Time course of nigrostriatal degeneration in parkinson's disease

Riederer, Peter; Wuketich, S

doi:10.1007/bf01249445

Cited by 523 publications

(137 citation statements)

References 41 publications

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“…The disease is believed to be a result of genetic predisposition or environmental factors (Corrigan et al , 1998) that lead to oxidative damage of mitochondrial proteins (Alam et al , 1997) and subsequent mitochondrial dysfunction (Schapira et al , 1990) and is characterized in patients by the loss of dopaminergic neurons in the substantia nigra of the midbrain (Hornykiewicz, 1966; Riederer & Wuketich, 1976). In addition to sporadic Parkinson's disease, there are also genetic forms of the disease that account for approximately 10% of all cases.…”

Section: Introductionmentioning

confidence: 99%

Synergistic recruitment of UbcH7~Ub and phosphorylated Ubl domain triggers parkin activation

et al. 2018

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The E3 ligase parkin ubiquitinates outer mitochondrial membrane proteins during oxidative stress and is linked to early‐onset Parkinson's disease. Parkin is autoinhibited but is activated by the kinase PINK1 that phosphorylates ubiquitin leading to parkin recruitment, and stimulates phosphorylation of parkin's N‐terminal ubiquitin‐like (pUbl) domain. How these events alter the structure of parkin to allow recruitment of an E2~Ub conjugate and enhanced ubiquitination is an unresolved question. We present a model of an E2~Ub conjugate bound to the phospho‐ubiquitin‐loaded C‐terminus of parkin, derived from NMR chemical shift perturbation experiments. We show the UbcH7~Ub conjugate binds in the open state whereby conjugated ubiquitin binds to the RING1/IBR interface. Further, NMR and mass spectrometry experiments indicate the RING0/RING2 interface is re‐modelled, remote from the E2 binding site, and this alters the reactivity of the RING2(Rcat) catalytic cysteine, needed for ubiquitin transfer. Our experiments provide evidence that parkin phosphorylation and E2~Ub recruitment act synergistically to enhance a weak interaction of the pUbl domain with the RING0 domain and rearrange the location of the RING2(Rcat) domain to drive parkin activity.

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Section: Introductionmentioning

confidence: 99%

Synergistic recruitment of UbcH7~Ub and phosphorylated Ubl domain triggers parkin activation

et al. 2018

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“…Accordingly, the aging factor itself appears to play an important role in the etiology of IPD as a key susceptibility factor. The loss of striatal dopamine occurring normally as aging progresses 23 and age-related accumulation of neuromelanin in the SN are both believed to be trigger factors involved in IPD. 24 " 25 Recently, a direct relationship between the distribution of neuromelanin-bearing neurons in the SN and the pattern of cell loss in IPD has been elucidated.…”

Section: Aging Neuromelanin and Ironmentioning

confidence: 99%

Environment, Genetics and Idiopathic Parkinson's Disease

Poirier¹,

Kogan²,

Gauthier³

1991

Can. j. neurol. sci.

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ABSTRACT:Since Idiopathic Parkinson's disease (IPD) was first described more than 170 years ago, there have been major advances in the understanding of the etiology of the disease as well as in its treatment. This article will review current knowledge concerning the role of the environment, genetic hypotheses and the aging factor in the etiology of IPD and proposes a complex interaction involving all these factors. Hypotheses regarding mitochondrial inhibition and free radical generation in IPD are discussed in relation to the mechanism of action of neurotoxins known to produce parkinsonian syndromes. RESUME: Depuis sa description initiale il y a un peu plus de 170 ans, de nombreuses decouvertes fondamentales et cliniques ont permis de mieux compredre la maladie de Parkinson. Cet article detaille certaines observations recentes concernant le role possible de l'environnement, la genetique et le vieillissement dans I'etiologie de la maladie de Parkinson. Les hypotheses concernant l'inhibition mitochondriale et la generation de radicaux libres dans la maladie de Parkinson sont discutees en rapport avec les mecanismes d'action de neurotoxines connues comme produisant des syndromes parkinsoniens.Can. J. Neurol. Sci. 1991; 18: 70-76 Idiopathic Parkinson's disease (IPD) is characterized by major clinical disturbances caused by dopamine depletion in the corpus striatum, resulting from neuronal loss in the substantia nigra (SN).1 The dopamine depletion is the result of a severe degeneration of the dopaminergic nigro-striatal pathway which normally inhibits the activity of a subpopulation of striatal neurons. While the physiological and neurochemical consequences of the dopamine depletion have been extensively documented, very little is known about the underlying cause of dopamine cell death or the mechanism by which dopamine cells degenerate. Numerous hypotheses have been presented including the following: a) IPD is the result of a random process.2 This hypothesis assumes that the age-related loss of neurons can be accelerated by the cumulative action of repeated insults of ordinary life (viruses, toxins, head injury, etc.). A revised form of this concept is also known as the "accelerated aging hypothesis". 3 b) IPD is the result of a lack of neurotrophic hormone. 4 It is hypothesized that a dopaminergic-specific growth factor is synthesized and stored in the target striatal cells and that the inability of these cells to provide the required dopaminergic neurotrophic hormone, thereby causes impairment to SN neurons, c) IPD is caused by a defect in the DNA repair mechanism.5 This hypothesis is derived from observations showing that cultured fibroblasts from parkinsonian patients are hypersensitive to the lethal effects of DNA-damaging agents such as x-rays. It postulates that somatic mutations occurring in early embryogenesis cause a lifelong accumulation of unrepaired DNA damage in neurons, resulting in lethal consequences on the SN. d) IPD is the result of a specific genetic defect(s) or genetic predisposition(s).3 '...

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“…There is only one paper 10 in the literature that claims to provide information on the rate of loss of nigral cells in Parkinson's disease. This report compares the dopamine levels found postmortem in the caudate in control subjects over the ages of 50-90 years, and parkinsonian patients over the same age range.…”

Section: Studies In Parkinson's Diseasementioning

confidence: 99%

Aging of the Nigrostriatal Pathway in Humans

Calne

Peppard

1987

Can. J. Neurol. Sci.

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Progressive degeneration of functionally related groups of neurons occurs in certain infective, toxic, nutritional and genetically determined neurological diseases. It also takes place in normal aging, and several of the regions that undergo selective decay with the passage of time seem to be the same target regions that are afflicted in degenerative disorders such as Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis (ALS). Infective etiology is relatively easy to exclude by a combination of immunological tests and transfer experiments. Genetic causation can be rendered unlikely when large kindreds are available for study. Nutritional deprivation and acute or subacute toxicity are accessible to explanation by examining the environment. The most difficult mechanism of pathogenesis to refute is chronic toxic damage, where the lesion may derive from long-term exposure to a relatively widespread noxious agent or agents. Variations in involvement of individuals within a population may stem from differing capacities to activate or inactivate a toxin. Inherent in this concept of etiology is recognition that compensatory potential within the central nervous system may contribute to prolonged existence of subclinical lesions so that a latent period may exist for several decades, between causal event and the onset of symptoms. Furthermore, progressive clinical deterioration may take place even though the cause may have been transient, many years before. The histological features associated with Parkinson's disease, Alzheimer's disease and ALS may be nonspecific indicators of neuronal "illness", there being a predilection for certain morphological markers to appear more frequently in particular circumstances and particular regions associated with the pathology of particular diseases. RESUME: Vieillissement du systeme nerveux et abiotrophie. Une degenerescence progressive de groupes de neurones qui sont relies entre eux par leur fonction survient dans certaines maladies neurologiques d'origine infectieuse, toxique, nutritionnelle ou genetique. Ce phenomene survient aussi dans le vieillissement normal et plusieurs regions qui subissent une degenerescence selective avec le temps semblent etre les memes regions qui sont la cible de maladies degeneratives comme la maladie de Parkinson, la maladie d'Alzheimer et la SLA. Une etiologie infectieuse est relativement facile a exclure au moyen d'une combinaison d'epreuves immunologiques et d'essais de transmission de la maladie. On peut pratiquement eliminer une etiologie genetique quand on peut etudier des grandes families. La carence nutritionnelle peut etre soumise a l'analyse epidemiologique. La toxicite aigiie et subaigile peut elle aussi generalement etre expliquable en examinant l'environnement. Le mecanisme pathogenique le plus difficile a refuter est l'intoxication chronique, le dommage pouvant alors resulter d'une exposition prolongee a un ou des agent(s) nocif(s) relativement repandu(s). Des variations dans le degre d'atteinte des individu...

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Time course of nigrostriatal degeneration in parkinson's disease

Cited by 523 publications

References 41 publications

Synergistic recruitment of UbcH7~Ub and phosphorylated Ubl domain triggers parkin activation

Synergistic recruitment of UbcH7~Ub and phosphorylated Ubl domain triggers parkin activation

Environment, Genetics and Idiopathic Parkinson's Disease

Aging of the Nigrostriatal Pathway in Humans

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