Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0752347 (Dementia with Lewy bodies)
 1,653 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously linked families with autosomal-dominant, late-onset parkinsonism to chromosome 12p11.2-q13.1 (PARK8). By high-resolution recombination mapping and candidate gene sequencing in 46 families, we have found six disease-segregating mutations (five missense and one putative splice site mutation) in a gene encoding a large, multifunctional protein, LRRK2 (leucine-rich repeat kinase 2). It belongs to the ROCO protein family and includes a protein kinase domain of the MAPKKK class and several other major functional domains. Within affected carriers of families A and D, six post mortem diagnoses reveal brainstem dopaminergic degeneration accompanied by strikingly diverse pathologies. These include abnormalities consistent with Lewy body Parkinson's disease, diffuse Lewy body disease, nigral degeneration without distinctive histopathology, and progressive supranuclear palsy-like pathology. Clinical diagnoses of Parkinsonism with dementia or amyotrophy or both, with their associated pathologies, are also noted. Hence, LRRK2 may be central to the pathogenesis of several major neurodegenerative disorders associated with parkinsonism.
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PMID:Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. 1554 3

The presence of alpha-synuclein Lewy body pathology is used to distinguish Parkinson's disease from parkinsonism, for which a broader spectrum of neuropathologies, including tau-immunopositive neurofibrillary tangles and ubiquitin inclusions, might accompany nigral neuronal loss. These neuropathologies define the endpoint of many neurodegenerative disorders but might be symptomatic rather than causative. Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) were recently discovered in late-onset parkinsonism, the phenotype of which can be clinically and pathologically indistinguishable from Parkinson's disease. However, in some kindreds with LRRK2- associated disease, pathologically distinct forms of parkinsonism, including nigral neuronal loss with Lewy body disease or tau-immunopositive neurofibrillary tangles, were discovered. Understanding the molecular function of the LRRK2 protein and its associated pathways might elucidate the switch between Lewy body pathology and neurofibrillary tangles, and holds promise for prospective therapeutics that might slow or halt progression of many forms of parkinsonism.
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PMID:LRRK2: a common pathway for parkinsonism, pathogenesis and prevention? 1640 42

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

We describe a Spanish family in which 3 of 4 siblings had dementia with Lewy bodies, 2 of them starting at age 26 years and the other at 29 years. The father has recently been diagnosed with Lewy body disease, with onset at 77 years. Neuropathological examination of the brain of the index patient disclosed unusual features characterized by diffuse Lewy body disease and generalized neurofibrillary tangle pathology but with no amyloid deposits in any region. Moreover, Lewy body pathology colocalized with neurofibrillary tangles in most affected neurons. Mutation screening that included all coding exons of presenilin 1 (PSEN1), presenilin 2 (PSEN2), alpha-synuclein (SNCA), beta-synuclein (SNCB), microtubule-associated protein tau (MAPT), leucine-rich repeat kinase 2 (LRRK2), glucocerebrosidase (GBA), and exons 16 and 17 of the amyloid precursor protein (APP) genes did not identify any mutation. Genome-wide single nucleotide polymorphism was performed in 4 family members and ruled out any pathogenic duplication or deletion in the entire genome. In summary, we report a unique family with pathologically confirmed early-onset dementia with Lewy bodies with widespread tau and alpha-synuclein deposition. The absence of mutations in genes known to cause Lewy body disease suggests that a novel locus or loci are implicated in this neurodegenerative disease.
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PMID:Early-onset familial lewy body dementia with extensive tauopathy: a clinical, genetic, and neuropathological study. 1910 44

Mutations in leucine-rich repeat kinase 2 gene (PARK8/LRRK2) encoding the protein Lrrk2 are causative of inherited and sporadic Parkinson's disease (PD) with phenotypic manifestations of frontotemporal lobar degeneration, corticobasal degeneration and associated motor neuron disease in some patients, and with variable penetrance. Neuropathology is characterized by loss of dopaminergic neurons in the substantia nigra pars compacta in all cases with accompanying Lewy pathology, or tau pathology or without intraneuronal inclusions, thus indicating that mutations in LRRK2 are not always manifested as Lewy body disease (LBD) or as alpha-synucleinopathy. Molecular studies have not disclosed clear association between nerve cell degeneration and modifications in the kinase activity of Lrrk2, and the pathogenesis of LRRK2 mutations remains unknown. Several morphological studies have suggested that Lrrk2 is a component of Lewy bodies and aberrant neurites in sporadic PD and Dementia with Lewy bodies, whereas other studies have indicated that Lrrk2 does not participate in Lewy body composition. Likewise, some studies have shown Lrrk2 immunoreactivity in hyper-phosphorylated tau inclusions in Alzheimer's disease (AD) and other tauopathies, whereas other studies did not find Lrrk2 in hyper-phosphorylated tau inclusions. We have used three currently used anti-Lrrk2 antibodies (NB-300-268, NB-300-267 and AP7099b) and concluded that these differences are largely dependent on the antibodies used and, particularly, on the interpretation of the origin of the multiple bands of low molecular weight species, in addition to the band corresponding to full-length Lrrk2, that recognize the majority of these antibodies. A review of the available data and our results indicate that full-length Lrrk2 is not a major component of Lewy bodies in LBDs, and of hyper-phosphorylated tau inclusions in AD and tauopathies. Bands of low molecular weight are probably not the result of post-mortem artefacts as they are also present in cultured cells processed under optimal conditions. Truncated forms of Lrrk2 and additional transcripts related with LRRK2, in the absence of spliced forms of Lrrk2 may account for Lrrk2 immunoreactivity in distinct intraneuronal inclusions.
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PMID:LRRK2 and neurodegeneration. 1914 48

Mutations of the leucine-rich repeat kinase 2 (LRRK2) gene are the leading cause of genetically inherited Parkinson's disease (PD) and its more severe variant diffuse Lewy body disease (DLB). Pathological mutations in Lrrk2 are autosomal dominant, suggesting a gain of function. Mutations in alpha-synuclein also produce autosomal dominant disease. Here we report an interaction between Lrrk2 and alpha-synuclein in a series of diffuse Lewy body (DLB) cases and in an oxidative stress cell based assay. All five cases of DLB, but none of five controls, showed co-immunoprecipitation of Lrrk2 and alpha-synuclein in soluble brain extracts. Colocalization was also found in pathological deposits in DLB postmortem brains by double immunostaining. In HEK cells transfected simultaneously with plasmids expressing Lrrk2 and alpha-synuclein, co-immunoprecipitation of Lrrk2 and alpha-synuclein was detected when they were exposed to oxidative stress by H(2)O(2). Taken together, these results suggest the possibility that in PD and related synucleinopathies, oxidative stress upregulates alpha-syn and Lrrk2 expression, paving the way for pathological interactions. New therapeutic approaches to PD and the synucleinopathies may result from limiting the interaction between Lrrk2 and alpha-synuclein.
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PMID:Lrrk2 interaction with alpha-synuclein in diffuse Lewy body disease. 1987 56