i) five LRRK2 peptides, (ii) the recombinant LRRK2 C-terminus and (iii) cDNA encoding the LRRK2 C-terminus, to examine their respective ability to induce the generation of LRRK2 specific antibodies. After this pre-screening the best antigen will then be selected for the generation of monoclonal antibodies."

Goldberg, Matthew and Albanesi, Joseph P. of the University of Texas are addressing major unanswered questions including ‘what causes LRRK2 protein to associate with cellular membranes’ and ‘can preventing LRRK2 membrane association mitigate the effects of LRRK2 mutations that cause Parkinson’s disease? Their project description states:- "We hypothesize that LRRK2 cycles between cytosolic and membrane-bound states according to various post-translational modifications. We will use an array of biochemical and cell biological methods to identify the cellular mechanisms that regulate LRRK2 membrane association. We will also determine if these mechanisms are affected by disease-linked LRRK2 mutations. We will attempt to generate variants of LRRK2 with reduced ability to associate with cellular membranes. These LRRK2 variants may be useful research tools to discover novel therapies for Parkinson’s disease based on inhibiting LRRK2-mediated neurotoxicity."

Yulan, Xiong and Dawson, Ted M. of the John Hopkins University School of Medicine have developed mutated LRRK2 forms of yeast. Their related project description states:- "A budding yeast model of LRRK2-induced toxicity has been established recently and revealed a key role of GTPase activity in pathobiology of LRRK2. We have performed a genome-wide genetic screen and identified the modifiers of LRRK2-induced toxicity based on this LRRK2-yeast model. The human homologs of the modifiers of LRRK2-induced toxicity identified from yeast model will be characterized and validated in cell culture and primary neuronal cultures in vitro. To validate the modifiers of LRRK2-induced toxicity in vivo, the human homologues of the yeast modifiers will be tested in preventing or exacerbating dopaminergic neurodegeneration and motor dysfunction in the LRRK2 Drosophila mode."

LRRK2 is a complex gene and Rudenko, Iakov N, Ruth Chia, and Mark R Cookson discuss what might be effective therapeutic strategies targeting this gene.