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)

Although iron accumulates in the brain in a number of pathological conditions, including Hallervorden-Spatz syndrome, Parkinson's disease, and neurosyphilis, studies of brain iron metabolism have been performed only rarely. Neuronal-enriched cultures were prepared from fetal mouse brain. After 18 days the cells were exposed to radiolabeled iron. Total iron uptake and incorporation into ferritin were rapid and linear over four hours. The addition of either methylamine or ammonium chloride, both known blockers of transferrin-iron release through their lysosomotropic properties, inhibited total iron uptake. Methylamine also inhibited the rate of ferritin-iron incorporation, most likely by interfering with transferrin-iron release. The data suggest that neuronal iron transport, much like that in other mammalian tissues, is transferrin mediated and that blockers of transferrin-iron release may be of value in conditions in which there is brain iron overload.
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PMID:Iron uptake by mammalian cortical neurons. 646 62

The substantia nigra and globus pallidus (two iron-rich brain areas) receive a substantial innervation from the neostriatum, a considerable amount of which is GABAergic. Because of this anatomic relationship and the finding that prevention of GABA degradation in these two areas decreases their histochemical levels of iron, GABAergic transmission/metabolism may be important in regulating brain iron levels. Therefore, the present study investigated the effects of denervation of striatal/pallidal inputs to globus pallidus/substantia nigra on iron levels and associated pathologic changes in globus pallidus/substantia nigra. Adult male Sprague-Dawley rats received unilateral ibotenic acid infusions resulting in comprehensive lesions of the entire neostriatum/globus pallidus complex, or of either the anterior neostriatum or the posterior neostriatum/globus pallidus. Animals were killed at one week or one month following surgery. Between one week and one month postlesioning, comprehensive neostriatum/globus pallidus lesions induced a progressive decrease in substantia nigra volume, as well as a progressive increase in both substantia nigra zona reticularis iron staining and substantia nigra iron concentration. By one month following neostriatum/globus pallidus lesions, a marked 73% loss of substantia nigra zona reticularis neurons occurred in association with a 65% increase in glial cell numbers within zona reticularis. Compared to comprehensive neostriatum/globus pallidus lesions at the one month postlesion time point, more restricted anterior neostriatum and posterior neostriatum/globus pallidus lesions induced a less severe atrophy of the substantia nigra, a small (anterior neostriatum lesions) to moderate (posterior neostriatum/globus pallidus lesions) increase in substantia nigra zona reticularis iron staining, and either no zona reticularis neuronal loss (anterior neostriatum lesions) or limited zona reticularis neuronal loss selectively within areas of increased iron staining. These results suggest that destruction of striatal/pallidal innervation to the substantia nigra's zona reticularis induces a disruption of zona reticularis iron homeostasis, resulting in a redistribution and/or accumulation of iron in the zona reticularis and consequent zona reticularis of the substantia nigra neurodegeneration. The results further suggest that loss or dysfunction of striatonigral/striatopallidal GABAergic neurons in several neurodegenerative diseases (including Hallervorden-Spatz syndrome, progressive supranuclear palsy, multiple system atrophy, and Parkinson's disease) may result in an increase or redistribution of nigral iron to cause loss of substantia nigra neurons.
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PMID:Time-dependent changes in iron levels and associated neuronal loss within the substantia nigra following lesions within the neostriatum/globus pallidus complex. 754 96

Hallervorden-Spatz syndrome (HSS) (OMIM #234200) is a rare, autosomal recessive neurode-generative disorder with brain iron accumulation as a prominent finding. Clinical features include extrapyramidal dysfunction, onset in childhood, and a relentlessly progressive course. Histologic study reveals massive iron deposits in the basal ganglia. Systemic and cerebrospinal fluid iron levels are normal, as are plasma levels of ferritin, transferrin and ceruloplasmin. Conversely, in disorders of systemic iron overload, such as haemochromatosis, brain iron is not increased, which suggests that fundamental differences exist between brain and systemic iron metabolism and transport. In normal brain, non-haem iron accumulates regionally and is highest in basal ganglia. Pathologic brain iron accumulation is seen in common disorders, including Parkinson's disease, Alzheimer's disease and Huntington disease. In order to gain insight into normal and abnormal brain iron transport, metabolism and function, our approach was to map the gene for HSS. A primary genome scan was performed using samples from a large, consanguineous family (HS1) (see Fig. 1). While this family was immensely powerful for mapping, the region demonstrating homozygosity in all affected members spans only 4 cM, requiring very close markers in order to detect linkage. The HSS gene maps to an interval flanked by D20S906 and D20S116 on chromosome 20p12.3-p13. Linkage was confirmed in nine additional families of diverse ethnic backgrounds.
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PMID:Homozygosity mapping of Hallervorden-Spatz syndrome to chromosome 20p12.3-p13. 894 32

The primary neuroaxonal dystrophies (NAD), which include infantile NAD and Hallervorden-Spatz syndrome (HSS), are characterized by dystrophic terminal axons and axonal swellings. Lewy bodies have been found in some cases. In Parkinson disease (PD) and dementia with Lewy bodies (DLB), Lewy bodies and neurites display prominent alpha-synuclein immunoreactivity. We examined 2 cases of HSS and 4 cases of infantile NAD with alpha-synuclein immunohistochemistry to test the hypothesis that these disorders with similar morphological findings might share a biochemical phenotype. Furthermore, we compared them to 8 cases of secondary or physiologic NAD of various causes and 2 cases of recent traumatic head injury. Alpha-synuclein positive neuronal cytoplasmic inclusions, including Lewy bodies, and neurites were numerous in 1 HSS and 1 infantile NAD case. In addition, axonal spheroids were immunostained in all 6 cases of primary NAD, 5 cases of secondary NAD, and 2 cases of recent head injury. Axonal spheroids were faintly stained in the 3 physiologic NAD cases. Alpha-synuclein positive axonal swellings may suggest a mechanism, such as axonal injury, leading to the neuronal cytoplasmic accumulation of alpha-synuclein in NAD and other disorders.
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PMID:Alpha-synuclein immunoreactivity is present in axonal swellings in neuroaxonal dystrophy and acute traumatic brain injury. 1060 51

We studied a 27-year-old woman who died after a 6-year history of progressive dementia, dystonia, ataxia, apraxia, spasticity, choreoathetosis, visual and auditory hallucinations, and optic atrophy. Magnetic resonance imaging showed decreased intensity in the globus pallidus, substantia nigra, and dentate nuclei in T2-weighted images, supporting the clinical diagnosis of neurodegeneration with brain iron accumulation type 1 (NBIA-1; formerly known as Hallervorden-Spatz syndrome). At autopsy the brain showed mild frontotemporal atrophy and discoloration of the globus pallidus and the substantia nigra pars reticularis. Histologically, features typical of NBIA-1 were found including widespread axonal spheroids and large deposits of iron pigment in the discolored regions. Additionally, excessive numbers of Lewy bodies (LBs) were found throughout all examined brain stem and cortical regions. LBs of both types, as well as Lewy neurites in this case of NBIA-1, were strongly labeled by antibodies against alpha-synuclein. These findings give further evidence that accumulation of alpha-synuclein is generally associated with LB formation, i.e., in Parkinson's disease, dementia with Lewy bodies and NBIA-1. The case presented here is particularly notable for its high number of LBs in all areas of the cerebral cortex.
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PMID:Alpha-synuclein accumulation in a case of neurodegeneration with brain iron accumulation type 1 (NBIA-1, formerly Hallervorden-Spatz syndrome) with widespread cortical and brainstem-type Lewy bodies. 1104 80

Hallervorden-Spatz syndrome (HSS) is an autosomal recessive neurodegenerative disorder associated with iron accumulation in the brain. Clinical features include extrapyramidal dysfunction, onset in childhood, and a relentlessly progressive course. Histologic study reveals iron deposits in the basal ganglia. In this respect, HSS may serve as a model for complex neurodegenerative diseases, such as Parkinson disease, Alzheimer disease, Huntington disease and human immunodeficiency virus (HIV) encephalopathy, in which pathologic accumulation of iron in the brain is also observed. Thus, understanding the biochemical defect in HSS may provide key insights into the regulation of iron metabolism and its perturbation in this and other neurodegenerative diseases. Here we show that HSS is caused by a defect in a novel pantothenate kinase gene and propose a mechanism for oxidative stress in the pathophysiology of the disease.
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PMID:A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. 1147 80

Multiple system atrophy is an adult onset neurodegenerative disease, featuring parkinsonism, ataxia, and autonomic failure, in any combination. The condition is relentlessly progressive and responds poorly to treatment. Death occurs on average six to seven years after the onset of symptoms. No familial cases of multiple system atrophy have been reported, and no environmental factors have been robustly implicated as aetiological factors. However, analytical epidemiological studies are hampered because the condition is relatively rare. The discovery of the glial cytoplasmic inclusion (GCI) in 1989 helped to define multiple system atrophy as a clinicopathological entity, and drew attention to the prominent, if not primary, role played by the oligodendrocyte in the pathogenesis of the condition. Subsequently, GCIs were shown to be positive for alpha-synuclein, with immunostaining for this protein indicating that white matter pathology was more widespread than had previously been recognised. The presence of alpha-synuclein in GCIs provides a link with Parkinson's disease, dementia with Lewy bodies, and neurodegeneration with brain iron accumulation, type 1 (or Hallervorden-Spatz syndrome), in which alpha-synuclein is also found within Lewy bodies. This has led to the term "synucleinopathy" to embrace this group of conditions. The GCIs of multiple system atrophy contain a range of other cytoskeletal proteins. It is unknown how fibrillogenesis occurs, and whether there is primary oligodendrocytic dysfunction, which then disrupts the neurone/axon as a consequence of the glial pathology, or whether the oligodendrocytic changes merely represent an epiphenomenon. Further research into this devastating condition is urgently needed to improve our understanding of the pathogenesis, and also to produce new treatment approaches.
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PMID:Multiple system atrophy: cellular and molecular pathology. 1172 18

The inherited movement disorders comprise a rapidly growing category of human disease. Advances in genetics have led to the identification of the gene mutation in Huntington's disease and three different gene mutations, which may lead to Parkinson's disease. In addition, gene mutations have been identified in less common movement disorders including Wilson's disease, Hallervorden-Spatz syndrome, paroxysmal kinesogenic choreoathetosis, neuroacanthocytosis, and some forms of dystonia. This article summarizes what is known about the genetic mutations that cause these movement disorders, as well as the clinical features of each disease and the symptomatic treatments currently available.
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PMID:Inherited movement disorders. 1243 29

Mutations in the pantothenate kinase 2 gene (PANK2) lead to pantothenate kinase-associated neurodegeneration (PKAN, formerly Hallervorden-Spatz syndrome). This neurodegenerative disorder is characterized by iron accumulation in the basal ganglia. Pantothenate kinase is the first enzyme in the biosynthesis of coenzyme A from pantothenate (vitamin B(5)). PANK2, one of four human pantothenate kinase genes, is uniquely predicted to be targeted to mitochondria. We demonstrate mitochondrial localization of PANK2 and speculate on mechanisms of secondary iron accumulation in PKAN. Furthermore, PANK2 uses an unconventional translational start codon, CUG, which is polymorphic in the general population. The variant sequence, CAG (allele frequency: 0.05), leads to skipping of the mitochondrial targeting signal and cytosolic localization of PANK2. This common variant may cause mitochondrial dysfunction and impart susceptibility to late-onset neurodegenerative disorders with brain iron accumulation, including Parkinson's disease.
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PMID:Mitochondrial localization of human PANK2 and hypotheses of secondary iron accumulation in pantothenate kinase-associated neurodegeneration. 1510 73

Pantothenate kinase-associated neurodegeneration (PKAN) may serve as a model for Parkinson disease (PD) since many PKAN patients suffer from parkinsonism and both conditions lead to iron accumulation in the basal ganglia. We screened the gene coding for pantothenate kinase 2 (PANK2) for sequence variants in PD. We found no mutations in 67 PD patients with affected sibs or early-onset disease. Moreover, PANK2 polymorphisms were not associated with late-onset idiopathic PD in 339 patients. We conclude that PANK2 variants exert, if any, only a very small effect in the genetic risk of PD.
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PMID:Mutations in the pantothenate kinase gene PANK2 are not associated with Parkinson disease. 1584 62


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