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)

Neurosin is a kallikrein-like serine protease expressed preferentially in the human brain. It is localized in senile plaques and neurofibrillary tangles in the brains of individuals with Alzheimer's disease (AD) and in Lewy bodies in patients with Parkinson's disease. Neurosin is present in the cerebrospinal fluid (CSF) as a proenzyme and does not show any enzymatic activity. We have developed a sandwich ELISA system using monoclonal and polyclonal antibodies against human neurosin and have measured neurosin levels in the CSF from AD and non-CNS disease patients. Both male and female patients with peripheral neuropathy showed statistically positive correlations between CSF neurosin concentrations and age (males, n = 52, r = 0.482, p < 0.005; females, n = 43, r = 0.365, p < 0.005). In contrast, such positive correlation was not observed in the CSF from patients with AD. Further, some such patients showed extremely low levels of CSF neurosin. Our results suggest that neurosin is an aging-related protease and that a decreased CSF concentration of neurosin may be a risk factor for developing AD.
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PMID:Decreased cerebrospinal fluid levels of neurosin (KLK6), an aging-related protease, as a possible new risk factor for Alzheimer's disease. 1248 Jul 53

Mutations in the parkin gene, PARK2, are a common cause of parkinsonism in familial as well as isolated cases with an age of onset <40 years and should be considered in the diagnostic work up of young-onset parkinsonism. We report a detailed clinical evaluation of a personal series of 24 patients with mutations in the parkin gene. The clinical presentation of most cases was broadly comparable to that of previous descriptions of autosomal recessive early-onset or juvenile parkinsonism and young-onset Parkinson's disease and also had similarities with phenotypes of dopa-responsive dystonia. However, our only case with consanguineous parents had an age of onset of 54 years. We report three new phenotypes at presentation: cervical dystonia; autonomic dysfunction and peripheral neuropathy; and pure exercise-induced dystonia. We emphasize a number of clinical features that can be seen in parkin disease: focal dystonia; early instability; freezing; festination or retropulsion; concurrent autonomic failure; dramatic response to anticholinergics; early or atypical L-dopa-induced dyskinesias; exquisite sensitivity to small doses of L-dopa; and recurrent psychosis, even taking L-dopa alone. We also report behavioural disorder prior to the onset of parkinsonism. Some relatives carrying a single parkin mutation without extrapyramidal symptoms or signs also had psychiatric symptoms that might be related to their carrier status.
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PMID:Parkin disease: a phenotypic study of a large case series. 1276 48

There is growing evidence that reduced neurotrophic support is a significant factor in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). In this review we discuss the structure and functions of neurotrophins such as nerve growth factor, and the role of these proteins and their tyrosine kinase (Trk) receptors in the aetiology and therapy of such diseases. Neurotrophins regulate development and the maintenance of the vertebrate nervous system. In the mature nervous system they affect neuronal survival and also influence synaptic function and plasticity. The neurotrophins are able to bind to two different receptors: all bind to a common receptor p75NTR, and each also binds to one of a family of Trk receptors. By dimerization of the Trk receptors, and subsequent transphosphorylation of the intracellular kinase domain, signalling pathways are activated. We discuss here the structure and function of the neurotrophins and how they have been, or may be, used therapeutically in AD, PD, Huntington's diseases, ALS and peripheral neuropathy. Neurotrophins are central to many aspects of nervous system function. However they have not truly fulfilled their therapeutic potential in clinical trials because of the difficulties of protein delivery and pharmacokinetics in the nervous system. With the recent elucidation of the structure of the neurotrophins bound to their receptors it will now be possible, using a combination of in silico technology and novel screening techniques, to develop small molecule mimetics with much improved pharmacotherapeutic profiles.
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PMID:Neurotrophins and neurodegeneration. 1278 19

The study was conducted to determine the prevalence of neurological diseases in a rural community in Eastern India through a community based survey with the help of trained doctors following on WHO protocol (1981) translated in local vernacular, among 20842 rural residents (male-11037, female-9805, census India-1991, the State of West Bengal in Eastern India) over a period of one yearfrom May 1992 to April 1993 in two phases. Professionals screened the patients by house to house survey in the first phase and later on they were examined in details in temporary clinics in second phase. A total of 606 patients were identified and classified according to well-defined diagnostic criteria. The commonest diseases per 100,000 were headache: 870, vertebral diseases with neurological involvement: 540, seizure disorders: 360, vertigo: 230, stroke: 147, movement disorders: 140, peripheral neuropathy: 80. The age and sex specific prevalence showed increasing frequency of neurological disorders with advancing age in both genders excepting slight dip in the fourth and fifth decades among females. In the present study prevalence of headache, epilepsy, stroke and Parkinson's disease was lower than that of in the Western countries. Different inclusion criteria, multiethnicity, different environmental factors, poor medical facility and insufficient number of aged population may be responsible for lower prevalence of chronic neurological disorders as compared to Western countries. Increase in the life expectancy in future will lead to increasing burden of chronic neurological diseases in absolute term in Indian society considering the one billion population at present.
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PMID:Epidemiological study of neurological disorders in a rural population of Eastern India. 1520 Feb 13

Two genes were identified for autosomal recessive forms of early onset Parkinson's disease: parkin and DJ-1. We describe 2 siblings with EOPD due to parkin mutations and peripheral neuropathy, which presented as neuropathy with liability to pressure palsies (HNPP) in the index case. RT-PCR experiments revealed that the parkin gene is expressed in sural nerves from both controls and patient with parkin-related disease. Our findings support the view that parkin may play a role in the peripheral nervous system.
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PMID:Does parkin play a role in the peripheral nervous system? A family report. 1530 Jun 70

Clinicians are often asked to make an assessment on whether a patient is medically fit to drive, even though few have been formally trained in this area. Driving is a complex task that requires having adequate operational, cognitive and higher executive functions that work together. These functions can be compromised to a greater or lesser extent in neurological disorders, such as stroke, traumatic brain injury, peripheral neuropathy, dementia, Parkinson's disease and epilepsy. There is insufficient standardized information relating to impaired function at this time. Because of this, state laws vary in their assessment of medical conditions as they relate to driver licensing. Wisconsin laws are reviewed as an example. There are numerous assessment tests for various functions, but they lack a validated correlation with actual driving performance. These and other factors, as well as practical recommendations for the practicing physicians, are the subjects of this review.
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PMID:Neurologic conditions: assessing medical fitness to drive. 1593 8

Neurotrophic factors are compounds that enhance neuronal survival and differentiation. Most of these compounds exert their pharmacological actions on selective types of neurons, and therefore, are considered promising new therapeutic agents for the treatment of different neurodegenerative disorders characterized by selective degeneration of certain neuronal groups. Those compounds have been used in humans for several neurological disorders including amyotrophic lateral sclerosis--ciliary derived neurotrophic factor (CNTF) and brain derived neurotrophic factor (BDNF), Alzheimer's disease and peripheral neuropathy--nerve growth factor (NGF) and Parkinson's disease (PD)--glial derived neurotrophic factor (GDNF). In spite of well founded clinical experiments by previous experimental work in animal models some of these trials have been negative. For instance, animal models of PD have shown that several neurotrophic factors, including GDNF and other compounds, reduce apoptosis and increase resistance of dopamine neurons to neurotoxins in vitro. These compounds prevent or recover the damage to dopamine neurons of rodents and primates produced by chemical or mechanical acute lesions including 6-OH-DA, MPTP, methamphetamine and axotomy. The differences between the promising results obtained in experimental models and the lack of clinical results or excessive toxicity found in humans could be attributed to the following reasons: (a) Lack of relevance between the pathogenesis of the experimental lesion and the corresponding neurodegenerative disorder. (b) Poor correlation between results obtained in acute, self-limited, selective deficit produced to experimental animals and those available in more complex, chronic and progressive disorders involving patients. (c) Inadequate delivery of the active product to the target area in the human brain. (d) Poor information from acute experiments in animals which does not predict long-term effects of chronic infusion in humans. Further experimental work, therefore, is needed to transfer these neurotrophic factors to the clinic.
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PMID:Neurotrophic factors in neurodegenerative disorders: model of Parkinson's disease. 1678 36

Neuronal DNA repair remains one of the most exciting areas for investigation, particularly as a means to compare the DNA repair response in mitotic (cancer) vs. post-mitotic (neuronal) cells. In addition, the role of DNA repair in neuronal cell survival and response to aging and environmental insults is of particular interest. DNA damage caused by reactive oxygen species (ROS) such as generated by mitochondrial respiration includes altered bases, abasic sites, and single- and double-strand breaks which can be prevented by the DNA base excision repair (BER) pathway. Oxidative stress accumulates in the DNA of the human brain over time especially in the mitochondrial DNA (mtDNA) and is proposed to play a critical role in aging and in the pathogenesis of several neurological disorders including Parkinson's disease, ALS, and Alzheimer's diseases. Because DNA damage accumulates in the mtDNA more than nuclear DNA, there is increased interest in DNA repair pathways and the consequence of DNA damage in the mitochondria of neurons. The type of damage that is most likely to occur in neuronal cells is oxidative DNA damage which is primarily removed by the BER pathway. Following the notion that the bulk of neuronal DNA damage is acquired by oxidative DNA damage and ROS, the BER pathway is a likely area of focus for neuronal studies of DNA repair. BER variations in brain aging and pathology in various brain regions and tissues are presented. Therefore, the BER pathway is discussed in greater detail in this review than other repair pathways. Other repair pathways including direct reversal, nucleotide excision repair (NER), mismatch repair (MMR), homologous recombination and non-homologous end joining are also discussed. Finally, there is a growing interest in the role that DNA repair pathways play in the clinical arena as they relate to the neurotoxicity and neuropathy associated with cancer treatments. Among the numerous side effects of cancer treatments, major clinical effects include neurocognitive dysfunction and peripheral neuropathy. These symptoms occur frequently and have not been effectively studied at the cellular or molecular level. Studies of DNA repair may help our understanding of how those cells that are not dividing could succumb to neurotoxicity with the clinical manifestations discussed in the following article.
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PMID:DNA repair in neurons: so if they don't divide what's to repair? 1687 37

Neurotrophic factors comprise a broad family of secreted proteins that have growth promoting, survival promoting and differentiation inducing activities. Disruption of neurotrophic factor signalling is a characteristic of many central and peripheral nervous system disorders, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, stroke, and peripheral neuropathy and pain. It follows that treating patients with neurotrophic factors might be beneficial in a range of neurological diseases. However, the promising results seen in animal models of disease have not translated well into clinical trials due to the poor pharmacokinetics associated with the intact proteins, in particular, their short in vivo half-life, low blood brain barrier permeability, limited diffusion, and undesirable effects through multiple receptor interactions. This has been the main motivation for the design of small molecule modulators of the neurotrophic factor pathways. The review gives a brief survey of the various strategies to design mimetics that have been reported in the literature with special emphasis on the tandem repeat peptide agonist approach for BDNF/NT-4/5 and N-cadherin mimetics.
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PMID:Tandem repeat peptide strategy for the design of neurotrophic factor mimetics. 1828 37

Restless-legs syndrome (RLS) is a sensorimotor disorder, characterized by an irresistible urge to move the legs usually accompanied or caused by uncomfortable and unpleasant sensations. It begins or worsens during periods of rest or inactivity, is partially or totally relieved by movements and is exacerbated or occurs at night and in the evening. RLS sufferers represent 2 to 3% of the general population in Western countries. Supportive criteria include a family history, the presence of periodic-leg movements (PLM) when awake or asleep and a positive response to dopaminergic treatment. The RLS phenotypes include an early onset form, usually idiopathic with a familial history and a late onset form, usually secondary to peripheral neuropathy. Recently, an atypical RLS phenotype without PLM and l-DOPA resistant has been characterized. RLS can occur in childhood and should be distinguished from attention deficit/hyperactivity disorder, growing pains and sleep complaints in childhood. RLS should be included in the diagnosis of all patients consulting for sleep complaints or discomfort in the lower limbs. It should be differentiated from akathisia, that is, an urge to move the whole body without uncomfortable sensations. Polysomnographic studies and the suggested immobilization test can detect PLM. Furthermore, an l-DOPA challenge has recently been validated to support the diagnosis of RLS. RLS may cause severe-sleep disturbances, poor quality of life, depressive and anxious symptoms and may be a risk factor for cardiovascular disease. In most cases, RLS is idiopathic. It may also be secondary to iron deficiency, end-stage renal disease, pregnancy, peripheral neuropathy and drugs, such as antipsychotics and antidepressants. The small-fiber neuropathy can mimic RLS or even trigger it. RLS is associated with many neurological and sleep disorders including Parkinson's disease, but does not predispose to these diseases. The pathophysiology of RLS includes an altered brain-iron metabolism, a dopaminergic dysfunction, a probable role of pain control systems and a genetic susceptibility with nine loci and three polymorphisms in genes serving developmental functions. RLS treatment begins with the elimination of triggering factors and iron supplementation when deficient. Mild or intermittent RLS is usually treated with low doses of l-DOPA or codeine; the first-line treatment for moderate to severe RLS is dopaminergic agonists (pramipexole, ropinirole, rotigotine). In severe, refractory or neuropathy-associated RLS, antiepileptic (gabapentin, pregabalin) or opioid (oxycodone, tramadol) drugs can be used.
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PMID:[Restless-legs syndrome]. 1865 14


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