Loss of insulin receptor immunoreactivity from the substantia nigra pars compacta neurons in Parkinson's disease

Moroo, Iku; Yamada, Tatsuo; Makino, Hideichi; Tooyama, Ikuo; McGeer, Patrick L.; McGeer, Edith G.; Hirayama, Keizo

doi:10.1007/bf00313602

Cited by 141 publications

(57 citation statements)

References 27 publications

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“…Also, evidence has accumulated that brain IR promote spermatogenesis and ovarian follicle maturation via pituitary luteinizing hormone (Brü ning et al, 2000), while increasing efficiency of synaptic transmission, learning, and memory (Zhao et al, 1999;Gispen and Biessels, 2000;Zhao and Alkon, 2001). IR and IR mRNA levels were significantly lower in substantia nigra of Parkinson's disease brain compared with normal and other neurodegenerative disease brains (Moroo et al, 1994;Takahashi et al, 1996). In Alzheimer's disease brain, insulin concentration was lower, and IR signaling was impaired compared with age-matched healthy humans (Zhao and Alkon, 2001;Hoyer, 2002).…”

Section: Discussionmentioning

confidence: 90%

Distinct Effects of Ketone Bodies on Down-Regulation of Cell Surface Insulin Receptor and Insulin Receptor Substrate-1 Phosphorylation in Adrenal Chromaffin Cells

Yokoo

Saitoh²,

Shiraishi³

et al. 2002

J Pharmacol Exp Ther

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Treatment (м24 h) of cultured bovine adrenal chromaffin cells with ketoacidosis-related concentrations (м3 mM) of acetoacetate (but not ␤-hydroxybutyrate, acetone, and acidic medium) caused a time-and concentration-dependent reduction of cell surface 125 I-insulin binding by ϳ38%, with no change in the K d value. The reduction of 125 I-insulin binding returned to control nontreated level at 24 h after the washout of acetoacetate-treated cells. Acetoacetate did not increase the internalization rate of cell surface insulin receptor (IR), as measured in the presence of brefeldin A, an inhibitor of cell surface vesicular exit from the trans-Golgi network. Acetoacetate (10 mM for 24 h) lowered cellular levels of the immunoreactive IR precursor molecule (ϳ190 kDa) and IR by 22 and 28%, respectively. Acetoacetate decreased IR mRNA levels by ϳ23% as early as 6 h, producing their maximum plateau reduction at 12 and 24 h. The half-life of IR mRNA was shortened by acetoacetate from 13.6 to 9.5 h. Immunoprecipitation followed by immunoblot analysis revealed that insulin-induced (100 nM for 10 min) tyrosine-phosphorylation of insulin receptor substrate-1 (IRS-1) was attenuated by 56% in acetoacetate-treated cells, with no change in IRS-1 level. These results suggest that chronic treatment with acetoacetate selectively down-regulated the density of cell surface functional IR via lowering IR mRNA levels and IR synthesis, thereby retarding insulin-induced activation of IRS-1.

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Section: Discussionmentioning

confidence: 90%

Distinct Effects of Ketone Bodies on Down-Regulation of Cell Surface Insulin Receptor and Insulin Receptor Substrate-1 Phosphorylation in Adrenal Chromaffin Cells

Yokoo

Saitoh²,

Shiraishi³

et al. 2002

J Pharmacol Exp Ther

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“…Dopaminergic neurons help motivate feeding behavior when glucose levels are low. This feedback loop is mediated by insulin receptors in the substantia nigra, and postmortem studies of Parkinson's disease show a loss of these receptors (11). Drugs that modulate central dopamine, such as bromocriptine, are known to affect peripheral glucose control.…”

Section: Resultsmentioning

confidence: 99%

Prospective Cohort Study of Type 2 Diabetes and the Risk of Parkinson's Disease

Driver

Smith²,

Buring³

et al. 2008

Diabetes Care

147

105

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OBJECTIVE—To evaluate the association between type 2 diabetes and newly reported Parkinson's disease. RESEARCH DESIGN AND METHODS—Our study included 21,841 participants in the Physicians’ Health Study, a cohort of U.S. male physicians. Diabetes and Parkinson's disease were self-reported via questionnaire. We used time-varying Cox regression to calculate adjusted relative risk (RR) for Parkinson's disease. RESULTS—Over 23 years, 556 individuals with Parkinson's disease were identified. Subjects with diabetes had an increased Parkinson's disease risk (multivariable-adjusted RR 1.34 [95% CI 1.01–1.77]). The association remained significant after exclusion of those with known vascular disease. The diagnosis of diabetes was clustered around the diagnosis of Parkinson's disease and was more apparent among men with short diabetes duration and those without complications from diabetes. CONCLUSIONS—Results of this large prospective study in men do not suggest that diabetes is a preceding risk factor for Parkinson's disease. Whether the positive association may be explained by ascertainment bias or a common underlying biological mechanism remains to be established.

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“…In primary fetal brain cell cultures, insulin plays a role in the control of metabolism and growth (8), and clinically it has been demonstrated that patients suffering from Alzheimer's and Parkinson's diseases exhibit reduced expression of IR in the brain (9). It also has been shown that learning acutely regulates expression and tyrosine phosphorylation of the IR in the hippocampus of rats (10).…”

mentioning

confidence: 99%

Role for neuronal insulin resistance in neurodegenerative diseases

Schubert

Gautam

Surjo

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

558

313

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Impairment of insulin signaling in the brain has been linked to neurodegenerative diseases. To test the hypothesis that neuronal insulin resistance contributes to defects in neuronal function, we have performed a detailed analysis of brain͞neuron-specific insulin receptor knockout (NIRKO) mice. We find that NIRKO mice exhibit a complete loss of insulin-mediated activation of phosphatidylinositol 3-kinase and inhibition of neuronal apoptosis. In intact animals, this loss results in markedly reduced phosphorylation of Akt and GSK3␤, leading to substantially increased phosphorylation of the microtubule-associated protein Tau, a hallmark of neurodegenerative diseases. Nevertheless, these animals exhibit no alteration in neuronal proliferation͞survival, memory, or basal brain glucose metabolism. Thus, lack of insulin signaling in the brain may lead to changes in Akt and GSK3␤ activity and Tau hyperphosphorylation but must interact with other mechanisms for development of Alzheimer's disease.

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Loss of insulin receptor immunoreactivity from the substantia nigra pars compacta neurons in Parkinson's disease

Cited by 141 publications

References 27 publications

Distinct Effects of Ketone Bodies on Down-Regulation of Cell Surface Insulin Receptor and Insulin Receptor Substrate-1 Phosphorylation in Adrenal Chromaffin Cells

Distinct Effects of Ketone Bodies on Down-Regulation of Cell Surface Insulin Receptor and Insulin Receptor Substrate-1 Phosphorylation in Adrenal Chromaffin Cells

Prospective Cohort Study of Type 2 Diabetes and the Risk of Parkinson's Disease

Role for neuronal insulin resistance in neurodegenerative diseases

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