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

Parkin is an E3 ubiquitin ligase involved in the ubiquitination of proteins that are important in the survival of dopamine neurons in Parkinson's disease (PD). We show that parkin is S-nitrosylated in vitro, as well as in vivo in a mouse model of PD and in brains of patients with PD and diffuse Lewy body disease. Moreover, S-nitrosylation inhibits parkin's ubiquitin E3 ligase activity and its protective function. The inhibition of parkin's ubiquitin E3 ligase activity by S-nitrosylation could contribute to the degenerative process in these disorders by impairing the ubiquitination of parkin substrates.
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PMID:S-nitrosylation of parkin regulates ubiquitination and compromises parkin's protective function. 1597 89

The identification of rare monogenic forms of Parkinson's disease (PD) has provided tremendous insight into the molecular pathogenesis of this disorder. Heritable mutations in alpha-synuclein, parkin, DJ-1 and PINK1 cause familial forms of PD. In the more common sporadic form of PD, oxidative stress and derangements in mitochondrial complex-I function are considered to play a prominent role in disease pathogenesis. However, the relationship of DJ-1 with other PD-linked genes and oxidative stress has not been explored. Here, we show that pathogenic mutant forms of DJ-1 specifically but differentially associate with parkin, an E3 ubiquitin ligase. Chemical cross-linking shows that pathogenic DJ-1 mutants exhibit impairments in homo-dimer formation, suggesting that parkin may bind to monomeric DJ-1. Parkin fails to specifically ubiquitinate and enhance the degradation of L166P and M26I mutant DJ-1, but instead promotes their stability in cultured cells. The interaction of parkin with L166P DJ-1 may involve a larger protein complex that contains CHIP and Hsp70, perhaps accounting for the lack of parkin-mediated ubiquitination. Oxidative stress also promotes an interaction between DJ-1 and parkin, but this does not result in the ubiquitination or degradation of DJ-1. Parkin-mediated alterations in DJ-1 protein stability may be pathogenically relevant as DJ-1 levels are dramatically increased in the detergent-insoluble fraction from sporadic PD/DLB brains, but are reduced in the insoluble fraction from parkin-linked autosomal recessive juvenile-onset PD brains. These data potentially link DJ-1 and parkin in a common molecular pathway at multiple levels that may have important implications for understanding the pathogenesis of inherited and sporadic PD.
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PMID:Association of DJ-1 and parkin mediated by pathogenic DJ-1 mutations and oxidative stress. 1552 61

We recently reported here that SNCA triplication results in a doubling in the amount of alpha-synuclein protein in blood from cases with hereditary Lewy body disease. This observation shows that alpha-synuclein levels in blood accurately reflect gene dosage, which we assume drives pathogenesis in these individuals. A previous report has suggested that parkin can affect alpha-synuclein metabolism in human brain. Here we have tested whether there is also an increase of alpha-synuclein in autosomal recessive juvenile Parkinsonism (ARJP). We find there is not and discuss this result in terms of the putative relationships between alpha-synuclein and parkin.
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PMID:Unaltered alpha-synuclein blood levels in juvenile Parkinsonism with a parkin exon 4 deletion. 1566 60

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

Autosomal-recessive juvenile parkinsonism (AR-JP) is caused by loss-of-function mutations of the parkin gene. Parkin, a RING-type E3 ubiquitin ligase, is responsible for the ubiquitination and degradation of substrate proteins that are important in the survival of dopamine neurons in Parkinson's disease (PD). Accordingly, the abnormal accumulation of neurotoxic parkin substrates attributable to loss of parkin function may be the cause of neurodegeneration in parkin-related parkinsonism. We evaluated the known parkin substrates identified to date in parkin null mice to determine whether the absence of parkin results in accumulation of these substrates. Here we show that only the aminoacyl-tRNA synthetase cofactor p38 is upregulated in the ventral midbrain/hindbrain of both young and old parkin null mice. Consistent with upregulation in parkin knock-out mice, brains of AR-JP and idiopathic PD and diffuse Lewy body disease also exhibit increased level of p38. In addition, p38 interacts with parkin and parkin ubiquitinates and targets p38 for degradation. Furthermore, overexpression of p38 induces cell death that increases with tumor necrosis factor-alpha treatment and parkin blocks the pro-cell death effect of p38, whereas the R42P, familial-linked mutant of parkin, fails to rescue cell death. We further show that adenovirus-mediated overexpression of p38 in the substantia nigra in mice leads to loss of dopaminergic neurons. Together, our study represents a major advance in our understanding of parkin function, because it clearly identifies p38 as an important authentic pathophysiologic substrate of parkin. Moreover, these results have important implications for understanding the molecular mechanisms of neurodegeneration in PD.
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PMID:Accumulation of the authentic parkin substrate aminoacyl-tRNA synthetase cofactor, p38/JTV-1, leads to catecholaminergic cell death. 1613 53

Excessive accumulation of alpha synuclein (a-syn) in the brain has been implicated in several degenerative neurological disorders, most notably Parkinson's disease. The aggregation of a-syn is the major component of intraneuronal inclusions, Lewy bodies, which are neuropathological features, observed in Parkinson's disease, Lewy body dementia, and other synucleopathies. Diverse cellular events can contribute to a-syn accumulation, aggregation, and to subsequent Lewy body formation. These factors include genetic mutations of synuclein, parkin, or the deubiquitinating enzyme, ubiquitin C-terminal hydrolase (UCH-L1), leading to reduced clearance of a-syn by the ubiquitin proteasomal pathway (UPP). Furthermore, intracellular insults include environmental factors and an age-related decrement in antioxidant defense systems that increase oxidative stress and can affect either the accumulation or clearance of a-syn. We have dynamically modeled a-syn processing in normal and in several disease states; focusing upon alterations in the aggregation and clearance of a-syn as influenced by the UPP and the oxidative stress pathways. Simulation of increased oxidative stress generates a free radical profile analogous to that reported in vivo following exposure to the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Varying model parameters of oxidative stress, UPP dysfunction, or both pathways, simulate kinetics of a-syn that corresponds with the neuropathology described for the sporadic and genetic forms of Parkinson's disease. This in silico model provides a mathematical framework that enables kinetic appraisal of pathway components to better identify and validate important pharmacological targets.
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PMID:Dynamic modeling of alpha-synuclein aggregation for the sporadic and genetic forms of Parkinson's disease. 1692 Feb 72

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

Parkinson disease (PD) belongs to a heterogeneous group of neurodegenerative disorders with movement alterations, cognitive impairment, and alpha-synuclein accumulation in cortical and subcortical regions. Jointly, these disorders are denominated Lewy body disease. Mutations in the parkin gene are the most common cause of familial parkinsonism, and a growing number of studies have shown that stress factors associated with sporadic PD promote parkin accumulation in the insoluble fraction. alpha-Synuclein and parkin accumulation and mutations in these genes have been associated with familial PD. To investigate whether alpha-synuclein accumulation might be involved in the pathogenesis of these disorders by interfering with parkin solubility, synuclein-transfected neuronal cells were transduced with lentiviral vectors expressing parkin. Challenging neurons with proteasome inhibitors or amyloid-beta resulted in accumulation of insoluble parkin and, to a lesser extent, alpha-tubulin. Similarly to neurons in the brains of patients with Lewy body disease, in co-transduced cells alpha-synuclein and parkin colocalized and co-immunoprecipitated. These effects resulted in decreased parkin and alpha-tubulin ubiquitination, accumulation of insoluble parkin, and cytoskeletal alterations with reduced neurite outgrowth. Taken together, accumulation of alpha-synuclein might contribute to the pathogenesis of PD and other Lewy body diseases by promoting alterations in parkin and tubulin solubility, which in turn might compromise neural function by damaging the neuronal cytoskeleton. These studies provide a new perspective on the potential nature of pathogenic alpha-synuclein and parkin interactions in Parkinson disease.
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PMID:alpha-Synuclein aggregates interfere with Parkin solubility and distribution: role in the pathogenesis of Parkinson disease. 1819 4

[123I] Meta-iodobenzylguanidine (MIBG) myocardial scintigraphy has been used to evaluate postganglionic cardiac sympathetic innervation in heart diseases and some neurological disorders. To see clinical usefulness of MIBG myocardial scintigraphy to differentiate Parkinson's disease (PD) and dementia with Lewy bodies (DLB) from related movement disorders and Alzheimer disease (AD), we performed MIBG myocardial scintigraphy in patients with these disorders. Cardiac uptake of MIBG is specifically reduced in PD and DLB, and this imaging approach is a sensitive diagnostic tool that possibly differentiates PD and DLB from related movement disorders and AD. To see pathological basis of the reduced cardiac uptake of MIBG in Lewy body disease, we immunohistochemically examined cardiac tissues from patients with PD, DLB, related movement disorders and AD using antibodies against tyrosine hydroxylase (TH) and phosphorylated neurofilament (NF). Not only TH- but also NF-immunoreactive (ir) axons in the epicardial nerve fascicles were markedly decreased in Lewy body disease, namely cardiac sympathetic denervation, which accounts for the reduced cardiac uptake of MIBG in Lewy body disease. Patients with PD and DLB have Lewy bodies (LBs) in the nervous system, whereas patients with multiple system atrophy (MSA), progressive supranuclear palsy, corticobasal degeneration, parkin-associated PD and AD have no LBs in the nervous system. Even in patients with MSA, cardiac sympathetic denervation was associated with the presence of LBs. Therefore, cardiac sympathetic denervation is closely related to the presence of LBs in a wide range of neurodegenerative processes. Taken together, we conclude that the reduced cardiac uptake of MIBG is a potential biomarker for the presence of LBs. Because alpha-synuclein is one of the key molecules in the pathogenesis of PD, we further investigate how alpha-synuclein aggregates are involved in degeneration of the cardiac sympathetic nerve in PD. We immunohistochemically examined cardiac tissues from patients with incidental Lewy body disease (ILBD) and PD using antibodies against TH and phosphorylated alpha-synuclein. We found that (1) alpha-synuclein aggregates in the epicardial nerve fascicles, namely the distal axons of the cardiac sympathetic nerve, were much more abundant in ILBD with preserved TH-ir axons than in ILBD with decreased TH-ir axons and PD; (2) alpha-synuclein aggregates in the epicardial nerve fascicles were closely related to the disappearance of TH-ir axons; (3) in ILBD with preserved TH-ir axons, alpha-synuclein aggregates were consistently more abundant in the epicardial nerve fascicles than in the paravertebral sympathetic ganglia (pSG); and (4) this distal-dominant accumulation of alpha-synuclein aggregates was reversed in ILBD with decreased TH-ir axons and PD, which both showed decreased or depleted TH-ir axons but more abundant alpha-synuclein aggregates in the pSG. These findings indicate that accumulation of alpha-synuclein aggregates in the distal axons of the cardiac sympathetic nervous system precedes that of neuronal somata or neurites in the pSG and that heralds centripetal degeneration of the cardiac sympathetic nerve in PD. This chronological and dynamic relationship between alpha-synuclein aggregates and distal-dominant degeneration of the cardiac sympathetic nervous system may represent the pathological mechanism underlying a common degenerative process in PD.
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PMID:[Clinical and pathological study on early diagnosis of Parkinson's disease and dementia with Lewy bodies]. 1838 27


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