2005 Fiscal Year Final Research Report Summary
Proteolipid storage disease causing neurodegeneration : Research from the lysosomal membraneproteins.
| Project/Area Number |
16590253
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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 |
Pathological medical chemistry
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| Research Institution | JUNTENDO UNIVERSITY |
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Principal Investigator |
EZAKI Junji Juntendo University, School of medicine, Biochemistry, Instructor, 医学部, 講師 (60232948)
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| Co-Investigator(Kenkyū-buntansha) |
TANIDA Isei Juntendo University, School of medicine, Biochemistry, Instructor, 講師 (30296868)
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| Project Period (FY) |
2004 – 2005
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| Keywords | neurodegenerative disease / proteolipid / autophagosome / TPP-I / Cln3p / Cln6p / autophagy / peroxisome |
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| Research Abstract |
The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disease. The characteristic feature of NCL is the accumulation of proteolipid subunit c of the mitochondrial ATP synthase complex. NCLs are caused by at least 8 mutant genes. Three lysosomal enzymes including palmitoyl-protein thioesterase 1 (PPT1), tripeptidyl peptidase 1 (TPP-I), and cathepsin D are responsible for NCLs. In addition, endosomal chloride channel 3 (Clcn3) and three proteins with unknown function (Cln3p, Cln5p, Cln6p and Cln8p) are also thought to be the causative protein of another type of NCLs.
We have been investigating the characteristics of Cln3p and Cln6p by biochemical techniques. Liver Cln3p was predominantly localized in the lysosomal membrane, not in endoplasmic reticulum or Golgi apparatus. Cln3p was detected in all organs tested (brain, liver, kidney, pancreas, and spleen). The amount of brain Cln3p was much lower than that of Cln3p of other tissues. The apparent molecular ma
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sses of liver Cln3p were determined to be about 60 kDa and 55 kDa, respectively. Both brain and liver Cln3p possess complex-type N-linked sugar chains. On the other hand, Cln6p was predominantly localized in the endoplasmic reticulum. Cln6p also detected in all tissues tested, however the Cln3p signal was faint in brain and liver by the immunoblotting analysis. The apparent molecular mass of Cln6p was 30 kDa without N-linked sugar chains.
Most cellular components, if not all, are regulated quantitatively to remain cell homeostasis. For this regulation, there are growing lines of evidence for the importance of the balance between biosynthesis and degradation. To investigate the problem, we analyzed the clearance of surplus peroxisomes using the conditional-knock out mice of Atg7. Following induction of peroxisomes by a 2-week treatment with phthalate esters. Although most of the excess peroxisomes in the control liver were selectively degraded within 1 week, this rapid removal was exclusively impaired in the mutant liver. Furthermore, morphological analysis revealed that surplus peroxisomes, but not mutant hepatocytes, were surrounded by autophagosomes in the control. These results indicated that the autophagic machinery is essential for the selective clearance of excess peroxisomes in mammals. Less
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[Journal Article] Impaiment of starvation-induced and constitutive autophagy in Atg7-deficient mice.2005
Author(s)
M.Komatsu, S.Wguri, T.Ueno, J.Iwata, S.Murata, I.Tanida, J.Ezaki, N.Mizushima, Y.Ohsumi, Y.Uchiyama, E.Kominami, K.Tanaka, T.Chiba
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Journal Title
J.Cell Biol. 169
Pages: 425-454
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Characterization of Cln3p, the gene product responsible for juvenile neuronal ceroid lipofuscinosis, as a lysosomal integral membrane glycoprotein.2003
Author(s)
J.Ezaki, I.M.Takeda-Ezaki, M.Koike, Y.Ohsawa, H.Taka, R.Mineki, K.Murayama, Y.Uchiyama, T.Ueno, E.Kominami
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Journal Title
J.Neurochem. 87
Pages: 1296-1308
Description
「研究成果報告書概要(欧文)」より
