Implication of GAPDH in neuronal apoptosis and neurodegenerative diseases
| Project/Area Number |
11672178
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Biological pharmacy
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| Research Institution | Josai University |
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Principal Investigator |
ISHITANI Ryoichi Josai University, Professor, 薬学部, 教授 (80077958)
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| Co-Investigator(Kenkyū-buntansha) |
TSUCHIYA Katsumi Josai University, Associate Professor, 薬学部, 助教授 (80095314)
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| Project Period (FY) |
1999 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 2000: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1999: ¥1,600,000 (Direct Cost: ¥1,600,000)
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| Keywords | Apoptosis / GAPDH / Neuronal death / Nuclear accumulation / Promoter core / Neurodegenerative disorders |
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| Research Abstract |
We have found that overexpression and subsequent nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is involved in neuronal apoptosis induced by several stimuli in which GAPDH antisense oligonucleotides specifically block the increment (2〜3 fold) of GAPDH mRNA contents occurring prior to neuronal death. However, these agents do not affect the basal, constitutive mRNA contents. This suggests that there may be distinct gene regulations for GAPDH mRNA expression. In the present studies, we cloned two types of promoter regions upstream of this gene ; viz., #104 (1.02-kb) and #302 (2.46-kb). These fragments were inserted into the pGL3 luciferase reporter system and transfected into cultured cerebellar granule neurons undergoing cytosine arabinonucleoside-induced apoptosis. The functional analysis of their constructs revealed that #104, but not #302, increased luciferase activity. Deletion and replacement mutation analysis of the #104 fragment disclosed the promoter core resident between the 154-bp and 84-bp domains (6-fold expression of the control). Furthermore, mounting evidence shows that gene products from several CAG repeat diseases selectively interact with GAPDH via the expanded polyglutamine stretches. Importantly, Huntington's disease-transgenic mice form pronounced neuronal intranuclear inclusions, containing ubiquitinated huntingtin, prior to developing a neurological phenotype. Herein, immunocytochemical examination of human post-mortem materials from the patient with Machado-Joseph disease clearly revealed the nuclear accumulated GAPDH immunoreactive profiles in neurons of the affected pontine nuclei. Double immunofluorescence staining displayed the co-localization of GAPDH with the ubiquitinated nuclear inclusions. Together, these findings suggest that the GAPDH nuclear accumulation may implicate in the pathogenesis of certain forms of neurodegenerative disorders.
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Report
(3 results)
Research Products
(6 results)
