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

Twenty years ago Parkinson's disease (PD) was thought of as an environmentally determined neurodegenerative disease. It is now known that there are two autosomal dominant disease genes, alpha-synuclein and dardarin, and three genes responsible for autosomal recessive PD, parkin, DJ-1 and PINK-1. Although these gene mutations are not common, their identification has led to a new understanding of the pathogenesis of PD, and to a development in the understanding of the clinical and pathological definitions of PD and Lewy body disease. Ultimately, these advances may lead to the development of new disease-modifying therapies, but more immediately these discoveries have led to a more coherent view of the spectrum of PD and Lewy body diseases and to accurate genetic diagnosis and counselling for some families.
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PMID:Genetics of Parkinson's disease. 1602 16

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

Studies of familial forms of Parkinson's disease (PD) have identified a growing number of genes that derive from the loci given the nomenclature PARK1-PARK13 (OMIM 168600). The alpha-synuclein gene has been implicated in rare autosomal dominant PD because of either mis-sense mutations (PARK1) or gene multiplications (PARK4). Moreover, UCHL1 (PARK5), LRRK2 (PARK8) and HTRA2 (PARK13) have been identified as causative genes for autosomal dominant PD, whereas parkin (PARK2), PINK1 (PARK6), DJ-1 (PARK7) and ATP13A2 (PARK9) have been identified as causative genes for autosomal recessive PD. Neuropathological examination of the kindreds of PARK1/4 showed Lewy body pathology ranging from classic PD to diffuse Lewy body disease. The pathological findings of PARK3 are similar to those of classic PD. In contrast, autopsies of patients with PARK2 showed nigral cell loss without Lewy bodies, although exceptions have been reported. Several kindreds of PARK8 included cases with Lewy body pathology, tau pathology, or with nigral cell loss in the absence of obvious protein deposition. Ubiquitin-positive inclusions that are negative for alpha-synuclein and tau are also seen in some cases. Moreover, widespread Lewy body pathology was also reported in several cases of familial Alzheimer's disease with presenilin-1 mutations.
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PMID:[Pathology of familial Parkinson's disease]. 1771 21

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

The leucine rich repeat kinase 2 (LRRK2/dardarin) is implicated in autosomal dominant familial and sporadic Parkinson's disease (PD); mutations in LRRK2 account for up to 40% of PD cases in some populations. LRRK2 is a large protein with a kinase domain, a GTPase domain, and multiple potential protein interaction domains. As such, delineating the functional pathways for LRRK2 and mechanisms by which PD-linked variants contribute to age-related neurodegeneration could result in pharmaceutically tractable therapies. A growing number of recent studies implicate dysregulation of mitogen activated protein kinases 3 and 1 (also known as ERK1/2) as possible downstream mediators of mutant LRRK2 effects. As these master regulators of growth, differentiation, neuronal plasticity and cell survival have also been implicated in other PD models, a set of common cell biological pathways may contribute to neuronal susceptibility in PD. Here, we review the literature on several major cellular pathways impacted by LRRK2 mutations--autophagy, microtubule/cytoskeletal dynamics, and protein synthesis--in context of potential signaling crosstalk involving the ERK1/2 and Wnt signaling pathways. Emerging implications for calcium homeostasis, mitochondrial biology and synaptic dysregulation are discussed in relation to LRRK2 interactions with other PD gene products. It has been shown that substantia nigra neurons in human PD and Lewy body dementia patients exhibit cytoplasmic accumulations of ERK1/2 in mitochondria, autophagosomes and bundles of intracellular fibrils. Both experimental and human tissue data implicate pathogenic changes in ERK1/2 signaling in sporadic, toxin-based and mutant LRRK2 settings, suggesting engagement of common cell biological pathways by divergent PD etiologies.
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PMID:ERKed by LRRK2: a cell biological perspective on hereditary and sporadic Parkinson's disease. 2422 20