Insulin receptor mRNA in the substantia nigra in Parkinson's disease

Takahashi, Mitsuo; Yamada, Tatsuo; Tooyama, Ikuo; Moroo, Iku; Kimura, Hiroshi; Yamamoto, Takayuki; Okada, Hidechika

doi:10.1016/0304-3940(96)12357-0

Cited by 112 publications

(66 citation statements)

References 18 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: 95%

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: 95%

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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“…The lack of IR activation leads to neurodegeneration in brain/neuron-specific IR knock-out mice (12). Dysregulation of insulin signaling in the central nervous system has been linked to the pathogenesis of neurodegenerative disorders such as Alzheimer and Parkinson disease (13,14). These studies clearly suggest that the IR pathway is important for neuronal survival and maintenance.…”

Section: Insulin Receptor (Ir)mentioning

confidence: 99%

Loss of Neuroprotective Survival Signal in Mice Lacking Insulin Receptor Gene in Rod Photoreceptor Cells

Rajala

Tanito

et al. 2008

Journal of Biological Chemistry

113

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Insulin receptor (IR) signaling provides a trophic signal for transformed retinal neurons in culture, but the role of IR activity in vivo is unknown. We previously reported that light causes increased tyrosine phosphorylation of the IR in vivo, which leads to the downstream activation of the phosphoinositide 3-kinase and Akt pathway in rod photoreceptor cells. The functional role of IR in rod photoreceptor cells is not known. We observed that light stress induced tyrosine phosphorylation of the IR in rod photoreceptor cells, and we hypothesized that IR activation is neuroprotective. To determine whether IR has a neuroprotective role on rod photoreceptor cells, we used the Cre/lox system to specifically inactivate the IR gene in rod photoreceptors. Rodspecific IR knock-out mice have reduced the phosphoinositide 3-kinase and Akt survival signal in rod photoreceptors. The resultant mice exhibited no detectable phenotype when they were raised in dim cyclic light. However, reduced IR expression in rod photoreceptors significantly decreased retinal function and caused the loss of photoreceptors in mice exposed to bright light stress. These results indicate that reduced expression of IR in rod photoreceptor cells increases their susceptibility to lightinduced photoreceptor degeneration. These data suggest that the IR pathway is important for photoreceptor survival and that activation of the IR may be an essential element of photoreceptor neuroprotection. Insulin receptor (IR)2 signaling provides a trophic signal for transformed retinal neurons in culture (1), but the role of the IR in vivo is unknown. IR activation has been shown to rescue retinal neurons from apoptosis through a phosphoinositide 3-kinase (PI3K) cascade (1). We previously reported that light induces tyrosine phosphorylation of the retinal IR and that this activation leads to the binding of PI3K to rod outer segment (ROS) membranes (2). More recently, we demonstrated that IR activation is mediated through the G-protein-coupled receptor rhodopsin (3). IR signaling is also involved in 17␤-estradiolmediated neuroprotection in the retina (4). Recent evidence suggests a down-regulation of IR kinase activity in diabetic retinopathy that is associated with the deregulation of downstream signaling molecules (5). Deletion of several downstream effector molecules of the IR signaling pathway, such as IRS-2 (6), Akt2 (7), and Bcl-xl (8), in the retina resulted in a photoreceptor degeneration phenotype. These studies clearly indicate the importance of the IR signaling pathway in the retina.The IR is highly conserved, and the high degree of IR signaling homology between Caenorhabditis elegans, Drosophila, and humans suggests functional conservation in mammalian retina. The IR regulates neuronal survival in C. elegans (9). In Drosophila, the IR serves an important function to guide retinal photoreceptor axons from the retina to the brain during development (10), and the IR influences the size and number of photoreceptors (11). The lack of IR activation leads to neurod...

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“…It is assumed that insulin deficiency contributes to the neurological and psychiatric complications of diabetes (44 -46). In addition, defects in insulin action in the CNS may be linked to the pathogenesis of neurodegenerative disorders such as Alzheimer disease (47) and Parkinson disease (48). In patients with Alzheimer disease, insulin levels are higher in plasma and lower in cerebrospinal fluid compared with control subjects (49,50).…”

mentioning

confidence: 99%

Insulin and Insulin-like Growth Factor 1 (IGF-1) Modulate Cytoplasmic Glucose and Glycogen Levels but Not Glucose Transport across the Membrane in Astrocytes

Muhič

Vardjan

Chowdhury

et al. 2015

Journal of Biological Chemistry

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Background: Astrocytes contain glycogen, an energy buffer in the brain. Results: Stimulation with insulin and IGF-1 decreases cytosolic glucose concentration in astrocytes without affecting glucose entry across the astrocyte plasma membrane. Conclusion: Insulin and IGF-1 boost the process of glycogen formation. Significance: This is the first high temporal resolution measurement of the decrease of glucose levels in astrocytes resulting from insulin and IGF-1 stimulation.

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Insulin receptor mRNA in the substantia nigra in Parkinson's disease

Cited by 112 publications

References 18 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

Loss of Neuroprotective Survival Signal in Mice Lacking Insulin Receptor Gene in Rod Photoreceptor Cells

Insulin and Insulin-like Growth Factor 1 (IGF-1) Modulate Cytoplasmic Glucose and Glycogen Levels but Not Glucose Transport across the Membrane in Astrocytes

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