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)

Genetic studies have led to major discoveries in the pathogenesis of various neurodegenerative diseases. Ubiquitin-positive familial frontotemporal dementia was recently found to be caused by mutations in the progranulin gene (PGRN), and the major constituent of the inclusions, TDP-43, was subsequently identified. The tau gene (MAPT) causes frontotemporal dementia with parkinsonism linked to chromosome 17. In Parkinson disease, LRRK2 mutations have emerged as a major cause of both familial and sporadic forms, adding to the previously known genes SNCA,PRKN,DJ1 and PINK1. Several genes have been implicated in Alzheimer disease, including the APP gene and the PSEN genes. Recently, variants in the sortilin-related receptor 1 gene, SORL1, were associated with Alzheimer disease.
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PMID:Etiology and pathophysiology of frontotemporal dementia, Parkinson disease and Alzheimer disease: lessons from genetic studies. 1832 68

Individuals with familial Parkinson's disease (PD) due to a monogenic defect can show considerable clinical and neuropathological variability. To identify factors underlying this variability, histopathological analysis was performed in two clinically different A53T alpha-synuclein heterozygotes from Family H, a multigenerational alpha-synuclein A53T kindred. To determine whether additional genetic factors could contribute to phenotypic variability, Family H and another multigenerational A53T kindred were analyzed for parkin polymorphisms. We identified a previously described variant in parkin exon 4 associated with increased PD risk (S167N). The two A53T heterozygotes had markedly different neuropathology and different parkin genotypes: A N167 homozygote had early onset rapidly progressive disease, early dementia, myoclonus and sleep disorder, while a S167 homozygote had late onset, slowly progressive disease and late dementia. Both had brainstem, cortical, and intraneuritic Lewy bodies (LB). The N167 individual had widespread cortical neurofibrillary degeneration, while the S167 individual had only medial temporal lobe neurofibrillary degeneration. The N167 individual had severe neuronal loss in CA2 associated with Lewy neurites (LN), while the S167 individual had severe neuronal loss in CA1 associated with TDP-43 immunoreactive neuronal inclusions. These findings implicate TDP-43 in the pathology of familial PD and suggest that parkin may act as a modifier of the A53T alpha-synuclein phenotype of familial PD. Furthermore, they suggest a mechanism by which a rare genetic variant that is associated with a minor increase of PD risk in the heterozygous state may, in the homozygous state, exacerbate a disease phenotype associated with a highly penetrant dominant allele.
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PMID:Clinical, neuropathological and genotypic variability in SNCA A53T familial Parkinson's disease. Variability in familial Parkinson's disease. 1838 63

Guam ALS/PDC is a severe tangle forming disorder endemic to Guam with features overlapping such neurodegenerative disorders as Alzheimer disease (AD), Parkinson disease (PD), progressive supranuclear palsy (PSP), ALS, corticobasal degeneration (CBD) and pallido-ponto-nigral degeneration (PPND). Since the prevalence is declining, we examined brain tissue from 35 clinically diagnosed Chamorro patients with ALS/PDC and two Chamorro controls autopsied between 1946 and 2006, to determine if distinct variations in the pathology could be identified up to this time. Although the age at autopsy increased by 4.5-5 years per decade, we identified no qualitative differences in pathological deposits with antibodies against tau, ubiquitin, A beta, alpha-synuclein and TDP-43, indicating that these more recently identified proteins have been involved in the neuropathogenesis over the past 6 decades. Tau and TDP-43 positive neuronal, oligodendroglial and astrocytic inclusions involving multiple nerve fiber tracts occurred in both the ALS and PDC types, reinforcing the concept that these forms are part of the same disorder. The results obtained may help to define the commonality of the Guam disease with other tangle forming disorders and may help in monitoring the epidemiological changes that are taking place.
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PMID:Enduring involvement of tau, beta-amyloid, alpha-synuclein, ubiquitin and TDP-43 pathology in the amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam (ALS/PDC). 1884 96

Mutations in LRRK2 are the single most common known cause of Parkinson's disease (PD). Two new PD patients with LRRK2 mutation were identified from a cohort with extensive postmortem assessment. One of these patients harbors the R793M mutation and presented with the typical clinical and pathological features of PD. A novel L1165P mutation was identified in a second patient. This patient had the classical and pathological features of PD, but additionally developed severe neuropsychological symptoms and dementia associated with abundant neurofibrillary tangles in the hippocampal formation; features consistent with a secondary diagnosis of tangle-predominant dementia. alpha-Synuclein-containing pathological inclusions in these patients also were highly phosphorylated at Ser-129, similar to other patients with idiopathic PD. These two PD patients also were characterized by the presence of occasional cytoplasmic TDP-43 inclusions in the temporal cortex, a finding that was not observed in three other patients with the G2019S mutation in LRRK2. These findings extend the clinical and pathological features that may be associated with LRRK2 mutations.
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PMID:Clinical and pathological characteristics of patients with leucine-rich repeat kinase-2 mutations. 1900 85

Ubiquitin immunoreactive (UBQ-ir) inclusions were present to variable extents in the inferior olivary nucleus (ION) in 37/48 (77%) patients with frontotemporal lobar degeneration (FTLD), in 10/11 (91%) patients with motor neurone disease (MND), in 5/5 (100%) patients with Alzheimer's disease (AD), 5/7 (71%) patients with dementia with Lewy bodies, 13/19 (68%) patients with Parkinson's disease, 11/11(100%) patients with Progressive Supranuclear Palsy, 2/6 (33%) patients with Multisystem Atrophy, 1/3 (33%) patients with Huntington's disease and in 14/14 (100%) normal elderly control subjects. In FTLD, UBQ-ir inclusions were present in 26/32 (81%) patients with FTLD-U, in 10/15 (67%) patients with tauopathy, and in the single patient with Dementia Lacking Distinctive Histology. In 13 FTLD-U patients, and in a single AD and in 2 MND patients, the UBQ-ir inclusions had a rounded, spicular or skein-type appearance, and these were also TDP-43 immunoreactive (TDP-43-ir). In all other affected patients in all diagnostic groups, and in control subjects, the UBQ-ir neuronal cytoplasmic inclusions (NCI) were of a conglomerated type, resembling a cluster of large granules or globules, but were never TDP-43-ir. In 3 of the 13 FTLD-U patients with spicular NCI, conglomerated NCI were also present but in separate cells. Double-labelling immunohistochemistry, and confocal microscopy, for UBQ and TDP-43 confirmed that only the spicular UBQ-ir inclusions in patients with FTLD-U, AD and MND contained TDP-43, though in these patients there were occasional TDP-43 immunoreactive inclusions that were not UBQ-ir. Nuclear TDP-43 immunoreactivity was absent in ION in FTLD-U, AD or MND when TDP-43 cytoplasmic inclusions were present, but remained in neurones with UBQ-ir, TDP-43 negative inclusions. The target protein within the UBQ-ir, TDP-43-negative inclusions remains unknown, but present studies indicate that this is not tau, neurofilament or internexin proteins. These TDP-43 negative, UBQ-ir inclusions appear to be more related to ageing than neurodegeneration, and are without apparent diagnostic significance. The pathophysiological mechanism leading to their formation, and any consequences their presence may have on nerve cell function, remain unknown.
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PMID:TDP-43 in ubiquitinated inclusions in the inferior olives in frontotemporal lobar degeneration and in other neurodegenerative diseases: a degenerative process distinct from normal ageing. 1933 Mar 39

TDP-43 is a nuclear protein involved in exon skipping and alternative splicing. Recently, TDP-43 has been identified as the pathological signature protein in frontotemporal lobar degeneration with ubiquitin-positive inclusions and in amyotrophic lateral sclerosis. In addition, TDP-43-positive inclusions are present in Parkinson disease, dementia with Lewy bodies, and 30% of Alzheimer disease cases. Pathological TDP-43 is redistributed from the nucleus to the cytoplasm, where it accumulates. An approximately 25-kDa C-terminal fragment of TDP-43 accumulates in affected brain regions, suggesting that it may be involved in the disease pathogenesis. Here, we show that overexpression of the 25-kDa C-terminal fragment is sufficient to cause the mislocalization and cytoplasmic accumulation of endogenous full-length TDP-43 in two different cell lines, thus recapitulating a key biochemical characteristic of TDP-43 proteinopathies. We also found that TDP-43 mislocalization is associated with a reduction in the low molecular mass neurofilament mRNA levels. Notably, we show that the autophagic system plays a role in TDP-43 metabolism. Specifically, we found that autophagy inhibition increases the accumulation of the C-terminal fragments of TDP-43, whereas inhibition of mTOR, a key protein kinase involved in autophagy regulation, reduces the 25-kDa C-terminal fragment accumulation and restores TDP-43 localization. Our results suggest that autophagy induction may be a valid therapeutic target for TDP-43 proteinopathies.
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PMID:Rapamycin rescues TDP-43 mislocalization and the associated low molecular mass neurofilament instability. 1965 85

TDP-43 has been found in inclusion bodies of multiple neurological disorders, including amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson's disease and Alzheimer's disease. Mutations in the TDP-43 encoding gene, TARDBP, have been subsequently reported in sporadic and familial ALS patients. In order to investigate the pathogenic nature of these mutants, the effects of three consistently reported TARDBP mutations (A315T, G348C and A382T) were tested in cell lines, primary cultured motor neurons and living zebrafish embryos. Each of the three mutants and wild-type (WT) human TDP-43 localized to nuclei when expressed in COS1 and Neuro2A cells by transient transfection. However, when expressed in motor neurons from dissociated spinal cord cultures these mutant TARDBP alleles, but less so for WT TARDBP, were neurotoxic, concomitant with perinuclear localization and aggregation of TDP-43. Finally, overexpression of mutant, but less so of WT, human TARDBP caused a motor phenotype in zebrafish (Danio rerio) embryos consisting of shorter motor neuronal axons, premature and excessive branching as well as swimming deficits. Interestingly, knock-down of zebrafisfh tardbp led to a similar phenotype, which was rescued by co-expressing WT but not mutant human TARDBP. Together these approaches showed that TARDBP mutations cause motor neuron defects and toxicity, suggesting that both a toxic gain of function as well as a novel loss of function may be involved in the molecular mechanism by which mutant TDP-43 contributes to disease pathogenesis.
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PMID:Gain and loss of function of ALS-related mutations of TARDBP (TDP-43) cause motor deficits in vivo. 1995 28

Emerging evidence suggests that misfolded proteins in the various neurodegenerative diseases can be targets for immunotherapy including vaccination antibody therapy. To date, vaccination strategies have been shown to be effective in Alzheimer's disease, Parkinson's disease, Huntington's disease and Prion disease. Interestingly, the subcellular localization of the target proteins varies, including cytosol, synaptosomes and extracellular spaces. We have documented that mutant SOD1 is secreted together with a neurosecretory protein chromogranin, and that vaccination against the SOD1 mutant is beneficial in delaying the onset and prolonging the lifespan. However, the mechanism of vaccination on the mutant SOD1 mice remains unclear. Moreover, vaccination induces diverse inflammatory reactions, which are reported to modify both the onset and the progression of ALS. Therefore, it is important to clarify the role of innate or acquired immunity in the pathogenesis of ALS to avoid the adverse reactions of the vaccination, and rather to apply it for amelioration. Passive immunization is also promising since only aberrant proteins can be targeted using a specific monoclonal antibody. The development of the current immunization techniques is very important for the future application, since key molecules for the sporadic ALS have emerged and are intensively investigated such as TDP-43.
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PMID:[Future perspectives of immunotherapy against ALS]. 2003 Feb 19

Prions are proteins that access self-templating amyloid forms, which confer phenotypic changes that can spread from individual to individual within or between species. These infectious phenotypes can be beneficial, as with yeast prions, or deleterious, as with mammalian prions that transmit spongiform encephalopathies. However, the ability to form self-templating amyloid is not unique to prion proteins. Diverse polypeptides that tend to populate intrinsically unfolded states also form self-templating amyloid conformers that are associated with devastating neurodegenerative disorders. Moreover, two RNA-binding proteins, FUS and TDP-43, which form cytoplasmic aggregates in amyotrophic lateral sclerosis, harbor a 'prion domain' similar to those found in several yeast prion proteins. Can these proteins and the neurodegenerative diseases to which they are linked become 'infectious' too? Here, we highlight advances that define the transmissibility of amyloid forms connected with Alzheimer's disease, Parkinson's disease and Huntington's disease. Collectively, these findings suggest that amyloid conformers can spread from cell to cell within the brains of afflicted individuals, thereby spreading the specific neurodegenerative phenotypes distinctive to the protein being converted to amyloid. Importantly, this transmissibility mandates a re-evaluation of emerging neuronal graft and stem-cell therapies. In this Commentary, we suggest how these treatments might be optimized to overcome the transmissible conformers that confer neurodegeneration.
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PMID:Prion-like disorders: blurring the divide between transmissibility and infectivity. 2035 30

Involvement of the peripheral nervous system (PNS) is relatively common in some neurodegenerative proteinopathies of the brain and may be pathogenetically and diagnostically important. In Parkinson's disease, neuronal alpha-synuclein aggregates are distributed throughout the nervous system, including the central nervous system (CNS), sympathetic ganglia, enteric nervous system, cardiac and pelvic plexuses, submandibular gland, adrenal medulla and skin. The pathological process may target the PNS and CNS at the same time. In multiple system atrophy, numerous glial cytoplasmic inclusions composed of filamentous alpha-synuclein are widely distributed in the CNS, while alpha-synuclein accumulation is minimal in the sympathetic ganglia and is restricted to neurons. Neurofibrillary tangles can occur in the sympathetic and spinal ganglia in tauopathy, although they appear to develop independently of cerebral Alzheimer's disease pathology. In amyotrophic lateral sclerosis, neuronal loss with TDP-43-positive neuronal cytoplasmic inclusions in the spinal ganglia is more frequent than previously thought. Peripheral ganglia and visceral organs are also involved in polyglutamine diseases. Further elucidation and characterization of PNS lesions will have implications for intravital biopsy diagnosis in neurodegenerative proteinopathy, particularly in Parkinson's disease.
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PMID:Involvement of the peripheral nervous system in synucleinopathies, tauopathies and other neurodegenerative proteinopathies of the brain. 2053 96


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