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)

Mutations within the amino acid sequence of Parkin, the encoded protein of the parkin gene, appear to trigger the degeneration of dopaminergic neurons in the substantia nigra. Here, the presence and anatomical distribution of Parkin within the rat was examined. Immunoblot analysis of tissue homogenates showed two major bands at 50 and 44kDa. Within the brain, Parkin-containing neurons were identified in the basal ganglia, including the substantia nigra and caudate-putamen. Parkin was visualized in the raphe nucleus, which as in the substantia nigra, was closely localized to monoaminergic-encoding neurons. In addition, Parkin was detected in laminar structures such as the cortex and hippocampus; a substantial number of Parkin-immunoreactive neurons was seen in the cerebellum as well. Parkin therefore is widely distributed in brain pathways implicated in the pathology of Parkinson's disease.
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PMID:Identification and distribution of Parkin in rat brain. 1059 51

Parkin gene, which is one of the causes of familial Parkinson's disease, was cloned in 1998, and it was found that mutations of this gene induces familial Parkinson's disease of autosomal recessive form (AR-JP). Clinical studies have revealed that almost cases of AR-JP are consanguineous or hereditary. However, AR-JP may also be caused by marriage between two carriers. We therefore investigated the existence of a homozygous deletion in the parkin gene in 10 patients with juvenile Parkinson's disease with the onset of age younger than 40 years without consanguinity or heredity. A large delection of the gene was found in 2 of the 10 patients with sporadic Parkinson's disease, and both of these deletion were exon 4. The present study clearly suggests that juvenile Parkinson's disease in Japan may be caused by abnormalities in parkin gene regardless of family history or consanguinity.
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PMID:[Two cases of sporadic juvenile Parkinson's disease caused by homozygous deletion of Parkin gene]. 1065 3

We report a 73-year-old Japanese woman with familial Parkinson's disease. The patient was well until her 67 years of the age, when she noted rest tremor in her right hand. Soon after her gait became short stepped. She visited our clinic on October 6, 1992 when she was 68 years old. She was alert and well oriented without dementia. She showed masked face, small voice, small stepped gait, retropulsion, resting tremor in her right hand, rigidity in the neck, and bradykinesia. She was treated with 400 mg/day of levodopa-carbidopa, which improved her symptoms, however, she developed wearing off phenomenon 3 years after the initiation of levodopa treatment. On August 26, 1998, she developed abdominal pain, diarrhea, and vomiting. She was admitted to another hospital, where abdominal plain x-ray revealed an evidence of intestinal obstruction (ileus). She was treated with nasogastric suction and intravenous fluid. Her condition did not improve and she was transferred to our hospital on August 29, 1998. Her family history revealed no consanguineous marriage. She had two elder brothers and three elder sisters. One of her brothers had been diagnosed as Parkinson's disease. Her husband also suffered from Parkinson's disease, however, her parents apparently did not have Parkinson's disease. On admission, she appeared to be drowsy. Her blood pressure was 102/70 mmHg, body temperature 36.2 degrees C. The lungs were clear and no cardiac murmur was present. Abdomen was flat and bowel sound was audible. No abnormal mass was palpable. Neurologic examination revealed mild consciousness disturbance, masked face, and small voice. No motor paralysis was noted. Muscle tone was hypotonic. No abnormal involuntary movement was noted. Abnormal laboratory findings on admission were as follows; WBC 11,300/microliter, amylase 1,373 IU/l, CK 446 IU/l, BUN 50 mg/dl, creatinine 1.17 mg/dl, CRP 22.7 mg/ dl, Na 134 mEq/l, K 3.1 mEq/l, and Cl 81 mEq/l. A chest x-ray film revealed pneumonic shadows in both lower lung fields. She was treated by nasointestinal suction, intravenous fluids, and chemotherapy for her infection. Her BP started to drop on September 2 and she developed cardiac arrest on the same day. She was discussed in a neurological CPC. The chief discussant arrived at the conclusion that the patient had a form of autosomal dominant familial Parkinson's disease. As parents did not have Parkinson's disease, some of the participants raised the possibility of autosomal recessive inheritance. But the age of onset was too late for autosomal recessive inheritance. Majority thought that the mode of inheritance was autosomal dominant with low penetrance. alpha-Synuclein mutation causes an autosomal dominant familial Parkinson's disease, but this type is very rare in non-Greek populations and the penetrance is high. Chromosome 2-linked autosomal dominant familial Parkinson's disease shows low penetrance. There are many other autosomal dominant forms of familial Parkinson's disease linked to yet unknown chromosome loci. Majority thought that this patient also had a form of Lewy-body positive autosomal dominant familial Parkinson's disease of unknown chromosome locus. Post mortem examination revealed ischemic intestinal lesion with strangulation. This was thought to be the cause of her death. In the central nervous system, the brain appeared to be normal by inspection. In the coronal sections, the substantia nigra and the locus coeruleus showed marked depigmentation. Histologic examination revealed marked neuronal loss and Lewy body formation in the remaining neurons. Pathologic examination was consistent with Parkinson's disease. Mutational analysis for the parkin gene was negative.
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PMID:[A 73-year-old woman with familial Parkinson's disease]. 1065 9

Mutations in the alpha-synuclein, parkin, and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) genes have been linked to some cases of familial Parkinson's disease. To provide insight into how these genes may relate to each other and contribute to the pathology of Parkinson's disease, their expression was examined in normal human brain. Tissue sections from multiple regions of 11 normal human brains were hybridized with radiolabeled and digoxygenin-labeled cRNA probes for alpha-synuclein, parkin, and UCH-L1 mRNA. Expression of each of these three genes was predominantly neuronal. Alpha-synuclein and parkin mRNAs were expressed in a restricted number of brain regions, whereas UCH-L1 mRNA was more uniformly expressed throughout brain. The melanin-containing dopamine neurons of the substantia nigra had particularly robust expression. The expression patterns of alpha-synuclein and parkin mRNAs were similar, suggesting that these two proteins may be involved in common pathways contributing to the pathophysiology of Parkinson's disease.
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PMID:Expression of alpha-synuclein, parkin, and ubiquitin carboxy-terminal hydrolase L1 mRNA in human brain: genes associated with familial Parkinson's disease. 1066 91

The rat parkin cDNA sequence was characterized after screening a rat hypothalamus cDNA library with a 32P-labeled probe containing the entire open reading frame of the human parkin cDNA. This sequence encompasses 1,576 bp and contains a single open reading frame that encodes a 465-amino acid protein. The rat parkin amino acid sequence exhibits a very striking homology to the human and mouse parkin, with 85 and 95% identity, respectively. Both the N-terminal ubiquitin and the ring-IBR (in between ring)-ring finger domains appear to be highly conserved among rat, human, and mouse parkin. An affinity-purified polyclonal antibody (ASP5p) was generated with a synthetic peptide corresponding to amino acids 295-311 of the parkin sequence, which is identical in the three species. Western blotting revealed that ASP5p recognizes a single 52-kDa band, which corresponds to the molecular mass of the parkin protein. Immunostaining with ASP5p showed that parkin is principally located in the cytoplasm of neurons that are widely distributed in the rat brain. Parkin-immunoreactive neurons abound in structures that are specifically targeted in Parkinson's disease, e.g., subtantia nigra, but are also present in unaffected structures, e.g., cerebellum. Furthermore, parkin-enriched glial cells can be detected in various nuclei of the rat brain. Thus, the role of parkin may be much more global than previously thought on the basis of genetic findings gathered in cases of early-onset parkinsonism.
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PMID:Cloning of rat parkin cDNA and distribution of parkin in rat brain. 1073 37

In most patients with Parkinson's disease (PD), the contribution of genetic factors as well as environmental factors remains to be elucidated. But, it has become clear that genetic factors contribute to the pathogenesis of PD after identification of the distinct genetic loci for certain forms of familial PD. We recently identified the novel large gene "parkin" responsible for an autosomal recessive form of familial parkinsonism (AR-JP). AR-JP is a distinct clinical and genetic entity characterized by early onset before 40 years. Pathological changes in this form revealed selective degeneration of the pigmented neurons in the substantia nigra and locus coeruleus, but no Lewy bodies were found. The parkin gene encodes a novel protein of 465 amino acids. The parkin gene is mildly homologous to ubiquitin at the N-terminal portion and has a RING-finger motif at the C-terminal portion. We found variable different homozygous deletions involving exons 3, 4, 5, 3 to 4, 3 to 5, and 3 to 7 in AR-JP families from Japan. In addition to exonic deletions, we identified a one base deletion in exon 5 in two AR-JP families. Although we have identified several mutations in parkin gene, characterization of its gene product, "Parkin protein" has not yet been established. To elucidate the molecular mechanism underlying the disease, we have analyzed the subcellular localization of the Parkin protein by immunohistochemical and immunoblotting studies on patients with AR-JP and sporadic PD using two antibodies. Parkin protein was absent in all regions of the brains of AR-JP patients. Parkin protein was not decreased in brains of sporadic PD patients. Parkin protein was located in both Golgi complex and cytosol. Taken together, the Parkin protein may play a role in vesicular transport system in association with the Golgi complex.
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PMID:[Parkin gene and its function; a key to understand nigral degeneration]. 1079 Oct 92

Autosomal recessive juvenile parkinsonism (AR-JP), one of the most common familial forms of Parkinson disease, is characterized by selective dopaminergic neural cell death and the absence of the Lewy body, a cytoplasmic inclusion body consisting of aggregates of abnormally accumulated proteins. We previously cloned PARK2, mutations of which cause AR-JP (ref. 2), but the function of the gene product, parkin, remains unknown. We report here that parkin is involved in protein degradation as a ubiquitin-protein ligase collaborating with the ubiquitin-conjugating enzyme UbcH7, and that mutant parkins from AR-JP patients show loss of the ubiquitin-protein ligase activity. Our findings indicate that accumulation of proteins that have yet to be identified causes a selective neural cell death without formation of Lewy bodies. Our findings should enhance the exploration of the molecular mechanisms of neurodegeneration in Parkinson disease as well as in other neurodegenerative diseases that are characterized by involvement of abnormal protein ubiquitination, including Alzheimer disease, other tauopathies, CAG triplet repeat disorders and amyotrophic lateral sclerosis.
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PMID:Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. 1088 78

Parkinson's Disease (PD) is the second most common chronic neurodegenerative disease characterized by the progressive loss of dopamine neurons, leading to rigidity, slowness of movement, rest tremor, gait disturbances, and imbalance. Although there is effective symptomatic treatment for PD, there is no proven preventative or regenerative therapy. The etiology of this disorder remains unknown. Recent genetic studies have identified mutations in alpha-synuclein as a rare cause of autosomal dominant familial PD and mutations in parkin as a cause of autosomal recessive familial PD. The more common sporadic form of PD is thought to be due to oxidative stress and derangements in mitochondrial complex I activity. Understanding the mechanism by which familial linked mutations and oxidative stress cause PD has tremendous potential for unraveling the mechanisms of dopamine cell death in PD. In this article, we review recent advances in the understanding of the role of genetics and oxidative stress in the pathogenesis of PD.
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PMID:Oxidative stress and genetics in the pathogenesis of Parkinson's disease. 1096 96

Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Immunostaining of substantia nigra sections from sporadic Parkinson's disease (PD) cases shows that Parkin accumulates in axonal spheroids and in some Lewy bodies. Because ubiquitin is a major component of Lewy bodies and axonal spheroids, we investigated whether Parkin is metabolized via the ubiquitin/proteosomal pathway. Treatment of BE-M17 neuroblastoma cells with the proteosomal inhibitor, MG132, produced a band corresponding to di-ubiquitinated Parkin that was apparent by immunoblot using two different anti-Parkin antibodies. This higher mol. wt band also co-immunoprecipitated with Parkin. These data suggest that Parkin plays a role in the pathophysiology of sporadic PD, and that Parkin is a substrate for ubiquitination that is degraded by the proteosomal complex.
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PMID:Parkin is metabolized by the ubiquitin/proteosome system. 1097 34

Parkinson's disease (PD) is a neurodegenerative disease with clinical features resulting from deficiency of dopamine in the nigrostriatal system. Most PD cases are sporadic and the primary cause of the disease is still unknown. Recently, familial PD and parkinsonism have received much attention because these forms of the disease might provide clues to the genetic risk factors involved in the pathogenesis of idiopathic PD. To date, two causative genes, alpha-synuclein and the parkin gene, have been identified. alpha-Synuclein is involved in the pathogenesis of an autosomal dominant form of PD and constitutes a major component of the Lewy body, which is a pathological hallmark of idiopathic PD. In addition, mutations in the parkin gene have been identified as the cause of autosomal recessive juvenile parkinsonism (AR-JP). AR-JP manifests itself as a highly selective degeneration of the substantia nigra and the locus coeruleus, but without Lewy body formation. In addition to these two genes, four chromosomal loci have been linked to other forms of familial PD. Furthermore, there are a number of other pedigrees of familial PD in which linkage to known genetic loci has been excluded. Molecular cloning of these disease genes and elucidation of the function of their gene products will greatly contribute to our understanding of the pathogenesis of idiopathic PD.
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PMID:Progress in the clinical and molecular genetics of familial parkinsonism. 1098 16


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