The dardarin G 2019 S mutation is a common cause of Parkinson's disease but not other neurodegenerative diseases
National Institute on Aging, Baltimore, Maryland, United States Neuroscience Letters
(Impact Factor: 2.03).
12/2005; 389(3):137-9. DOI: 10.1016/j.neulet.2005.07.044
Mutations in the leucine-rich kinase 2 gene (LRRK 2) encoding dardarin, on chromosome 12, are a common cause of familial and sporadic Parkinson's disease. The most common mutation, a heterozygous 6055 G>A transition (G 2019 S) accounts for approximately 3--10% of familial Parkinson's disease and 1--8% sporadic Parkinson's disease in several European-derived populations. Some families with disease caused by LRRK 2 mutations have been reported to include patients with highly variable clinical and pathological features. We screened for the most common LRRK 2 mutation in a series of patients with Parkinson's Disease, Alzheimer's disease, Progressive Supranuclear Palsy, Multiple System Atrophy and frontotemporal dementia, as well as in neurologically normal controls. The mutation was found only in Parkinson's disease patients or their relatives and not in those with other neurodegenerative disease.
Available from: PubMed Central
- "The G2019S mutation of Leucine-rich repeat kinase 2 (LRRK2) is a relatively common autosomal dominant mutation that causes familial PD [70-72]. Nguyen et al.  recently reported interesting phenotypes in iPSC-derived neuronal cultures from one patient with a G2019S mutation, which they compared with neurons from one control individual. "
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ABSTRACT: A crucial limitation to our understanding of Alzheimer's disease (AD) is the inability to test hypotheses on live, patient-specific neurons. Patient autopsies are limited in supply and only reveal endpoints of disease. Rodent models harboring familial AD mutations lack important pathologies, and animal models have not been useful in modeling the sporadic form of AD because of complex genetics. The recent development of induced pluripotent stem cells (iPSCs) provides a method to create live, patient-specific models of disease and to investigate disease phenotypes in vitro. In this review, we discuss the genetics of AD patients and the potential for iPSCs to capture the genomes of these individuals and generate relevant cell types. Specifically, we examine recent insights into the genetic fidelity of iPSCs, advances in the area of neuronal differentiation, and the ability of iPSCs to model neurodegenerative diseases.
Available from: Birgitt Schuele
- "A common autosomal dominant missense mutation, G2019S in the Leucine- Rich Repeat Kinase 2 (LRRK2) gene, has previously been identified in 0.6%–1.6% and 2%–8% of sporadic and familial PD cases, respectively (Hernandez et al., 2005; Nichols et al., 2005; Paisan-Ruiz et al., 2005). The penetrance of the G2019S mutation is age dependent, increasing from 17% at age 50 to 85% penetrance at age 70 (Kachergus et al., 2005). "
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ABSTRACT: Studies of Parkinson's disease (PD) have been hindered by lack of access to affected human dopaminergic (DA) neurons. Here, we report generation of induced pluripotent stem cells that carry the p.G2019S mutation (G2019S-iPSCs) in the Leucine-Rich Repeat Kinase-2 (LRRK2) gene, the most common PD-related mutation, and their differentiation into DA neurons. The high penetrance of the LRRK2 mutation and its clinical resemblance to sporadic PD suggest that these cells could provide a valuable platform for disease analysis and drug development. We found that DA neurons derived from G2019S-iPSCs showed increased expression of key oxidative stress-response genes and α-synuclein protein. The mutant neurons were also more sensitive to caspase-3 activation and cell death caused by exposure to stress agents, such as hydrogen peroxide, MG-132, and 6-hydroxydopamine, than control DA neurons. This enhanced stress sensitivity is consistent with existing understanding of early PD phenotypes and represents a potential therapeutic target.
Available from: George Jackson
- "Mutations in parkin are the second most common genetic cause of PD, after LRRK2/ dardarin (Foroud et al., 2003; Kitada et al., 1998; Klein et al., 2003) (Gilks et al., 2005; Hedrich et al., 2004; Hernandez et al., 2005; Lincoln et al., 2003). Parkin mutations originally were identified in families with autosomal recessive juvenile parkinsonism (AR- JP) (Kitada et al., 1998). "
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ABSTRACT: Neurodegenerative diseases encompass a large group of neurological disorders. Clinical symptoms can include memory loss, cognitive impairment, loss of movement or loss of control of movement, and loss of sensation. Symptoms are typically adult onset (although severe cases can occur in adolescents) and are reflective of neuronal and glial cell loss in the central nervous system. Neurodegenerative diseases also are considered progressive, with increased severity of symptoms over time, also reflective of increased neuronal cell death. However, various neurodegenerative diseases differentially affect certain brain regions or neuronal or glial cell types. As an example, Alzheimer disease (AD) primarily affects the temporal lobe, whereas neuronal loss in Parkinson disease (PD) is largely (although not exclusively) confined to the nigrostriatal system. Neuronal loss is almost invariably accompanied by abnormal insoluble aggregates, either intra- or extracellular. Thus, neurodegenerative diseases are categorized by (a) the composite of clinical symptoms, (b) the brain regions or types of brain cells primarily affected, and (c) the types of protein aggregates found in the brain. Here we review the methods by which Drosophila melanogaster has been used to model aspects of polyglutamine diseases, Parkinson disease, and amyotrophic lateral sclerosis and key insights into that have been gained from these models; Alzheimer disease and the tauopathies are covered elsewhere in this special issue.
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