| Project/Area Number |
10670575
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Neurology
|
|---|
| Research Institution | The University of Tokyo |
|---|
Principal Investigator |
KWAK Shin The University of Tokyo, Hospital, Faculty of Medicine, Assistant Professor, 医学部・附属病院, 助教授 (40160981)
|
|---|
| Project Period (FY) |
1998 – 1999
|
| Project Status |
Completed (Fiscal Year 1999)
|
| Budget Amount *help |
¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 1999: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 1998: ¥1,800,000 (Direct Cost: ¥1,800,000)
|
|---|
| Keywords | ALS / amyotrophic lateral sclerosis / glutamate receptor / AMPA receptor / GluR2 / RNA editing / RT-PCR / Neuronal death / カルシウム透過性 |
|---|
| Research Abstract |
Amyotrophic lateral sclerosis (ALS) is a degenerative neurological disease in which AMPA/kainate receptor-mediated delayed neurotoxicity most plausibly plays a central role. It has been demonstrated that a rise in intracellular calcium concentration preceded AMPA receptor-mediated neuronal death in the cultured spinal motoneurons. AMPA receptors are composed of a combination of four subunits of four different GluR subunits (GluR1 - GluR4) and their calcium permeability is regulated by the presence of the Ghilt2 subunit that is edited at the Q/R site in the subunit assembly. We investigated the expression and editing efficiency of GluR2 mRNA in the spinal cord of ALS cases and the spinal cord of cases with other neurological diseases and that of normal cases using reverse transcription-polymerase chan reaction (RT-PCR) combined with restriction enzyme cleavage. We found that expression of GluR2 mRNA is lower in the ventral gray of the ALS cases and disease controls than that in the normal controls. In addition, the editing efficiency was significantly lower only in the ventral gray of ALS cases than in any spinal region of the disease and normal controls. The above molecular changes of GluR2 mRNA may increase calcium influx through AMPA receptors, thereby promoting neuronal vulnerability. While reduction of GluR2 mRNA is a non-selective observation that is observed in various pathological conditions, the decrement of GluR2 mRNA editing has not been demonstrated in any experimental or pathological brain areas of neurodegenerative diseases, such as neocortices of Alzheimer's and Pick's diseases, striatum of Huntington's disease, cerebellum of Machado-Joseph disease, dendatoruburopallidoluysian atrophy and mustiple system atrophy. These results suggest that the alteration of GluR2 mRNA, particularly the reduction of RNA editing, is closely linked to the etiology of ALS.
|
