Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0007758 (cerebellar ataxia)
 3,609 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Serum levels of insulin and insulin-like growth factors and their binding proteins (IGFs and IGFBPs, respectively) are changed in human neurodegenerative diseases of very different etiology, such as Alzheimer's disease, amyotrophic lateral sclerosis, or cerebellar ataxia. However, the significance of these endocrine disturbances is not clear. We now report that in two very different inherited neurodegenerative conditions, ataxia-telangiectasia (AT) and Charcot-Marie-Tooth 1A (CMT-1A) disease, serum levels of IGFs are also altered. Both types of patients have increased serum IGF-I and IGFBP-2 levels, and decreased serum IGFBP-1 levels, while only AT patients have high serum insulin levels. Furthermore, serum IGFs are also changed in three different animal models of neurodegeneration: neurotoxin-induced motor discoordination, diabetic neuropathy, and hereditary cerebellar ataxia. In these three models, serum insulin levels are significantly decreased, serum IGF-I and IGFBP-1, -2, and -3 are decreased in diabetic and neurotoxin-injected rats, while serum IGFBP-1 is increased in hereditary ataxic rats. Altogether, these observations indicate that a great variety of neurodegenerative diseases show endocrine perturbations, resulting in changes in serum IGFs levels. These perturbations are disease-specific and are probably due to metabolic and endocrine derangements, nerve cell death, and sickness-related disturbances associated to the neurodegenerative process. Our observations strongly support the need to evaluate serum IGFs in other neurodegenerative conditions.
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PMID:Neurodegeneration is associated to changes in serum insulin-like growth factors. 1111 63

IGF-I is an anabolic growth factor essential for growth and development, both as a mediator of growth hormone (GH) action and as a local stimulator of cell proliferation and differentiation. Although the importance of IGF-I in postnatal growth has been studied for several decades, its functions in pathological states are not fully understood. The weaver (wv) mutant mouse is a commonly used model for studying hereditary cerebellar ataxia and provides us with an opportunity to study the function of IGF-I in postnatal growth during neurodegeneration. In prepubertal wv mice, we found a parallel decrease in body weight and serum IGF-I. This parallel relationship was maintained in females, but not in males, as wv mice entered puberty. Interestingly, we found an increase in the levels of circulating IGF-I and hepatic mRNA preceded the catch-up of body weight of pubertal male wv mice. The increase in IGF-I levels coincided with a surge of circulating androgen at the onset of male puberty, suggesting that androgen might trigger the increase in IGF-I production in the pubertal and adult male wv mice. Overall, our results support the concept that IGF-I plays an important role in postnatal growth during and after neurodegeneration of wv mice. In addition, IGF-I's regulation of systemic growth during and after puberty is likely modulated by androgen in male wv mice.
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PMID:Igf-I and postnatal growth of weaver mutant mice. 1588 23

IGF-I is a well-established anabolic growth factor essential for growth and development. Although the role of the GH/IGF-I axis is established for normal postnatal growth, its functional state in neurodegenerative diseases is not fully characterized. The weaver mutant mouse is a commonly used model for studying hereditary cerebellar ataxia and provides an opportunity to investigate the function of IGF-I in postnatal growth following neurodegeneration. Previously, we reported that weaver mice are growth retarded and their body weights correlate with a decrease in circulating IGF-I levels. Because weaver mice have the same food intake/body weight ratios as their wild type littermates, our observation suggests that an impairment of the GH/IGF-I axis, rather than poor nutrition, likely contributes to their growth retardation. This study further investigated the etiology of reduced circulating IGF-I levels. We found that GH levels in weaver mice were reduced following acute insulin injection, but the hepatic GH receptor transduction pathway signaled normally as evidenced by increased STAT5b phosphorylation and IGF-I mRNA levels in response to acute GH administration. In addition, 2-week GH treatment induced a significant increase in body weight and circulating IGF-I levels in homozygous weaver mice but not in wild type littermates. In summary, a deficiency in the GH/IGF-I axis may be partially responsible for postnatal growth retardation in weaver mutant mice. This deficiency may occur at the level of the pituitary and/or hypothalamus and can be improved with GH administration.
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PMID:Role of the GH/IGF-I axis in the growth retardation of weaver mice. 1804 Aug 96

Our recent report on a parallel decrease in the body weights and serum IGF-I levels of weaver mice suggests that IGF-I's endocrine function may be impaired in neurodegenerative diseases. To further understand the overall effects of IGF-I deficiency on the postnatal growth, we measured bone mineral density (BMD), bone mineral content (BMC), lean body mass (LBM) and fat mass in male and female weaver mice and wild-type littermates on D21 (prepuberty), D45 (puberty), and D60 (postpuberty) using dual-energy X-ray absorptiometry (DEXA). In both male and female weaver mice, we found that the levels of circulating IGF-I paralleled those of BMD, BMC, and LBM, but not the fat mass. Male weaver mice have normal fat mass at all three ages studied, whereas female weaver mice showed a trend to increase their fat mass as they mature. To determine whether circulating IGF-I is a determinant of body composition, we crossbred IGF-I transgenic mice with homozygous weaver mice, which resulted in a significant increase in circulating IGF-I levels in both male and female weaver mice and normalization of their BMD, BMC and body weights. In summary, our results demonstrated that normal circulating IGF-I levels are important in maintaining BMD, BMC, and body composition in neurodegenerative diseases, such as hereditary cerebellar ataxia.
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PMID:IGF-I improved bone mineral density and body composition of weaver mutant mice. 1855 Apr 7

Globoid cell leukodystrophy (GLD) is an autosomal recessive, lysosomal storage disease caused by deficiency of the enzyme galactocerebrosidase (GALC). The absence of GALC activity leads to the accumulation of the toxic substance psychosine and the preferential loss of myelinating cells in the central and peripheral nervous systems. Profound demyelination, astrogliosis and axonopathy are the hallmarks of the pathogenesis of GLD, and cerebellar ataxia is one of the dominant manifestations in adolescents and adults affected with GLD. To date, studies regarding cerebellar degeneration in GLD are limited. In this study, the efficacy of cerebellum-targeted gene therapy on the cerebellar neuropathology in twitcher mice (a murine model of GLD) has been validated. We observed degeneration of Purkinje cells, Bergmann glia, and granule cells in addition to astrocytosis and demyelination in the cerebellum of the twitcher mice. Ultrastructural analysis revealed dark cell degeneration and disintegration of the cellular composition of Purkinje cells in untreated twitcher mice. In addition, the expressions of neurotrophic factors CNTF, GDNF and IGF-I were up-regulated and the expression of BDNF was down-regulated. Intracerebellar-mediated gene therapy efficiently corrected enzymatic deficiency by direct transduction to Purkinje cells and cross-correction in other cell types in the cerebellum, leading to the amelioration of both neuroinflammation and demyelination. The population, dendritic territory, and axonal processes of Purkinje cells remained normal in the cerebellum of treated twitcher mice, where radial fibers of Bergmann glia spanned the molecular layer and collateral branches ensheathed the dendritic processes of Purkinje cells. Moreover, the aberrant expressions of neurotrophic factors were mitigated in the cerebellum of treated twitcher mice, indicating the preservation of cellular function in addition to maintaining the neuronal architecture. The life span of the treated twitcher mice was significantly prolonged and their neurobehavioral performance was improved. Taken together, our findings underscore the complexity of cerebellar neurodegeneration in GLD and highlight the potential effectiveness of gene therapy in mitigating neuropathological deficits in GLD and other neurodegenerative disorders in which Purkinje cells are involved.
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PMID:Mitigation of cerebellar neuropathy in globoid cell leukodystrophy mice by AAV-mediated gene therapy. 2611 66