Metabolic Modification of Some Neurologic Disorders

Cotzias, George C.

doi:10.1001/jama.1969.03160330055011

Cited by 47 publications

(8 citation statements)

References 35 publications

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“…However, all our findings suggested that neuronal degenerations might occur in SN as well as striatum of mice exposed to Mn. The present findings were compatible with some human pathologic findings [19][20][21][22][23] , animal pathologic finding 24) , and animal biochemical findings 25,26) . The present finding was also in accordance with our recent brain MRI studies on humans showing that Mn frequently deposits in midbrain as well as globus pallidus 27,28) and the hypertrophy of astrocytes by Mn intoxication in mouse brain finally 7) .…”

Section: Discussionsupporting

confidence: 91%

cDNA Array Analysis of Gene Expression Profiles in Brain of Mice Exposed to Manganese

Baek¹,

Cho²,

Kim³

et al. 2004

INDUSTRIAL HEALTH

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This study is performed to detect changes of gene expression in substantia nigra (SN) and striatum in manganese (Mn)-exposed mice brain. The cDNA array is a recently developed molecular biological method that can detect the differential expression of several hundreds of genes simultaneously and is therefore advantageous in the study of trace metal intoxication effect at the genetic level. Using this technology, we discovered 5 genes in the mouse striatum and 9 genes in SN changed by more than 50% following Mn exposure. Depression were observed in two genes (neural cell adhesion protein BIG2, heavy neurofilament subunit genes) in striatum and three genes (light neurofilament subunit, brain acyl-CoA synthetase II, heavy neurofilament subunit genes) in the SN. However three genes (N-acetylglucosaminyltransferase I, S100β β β β β, and synaptonemal complex protein I genes) in striatum and six genes (noggin, striatin, Ost oncogene, S100β β β β β, calcium/calmodulindependent protein kinase kinase beta, and N-acetylglucosaminyltransferase I genes) in SN were elevated following Mn exposure. Immunohistochemical study revealed that protein levels of S100β β β β β also increased following Mn treatment. Activated astrocytes overexpressing S100β β β β β are invariably and intimately associated with decreased expression of heavy and light neurofilament subunits which is a distinguishing feature of neurodegeneration by Mn exposure. All our findings suggested that neuronal degenerations occur in SN as well as striatum of mice exposed to Mn.

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Section: Discussionsupporting

confidence: 91%

cDNA Array Analysis of Gene Expression Profiles in Brain of Mice Exposed to Manganese

Baek¹,

Cho²,

Kim³

et al. 2004

INDUSTRIAL HEALTH

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“…To date, several small trials have supplemented LNS patients with exogenous sources of substrate needed in the dopamine synthesis pathway. One such molecule, L-DOPA, is synthesized into dopamine by DOPA decarboxylase and is widely used to increase levels of dopamine in the brain, most notably to treat Parkinson's disease [Cotzias, 1969;Lloyd et al, 1975] and general dystonia [Lubarr and Bressman, 2011].…”

Section: Dopaminementioning

confidence: 99%

Lesch-Nyhan Syndrome: Models, Theories, and Therapies

et al. 2016

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Lesch-Nyhan syndrome (LNS) is a rare X-linked disorder caused by mutations in HPRT1, an important enzyme in the purine salvage pathway. Symptoms of LNS include dystonia, gout, intellectual disability, and self-mutilation. Despite having been characterized over 50 years ago, it remains unclear precisely how deficits in hypoxanthine and guanine recycling can lead to such a profound neurological phenotype. Several studies have proposed different hypotheses regarding the etiology of this disease, and several treatments have been tried in patients, though none have led to a satisfactory explanation of the disease. New technologies such as next-generation sequencing, optogenetics, genome editing, and induced pluripotent stem cells provide a unique opportunity to map the precise sequential pathways leading from genotype to phenotype.

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“…However, Cotzias and colleagues showed in their seminal papers that levodopa was dramatically effective in parkinsonian patients from Chilean Mn mines. 31,32 Therefore, it is reasonable to suspect that Cotzias' patients who showed a favorable response to levodopa had predominant presynaptic dopaminergic lesions and minor, if any, postsynaptic lesions. Pathological studies from these patients were not performed.…”

Section: Mn Induces Pdmentioning

confidence: 99%

Dopamine transporter density is decreased in parkinsonian patients with a history of manganese exposure: What does it mean?

Kim

et al. 2002

Movement Disorders

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Manganese (Mn) exposure can cause parkinsonism. Pathological changes occur mostly in the pallidum and striatum. Two patients with a long history of occupational Mn exposure presented with Mn-induced parkinsonism. In one patient, magnetic resonance imaging (MRI) showed findings consistent with Mn exposure, and Mn concentration was increased in the blood and urine. However, this patient's clinical features were typical of idiopathic Parkinson disease (PD). Previous pathological and positron emission tomography studies indicate that striatal dopamine transporter density is normal in Mn-induced parkinsonism, whereas it is decreased in PD. Therefore, we performed [(123)I]-(1r)-2 beta-carboxymethoxy-3beta-(4-iodophenyl)tropane ([(123)I]-beta-CIT) single-photon emission computed tomography. Severe reduction of striatal beta-CIT binding was indicated, which is consistent with PD. We propose three interpretations: (1) the patients have PD, and Mn exposure is incidental; (2) Mn induces selective degeneration of presynaptic dopaminergic nerve terminals, thereby causing parkinsonism; or (3) Mn exposure acts as a risk of PD in these patients. Our results and careful review of previous studies indicate that the axiom that Mn causes parkinsonism by pallidal lesion may be over-simplified; Mn exposure and parkinsonism may be more complex than previously thought. Further studies are required to elucidate the relationship between Mn and various forms of parkinsonism.

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Metabolic Modification of Some Neurologic Disorders

Cited by 47 publications

References 35 publications

cDNA Array Analysis of Gene Expression Profiles in Brain of Mice Exposed to Manganese

cDNA Array Analysis of Gene Expression Profiles in Brain of Mice Exposed to Manganese

Lesch-Nyhan Syndrome: Models, Theories, and Therapies

Dopamine transporter density is decreased in parkinsonian patients with a history of manganese exposure: What does it mean?

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