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

Here, we investigated if TAR-DNA-binding protein-43 (TDP-43), the disease protein in frontotemporal lobar degeneration and ubiquitin inclusions with or without motor neuron disease as well as amyotrophic lateral sclerosis, also formed inclusions in Lewy body (LB) disorders including Parkinson's disease (PD) without or with dementia (PDD), and dementia with LBs (DLB) alone or in association with Alzheimer's disease (AD). Immunohistochemical analyses of TDP-43 in clinically well characterized and pathologically confirmed cases of DLB + AD, PD and PDD demonstrated TDP-43 pathology in the following percentage of cases: DLB + AD = 25/80 (31.3%); PD = 5/69 (7.2%); PDD = 4/21 (19%), while DLB and normal controls exhibited no (0/10, 0%) and one cases (1/33, 3%) presenting TDP-43 pathology, respectively. Significant differences in the prevalence of TDP-43 lesions were noted between disease versus normal brains (P < 0.001) as well as demented versus non-demented brains (P < 0.001). Statistical analyses revealed a positive relationship between TDP-43 lesions and several clinical and pathological parameters in these disorders suggesting the TDP-43 pathology may have co-morbid effects in LB diseases. This study expands the concept of TDP-43 proteinopathies by implicating TDP-43 lesions in mechanisms of neurodegeneration in LB disorders.
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PMID:Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases. 1765 32

Fatigue without coincident depression may accompany many neurological disorders, including multiple sclerosis, Parkinson's disease, motor neuron disease, stroke and post-polio syndrome, and is frequently reported by patients as a predominant complaint. The pathophysiology of fatigue is unknown. The role of various mechanisms has been suggested, including the effect of proinflammatory cytokines (TNF-alpha, IL-1beta and IL-6) on glutaminergic transmission, hypothalamo-pituitary-adrenal (HPA) axis dysfunction, disturbances of astroglia metabolism and decreased levels of the neurotransmitters noradrenaline and serotonin. The diagnosis of fatigue syndrome is based on exclusion of depression and additional organic conditions (anaemia, cardiovascular disorders, kidney diseases or hypothyroidism). The treatment of fatigue syndrome is complex. Physical activity, rehabilitation, psychotherapy and avoidance of factors which may increase fatigue, such as fever, anxiety, depression, pain, sleep disturbances, as well as some drugs like opioids and benzodiazepines, are important. Pharmacological treatment leads to slight improvement. Amantadine, modafinil and pemoline are administered to such patients.
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PMID:[Fatigue syndrome in chronic neurological disorders]. 1787 43

Retinoic acid (RA) is involved in the induction of neural differentiation, motor axon outgrowth and neural patterning. Like other developmental molecules, RA continues to play a role after development has been completed. Elevated RA signalling in the adult triggers axon outgrowth and, consequently, nerve regeneration. RA is also involved in the maintenance of the differentiated state of adult neurons, and disruption of RA signalling in the adult leads to the degeneration of motor neurons (motor neuron disease), the development of Alzheimer's disease and, possibly, the development of Parkinson's disease. The data described here strongly suggest that RA could be used as a therapeutic molecule for the induction of axon regeneration and the treatment of neurodegeneration.
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PMID:Retinoic acid in the development, regeneration and maintenance of the nervous system. 1788 53

Glial-derived neurotrophic factor (GDNF) is a neurotrophin that could be developed as a neurotherapeutic for Parkinson's disease, stroke, and motor neuron disease. However, GDNF does not cross the blood-brain barrier (BBB). Human GDNF was re-engineered by fusion of the mature GDNF protein to the carboxyl terminus of the chimeric monoclonal antibody (MAb) to the human insulin receptor (HIR). The HIRMAb-GDNF fusion protein is bi-functional, and both binds the HIR, to trigger receptor-mediated transport across the BBB, and binds the GDNF receptor (GFR)-alpha1, to activate GDNF neuroprotection pathways behind the BBB. COS cells were dual transfected with the heavy chain (HC) and light chain fusion protein expression plasmids, and the HC of the fusion protein was immunoreactive with antibodies to both human IgG and GDNF. The HIRMAb-GDNF fusion protein bound with high affinity to the extracellular domain of both the HIR, ED(50) = 0.87 +/- 0.13 nM, and the GFRalpha1, ED(50) = 1.68 +/- 0.17 nM. The HIRMAb-GDNF fusion protein activated luciferase gene expression in human neural SK-N-MC cells dual transfected with the c-ret kinase and a luciferase reporter gene under the influence of the rat tyrosine hydroxylase promoter, and the ED(50), 1.68 +/- 0.45 nM, was identical to the ED(50) in the GFRalpha1 binding assay. The fusion protein was active in vivo in a rat middle cerebral artery occlusion model, where the stroke volume was reduced 77% (P < 0.001). In conclusion, these studies describe the re-engineering of GDNF, to make this neurotrophin transportable across the human BBB.
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PMID:GDNF fusion protein for targeted-drug delivery across the human blood-brain barrier. 1808 Mar 33

Clinically, seizures from supplementary motor area (SMA) are characterized by asymmetric bilateral tonic posturing without loss of awareness, and its dysfunction is also strongly related to the clinical cardinal features in patients with Parkinson's disease and dystonia. By investigating Bereitschaftspotentials (BPs) from SMA, the following normal functions are elucidated. 1) SMA proper, a caudal part of SMA showed a somatotopy of BP generators in accordance with each part of the voluntary movements in the body, 2) bilateral SMAs were involved in each side of the body movements equally, and the amplitude did not differ from one in the contralateral primary motor area (MI), 3) pre-SMA was strongly related sensorimotor integration, decision making, repetitive rate of voluntary movements, voluntary motor inhibition and negative motor response. We look forward to clinical application of brain potentials from SMA in the field of brain-computer interface such as assessment and restorative approach in patients with spinal cord injury, paraplegia or motor neuron disease.
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PMID:[Human supplementary motor area: a role in voluntary movements and its clinical significance]. 1821 Jul 84

Axonal degeneration is a prominent feature of many neurological disorders that are associated with mitochondrial dysfunction, including Parkinson's disease, motor neuron disease, and inherited peripheral neuropathies. Studies of the Wld(s) mutant mouse, which undergoes delayed Wallerian degeneration in response to axonal injury, suggest that axonal degeneration is an active process. Wld(s) mice also have slower axonal degeneration and disease progression in numerous models of neurodegenerative disease. The Wld(s) mutation results in the production of a chimeric protein that contains the full-length coding sequence of nicotinamide mononucleotide adenylyltransferase 1 (Nmnat1), which alone is sufficient for axonal protection in vitro. To test the effects of increased Nmnat expression on axonal degeneration induced by mitochondrial dysfunction, we examined dorsal root ganglion (DRG) neurons treated with rotenone. Rotenone induced profound axonal degeneration in DRG neurons; however, this degeneration was delayed by expression of Nmnat. Nmnat-mediated protection resulted in decreased axonal accumulation and sensitivity to reactive oxygen species (ROS) but did not affect the change in the rate of rotenone-induced loss in neuronal ATP. Nmnat also prevented axonal degeneration caused by exposure to exogenous oxidants and reduced the level of axonal ROS after treatment with vincristine, further supporting the idea that Nmnat promotes axonal protection by mitigating the effects of ROS.
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PMID:Nmnat delays axonal degeneration caused by mitochondrial and oxidative stress. 1846 39

Parkinson's disease (PD), Alzheimer's disease (AD), and motor neuron disease (MND) share epidemiological, clinical, and pathological features. Few studies have reported comprehensively on individuals who demonstrate a neurodegenerative 'overlap' syndrome, comprising idiopathic parkinsonism, dementia, and motor neuron dysfunction. We describe clinical, electrophysiological, and pathological features in six patients with neurodegenerative 'overlap' syndrome. All had cardinal features of PD (duration 6-26 years), and any mixture of dementia (slowly advancing), fasciculations, hyperreflexia, Babinski signs and mild atrophy and weakness of distal muscles (slowly progressive). EMG often demonstrated a lack of denervation in conjunction with abnormal MEPs (high thresholds). Patients had either 6FD-PET or pathological studies consistent with PD. Pathological studies also demonstrated moderate numbers of neurofibrillary tangles and plaque formation, typically with sparing of motor neurons in the spinal cord. We conclude that neurodegenerative 'overlap' syndrome may represent forme frustes of traditionally accepted diagnostic categories. Patients with parkinsonism, fasciculations, hyperreflexia and mild atrophy are unlikely to demonstrate active denervation on EMG; their prognosis is better than for classical MND. Neurodegenerative overlap syndrome (clinicopathological mixtures of PD, AD, and MND) may develop in some individuals as a reflection of common etiology, pathogenesis or susceptibility.
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PMID:Neurodegenerative 'overlap' syndrome: Clinical and pathological features of Parkinson's disease, motor neuron disease, and Alzheimer's disease. 1859 Sep 98

Dropped head syndrome is primarily based on weakness localized at neck extensors. It may result from motor neuron disease, myasthenia gravis, and chronic inflammatory demyelinating polyneuropathy and also from various neuromuscular diseases including inflammatory, dystrophic and metabolic myopathies. Camptocormia (CC) on the other hand is an unusual condition characterized by progressive weakness of the extensor vertebral muscles and results in involuntary trunk flexion. CC may emerge as a clinical feature of many different conditions such as several myopathies and Parkinson's disease. The association of dropped head syndrome with CC has been rarely published in the literature. However, this is the only case presenting with concomitant dropped head syndrome and CC as a clinical picture of myotonic dystrophy (MD). In this report we aimed to represent a female patient, who was diagnosed as having myotonic dystrophy, with concurrent dropped head syndrome and CC.
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PMID:Camptocormia and dropped head syndrome as a clinic picture of myotonic myopathy. 1863 87

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

DNA methylation occurs predominantly at cytosines that precede guanines in dinucleotide CpG sites; it is one of the most important mechanisms for epigenetic DNA regulation during normal development and for aberrant DNA in cancer. To determine the feasibility of DNA methylation studies in the postmortem human brain, we evaluated brain samples with variable postmortem artificially increased delays up to 48 hours. DNA methylation was analyzed in selected regions of MAPT, APP, and PSEN1 in the frontal cortex and hippocampus of controls (n=26) and those with Alzheimer disease at Stages I to II (n=17); Alzheimer disease at Stages III to IV (n=15); Alzheimer disease at Stages V to VI (n=12); argyrophilic grain disease (n=10); frontotemporal lobar degeneration linked to tau mutations (n=6); frontotemporal lobar degeneration with ubiquitin-immunoreactive inclusions (n=4); frontotemporal lobar degeneration with motor neuron disease (n=3); Pick disease (n=3); Parkinson disease (n=8); dementia with Lewy bodies, pure form (n=5); and dementia with Lewy bodies, common form (n=15). UCHL1 (ubiquitin carboxyl-terminal hydrolase 1 gene) was analyzed in the frontal cortex of controls and those with Parkinson disease and related synucleinopathies. DNA methylation sites were very reproducible in every case. No differences in the percentage of CpG methylation were found between control and disease samples or among the different pathological entities in any region analyzed. Because small changes in methylation of DNA promoters in vulnerable cells might have not been detected in total homogenates, however, these results should be interpreted with caution, particularly as they relate to chronic degenerative diseases in which small modifications may be sufficient to modulate disease progression.
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PMID:DNA methylation of Alzheimer disease and tauopathy-related genes in postmortem brain. 1960 65


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