Abstracts & Commentary
Synopsis: LRRK2 may be central to the pathogenesis of several major neurodegenerative disorders associated with Parkinsonism.
Sources: Paisán-Ruíz C, et al. Cloning of the Gene Containing Mutations that Cause PARK8-Linked Parkinson’s Disease. Neuron. 2004;44:595-600; Zimprich A, et al. Mutations in LRRK2 Cause Autosomal Dominant Parkinsonism With Pleomorphic Pathology. Neuron. 2004;44:601-607.
Despite the rarity of familial Parkinson’s disease (PD), recent identification of the genes involved has helped elucidate molecular mechanisms that may go awry in this disease. Now, a sixth gene leading to familial PD has been identified independently by 2 groups exploiting high resolution mapping techniques and sequencing of multiple candidate genes. The PARK8 locus was identified in 2002 in the Japanese Sagamihara kindred, associated with autosomal dominant inheritance of PD. The locus has since been associated with other unrelated families in Europe and North America, and individuals have a clinical phenotype of typical late-onset PD, with an excellent levodopa response. Paisán-Ruíz and colleagues identified the gene LRRK2 (leucine-rich repeat kinase 2) as that corresponding to the PARK8 locus, in a study of 1 English and 4 Basque families. They identified 2 disease-segregating missense mutations, and if unaffected individuals under 79 years old were excluded, penetrance was 100%. Moreover, of 107 sporadic cases, 5 individuals carried one of these missense mutations. Independently, Zimprich et al analyzed 46 families, identifying 5 missense mutations (2 identical to those in the Basque and English families) and 1 putative splice site mutation in LRRK2. Over 1000 control chromosomes studied by each group had no such LRRK2 mutations. The predicted protein structure comprises 12 leucine-rich repeats, a non-receptor tyrosine kinase-like domain, a Ras/small GTPase superfamily domain, and a WD40 domain. Corresponding mRNA was detected throughout the brain, as well as other tissues including liver and cardiac muscle.
Commentary
The newly identified gene for the PARK8 locus, LRRK2, now joins alpha-synuclein and ubiquitin C-terminal hydrolase L1 (UCH-L1), the genes responsible for autosomal dominant inheritance of PD. In contrast, parkin, PTEN-induced putative kinase 1 (PINK1), and DJ-1 lead to autosomal recessive familial PD. Cloning of the gene for PARK8 also follows hot on the heels of identification of the glucocerebrosidase gene as a possible susceptibility factor for PD.1,2 Abnormal folding, aggregation, and deposition of alpha-synuclein is thought to contribute to dopamine neuron dysfunction and demise in PD, and involvement of parkin and UCH-L1 highlight a role for cellular protein degradation via the ubiquitin-proteasome system. How PINK1 and DJ-1 mutations lead to PD is less clear, but DJ-1 is suggested to protect against oxidative damage, and identification of PINK1, a mitochondrial protein kinase, supports current concepts of mitochondrial pathology in PD. Where, then, does LRRK2 fit into this picture? As yet we can only infer function from its predicted structure, and this is complicated by identification of several quite different domain types, as noted above. It may have activity as a cytoplasmic tyrosine kinase, and one region fits a recently defined multifunctional Ras/GTPase family, termed ROCO, whose members have diverse activities including a role in cytoskeleton organization. Additionally, the presence of LRR domains suggest that LRRK2 acts as part of a protein complex. Finally, it is fascinating that PARK8 families display remarkable neuropathological heterogeneity.3 Patterns observed to date include: neuronal loss and gliosis in the subtantia nigra with nigral Lewy bodies; pure nigral degeneration without Lewy bodies or other pathology determined; widespread Lewy body disease including the cortex; and neurofibrillary tangles in the absence of Lewy bodies. It remains to be determined whether LRRK2 mutations could therefore account for other neurodegenerative diseases with these pathologies. Moreover, understanding its function and dysfunction will broaden the scope of current possibilities for targeted therapeutic intervention. — Claire Henchcliffe
Claire Henchcliffe, MD, is Assistant Professor in the Department of Neurology at the Weill Medical College of Cornell University.
References
1. Feany MB. New Genetic Insights Into Parkinson’s Disease. N Engl J Med. 2004;351:1937-1940.
2. Aharon-Peretz J, et al. Mutations in the Glucocerebrosidase Gene and Parkinson’s Disease in Ashkenazi Jews. N Engl J Med. 2004;351:1972-1977.
3. Wszolek ZK, et al. Autosomal Dominant Parkinsonism Associated With Variable Synuclein and Tau Pathology. Neurology. 2004;62:1619-1622.
LRRK2 may be central to the pathogenesis of several major neurodegenerative disorders associated with Parkinsonism.
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