Aetiology of Parkinson's Disease

Calne, D. B.; Langston, J. William

doi:10.1016/s0140-6736(83)90802-4

Cited by 427 publications

(173 citation statements)

References 19 publications

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“…MAO-B is responsible for conversion of MPTP to its toxic form MPP ϩ . MPP ϩ is selectively transported into dopaminergic neurons causing toxic effects via direct inhibition of mitochondrial complex I activity (40,41). Exogenous or endogenous toxins similar to MPTP or rotenone may act in concert with age-related elevations in brain MAO-B levels to elicit the disease.…”

mentioning

confidence: 99%

Oxidative α-Ketoglutarate Dehydrogenase Inhibition via Subtle Elevations in Monoamine Oxidase B Levels Results in Loss of Spare Respiratory Capacity

Kumar

Nicholls

Andersen

2003

Journal of Biological Chemistry

114

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Age-related increases in brain monoamine oxidase B (MAO-B) and its ability to produce reactive oxygen species as a by-product of catalysis could contribute to neurodegeneration associated with Parkinson's disease. This may be via increased oxidative stress and/or mitochondrial dysfunction either on its own or through its interaction with endogenous or exogenous neurotoxic species. We have created genetically engineered dopaminergic PC12 cell lines with subtly increased levels of MAO-B mimicking those observed during normal aging. In our cells, increased MAO-B activity was found to result in increased H 2 O 2 production. This was found to correlate with a decrease in mitochondrial complex I activity which may involve both direct oxidative damage to the complex itself as well as oxidative effects on the tricarboxylic acid cycle enzyme ␣-ketoglutarate dehydrogenase (KGDH) which provides substrate for the complex. Both complex I and KGDH activities have been reported to be decreased in the Parkinsonian brain. These in vitro events are reversible by catalase addition. Importantly, MAO-B elevation was found to abolish the spare KGDH threshold capacity, which can normally be significantly inhibited before it affects maximal mitochondrial oxygen consumption rates. Our data suggest that H 2 O 2 production via subtle elevations in MAO-B levels can result in oxidative effects on KGDH that can compromise the ability of dopaminergic neurons to cope with increased energetic stress.

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confidence: 99%

Oxidative α-Ketoglutarate Dehydrogenase Inhibition via Subtle Elevations in Monoamine Oxidase B Levels Results in Loss of Spare Respiratory Capacity

Kumar

Nicholls

Andersen

2003

Journal of Biological Chemistry

114

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“…Since l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was found to induce parkinsonism (4,5), particular attention has been focused on the possible role of environmental toxic agents in causing damage to the nervous system (1,2). Intake of the cycad seed containing an amino acid, [>'-N-methylamino-L-alanine (BMAA), has been suggested to link to the genesis of amyotrophic lateral sclerosisparkinsonism-dementia complex (9,10).…”

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confidence: 99%

<b>TETRAHYDROISOQUINOLINE AND 1-METHYL-TETRAHYDROISOQUINOLINE ARE PRESENT IN THE HUMAN BRAIN: RELATION TO PARKINSON’S </b><b>DISEASE </b>

Ohta¹,

Kohno²,

Makino³

et al. 1987

Biomed. Res.

140

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ABSTRACT1,2,3,4-Tetrahydroisoquinoline (TIQ) and 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) were detected in two regions (frontal lobe and caudate nucleus) of eight human brains, four from the control and four from patients with parkinsonism. The TIQ content did not significantly differ between control and parkinsonian brains in both regions. In contrast, the 1MeTIQ content was markedly reduced in the parkinsonian brain, particularly in the frontal lobe, suggesting an important role of this amine in parkinsonism.

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“…Moreover, oxidative stress preferentially affects DA neurons in the SNpc, which are particularly vulnerable as they operate under high oxidant conditions due to reduced levels of the anti-oxidant glutathione (Misra & Kalita, 2010;Sian et al, 1994). Accordingly, it has been postulated that pre-exposure to environmental toxins such as heavy metals, organophosphate compounds, neurotoxins, and pesticides like paraquat and rotenone which can induce oxidative stress and the generation of free radicals, increases the susceptibility to the development of PD in later life (Calne & Langston, 1983;Jang et al, 2009a). Pathological and clinical evidence has also identified the involvement of the gastrointestinal tract in enhancing susceptibility to idiopathic Parkinsonism, with Helicobacter pylori infection proposed as a potential trigger in disease progression (Tansey & Goldberg, 2010;Weller et al, 2005).…”

Section: Systemic Inflammation and Parkinson's Diseasementioning

confidence: 99%