Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in LRRK2/PARK8 are linked to autosomal dominant forms of Parkinson's disease, but the pathogenic mechanism of LRRK2-associated Parkinson's disease is not fully understood. Moreover, in vivo functions of LRRK2 have not been addressed so far. Thus, we generated and characterized transgenic animals and loss-of-function mutants for LRRK, a sole Drosophila orthologue of human LRRK2. While transgenic expression of pathogenic mutant and wild type LRRK did not show any significant defects, LRRK loss-of-function mutants exhibited severely impaired locomotive activity. Moreover, dopaminergic neurons in LRRK mutants showed a severe reduction in tyrosine hydroxylase immunostaining and shrunken morphology, implicating their degeneration in the mutants. Collectively, our findings unprecedentedly show in vivo that LRRK2 is critical for the integrity of dopaminergic neurons and intact locomotive activity in Drosophila.
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PMID:Loss of LRRK2/PARK8 induces degeneration of dopaminergic neurons in Drosophila. 1749 48

Mutations in the LRRK2 gene cause autosomal dominant, late-onset parkinsonism, which presents with pleomorphic pathology including alpha-synucleopathy. To promote our understanding of the biological role of LRRK2 in the brain we examined the distribution of LRRK2 mRNA and protein in postmortem human brain tissue from normal and neuropathological subjects. In situ hybridization and immunohistochemical analysis demonstrate the expression and localization of LRRK2 to various neuronal populations in brain regions implicated in Parkinson's disease (PD) including the cerebral cortex, caudate-putamen and substantia nigra pars compacta. Immunofluorescent double labeling studies additionally reveal the prominent localization of LRRK2 to cholinergic-, calretinin- and GABA(B) receptor 1-positive, dopamine-innervated, neuronal subtypes in the caudate-putamen. The distribution of LRRK2 in brain tissue from sporadic PD and dementia with Lewy bodies (DLB) subjects was also examined. In PD brains, LRRK2 immunoreactivity localized to nigral neuronal processes is dramatically reduced which reflects the disease-associated loss of dopaminergic neurons in this region. However, surviving nigral neurons occasionally exhibit LRRK2 immunostaining of the halo structure of Lewy bodies. Moreover, LRRK2 immunoreactivity is not associated with Lewy neurites or with cortical Lewy bodies in sporadic PD and DLB brains. These observations indicate that LRRK2 is not a primary component of Lewy bodies and does not co-localize with mature fibrillar alpha-synuclein to a significant extent. The localization of LRRK2 to key neuronal populations throughout the nigrostriatal dopaminergic pathway is consistent with the involvement of LRRK2 in the molecular pathogenesis of familial and sporadic parkinsonism.
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PMID:Localization of Parkinson's disease-associated LRRK2 in normal and pathological human brain. 1751 2

The pathogenesis of Parkinson's disease (PD) is not understood and there are currently no accepted disease modifying, neuroprotective treatments. There are two autosomal dominant PD genes, leucine-rich repeat kinase (LRRK)2 and alpha-synuclein. LRRK2 mutations are very common in patients with PD, accounting for 40% of patients with sporadic, nonfamilial disease in some ethnic groups. Alpha-synuclein mutations are much less frequent, but the importance of alpha-synuclein has been confirmed by the demonstration of alpha-synuclein deposition as Lewy bodies in patients with PD and Lewy body dementia. Pathogenic mutations in alpha-synuclein accelerate the formation of oligomers and fibrils. Mutations in LRRK2 lead to an enhancement in LRRK2 kinase activity. The further study and understanding of the route by which alpha-synuclein and LRRK2 lead to PD, and how these processes can be therapeutically manipulated, is likely to lead to new disease-modifying treatments.
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PMID:Autosomal dominant Parkinson's disease and the route to new therapies. 1756 48

The past 10 years has seen a shift in our etiological concepts of Parkinson's disease, moving from a nearly exclusively environmentally mediated disease towards a complex disorder with important genetic contributors. The identification of responsible mutations in certain genes, particularly alpha-synuclein, Parkin, PINK1, DJ-1 and LRRK2, has increased our understanding of the clinical and pathological changes underlying Parkinson's disease, with implications for patient diagnosis, management and future research. This review will outline the specific genetic advances, discuss their implications for clinical practice and hint at future directions for research into this common and disabling disease.
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PMID:Genetics of Parkinson's disease and parkinsonism. 1756 49

The association of six genes with monogenic forms of parkinsonism has unambiguously established that the disease has a genetic component. Of these six genes, LRRK2 (leucine-rich repeat kinase 2, or PARK8), parkin (PARK2), and PINK1 (PTEN-induced putative kinase 1, or PARK6) are the most clinically relevant because of their mutation frequency. Insights from initial familial studies suggest that LRRK2-associated parkinsonism is dominantly inherited, whereas parkinsonism linked to parkin or PINK1 is recessive. However, screening of patient cohorts has revealed that up to 70% of people heterozygous for LRRK2 mutations are unaffected, and that more than 50% of patients with mutations in parkin or PINK1 have only a single heterozygous mutation. Deciphering the role of heterozygosity in parkinsonism is important for the development of guidelines for genetic testing, for the counselling of mutation carriers, and for the understanding of late-onset Parkinson's disease. We discuss the roles of heterozygous LRRK2 mutations and heterozygous parkin and PINK1 mutations in the development of parkinsonism, and propose an integrated aetiological model for this complex disease.
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PMID:Deciphering the role of heterozygous mutations in genes associated with parkinsonism. 1758 54

Pathogenic substitutions in leucine-rich repeat kinase 2 (LRRK2, Lrrk2) have been genetically linked to familial, late-onset Parkinsonism. End-stage disease is predominantly associated with nigral neuronal loss and Lewy body pathology, but patients may have gliosis, tau or ubiquitin inclusions (pleomorphic pathology). The anatomical distribution of Lrrk2 protein may provide insight into its function in health and neurodegeneration, thus we performed a comparative study with 'in-house' and commercially available Lrrk2 antibodies using brain tissue from wild type and human Lrrk2 transgenic bacterial artificial chromosome (BAC) mice, and from diffuse Lewy body disease (DLBD) patients. Lrrk2 protein was ubiquitously expressed and relatively abundant in most brain regions, including the substantia nigra, thalamus and striatum. Lrrk2 was not a major component of Lewy body or neuritic pathology associated with Parkinson's disease. However, selective loss of dopaminergic neurons in Lrrk2-associated Parkinsonism argues the protein may have regional-specific interactions. Lrrk2 immunohistochemical staining was present in the subventricular zone, a region containing stem cells that give rise to both neurons and glia. A role for Lrrk2 in neurogenesis might provide further insight into the aberrant role of mutant protein in age-associated neurodegeneration with pleomorphic pathology.
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PMID:A comparative analysis of leucine-rich repeat kinase 2 (Lrrk2) expression in mouse brain and Lewy body disease. 1761 Oct 37

The level of leucine-rich repeat kinase 2 (Lrrk2) mRNA expression was measured by reverse transcription-polymerase chain reaction in anterior striatum from normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets (Callithrix jacchus) that had L-3,4-dihydroxyphenylalanine methyl ester (L-DOPA)-induced dyskinesia. The level of striatal Lrrk2 mRNA was increased in MPTP-treated common marmosets that had L-DOPA-induced dyskinesia compared with normal animals that did not receive l-DOPA. Marmosets that exhibited higher levels of dyskinesia had the greatest increase in striatal Lrrk2 mRNA. Lrrk2 mRNA expression was also measured in human striatum and substantia nigra from control subjects and patients dying with Parkinson's disease. In contrast to marmoset tissue, no alteration in Lrrk2 mRNA expression was found in parkinsonian human brain. However, the brain was from patients who had an overall low level of dyskinesia. The correlation between striatal Lrrk2 mRNA levels in MPTP-treated common marmoset striatum and L-DOPA-induced dyskinesia indicates that LRRK2 may have a role in the molecular alterations that cause L-DOPA-induced dyskinesia.
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PMID:Striatal leucine-rich repeat kinase 2 mRNA is increased in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned common marmosets (Callithrix jacchus) with L-3, 4-dihydroxyphenylalanine methyl ester-induced dyskinesia. 1761 47

A common LRRK2 missense variant, Gly2385Arg, has been found to be a genetic risk factor for Parkinson's disease (PD) in ethnic Chinese and Japanese. However, the presence of the variant in other non-Chinese Asian patients has not been fully clarified. We performed genetic analysis of the Gly2385Arg variant in 472 non-Chinese Asian subjects in Singapore (comprising of 166 PD and 306 controls of Malay/Indian ethnicity). The frequency of the heterozygous Gly2385Arg genotype was not significantly different in PD compared with controls (1.2% vs. 0.8%, odds ratio = 2.83, 95% CI 0.40, 20.2, P = 0.3). No subjects carried the homozygous genotype. Stratification by Malay and Indian ethnicity revealed that there were two carriers each among 98 (2.0%) Malay PD and 173 (1.2%) Malay controls (odds ratio = 1.78, 95% CI 0.25, 12.8, P = 0.6), but there were no carriers among 66 Indian PD and 133 Indian controls. We demonstrated that the Gly2385Arg variant could be detected in our Malay subjects. However, its frequency was much lower than the 8 to 10% prevalence previously reported in our Singaporean and Taiwanese Chinese PD population. The relevance of Gly2385Arg as a genetic risk factor may be restricted to selected Asian races, and more studies will be needed to confirm our observations.
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PMID:Analysis of LRRK2 Gly2385Arg genetic variant in non-Chinese Asians. 1765 42

Parkinson's disease (PD) is a progressive neurodegenerative movement disorder and in most patients its aetiology remains unknown. Molecular genetic studies in familial forms of the disease identified key proteins involved in PD pathogenesis, and support a major role for mitochondrial dysfunction, which is also of significant importance to the common sporadic forms of PD. While current treatments temporarily alleviate symptoms, they do not halt disease progression. Drugs that target the underlying pathways to PD pathogenesis, including mitochondrial dysfunction, therefore hold great promise for neuroprotection in PD. Here we summarize how the proteins identified through genetic research (alpha-synuclein, parkin, PINK1, DJ-1, LRRK2 and HTRA2) fit into and add to our current understanding of the role of mitochondrial dysfunction in PD. We highlight how these genetic findings provided us with suitable animal models and critically review how the gained insights will contribute to better therapies for PD.
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PMID:Genetic findings in Parkinson's disease and translation into treatment: a leading role for mitochondria? 1768 Aug 6

Parkinson's disease (PD) is an etiologically heterogeneous disorder characterized by parkinsonism (bradykinesia, resting tremor, rigidity, and postural instability) with good response to L-dopa. PD is the second most prevalent neurodegenerative disorder after Alzheimer disease. Although the majority of PD cases are sporadic, 5-10% of PD is monogenic form of PD as familial PD (FPD). Multifactorial genetic-environmental interaction has been thought in PD pathogenesis, although these interactions are still poorly understood. In 2004, LRRK2 was identified as the causative gene for PARK8 originally mapped in the large Japanese Sagamihara family with late-onset autosomal dominant PD (ADPD). Patients with LRRK2 mutations account for approximately 2-13% of ADPD and 0.5-3% of sporadic PD. Genetically, LRRK2 mutations have been distributed worldwide with some ethnic differences by single founder effect such as G2019S, R1441G, and G2385R variants. LRRK2 G2385R was reported to be a risk factor for sporadic PD in Asia. Clinically, most patients with LRRK2 mutations develop typical idiopathic PD, however, variable clinical features and pathologies such as diffuse Lewy body disease, multiple system atrophy, progressive supranuclear palsy, and amyotrophic lateral sclerosis have been reported. Although Lewy bodies have been considered as a pathological hallmark for sporadic PD classically, some FPD and sporadic PD patients with heterozygous LRRK2 mutations or homozygous parkin mutations have no Lewy bodies. On the other hand, LRRK2 was reported as a component of Lewy bodies. Based on the variability, multifunction of LRRK2 such as phosphorylation of other proteins, especially, alpha-synuclein and tau, have been suggested. As interaction of Parkin and LRRK2 was reported, interaction and intersection among the autosomal-recessive or autosomal-dominant PD proteins could be involved in some common pathways, and LRRK2 may play an important role as a key FPD gene product. Identification of PARK8 and LRRK2 has given meaningful insights in not only PD but also numerous neurodegenerative disorders such as synucleinopathies and tauopathies with or without Lewy bodies.
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PMID:[Clinical molecular genetics for PARK8 (LRRK2)]. 1771 20


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