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A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Abeta.

ABSTRACT: Through functional expression screening, we identified a gene, designated Humanin (HN) cDNA, which encodes a short polypeptide and abolishes death of neuronal cells caused by multiple different types of familial Alzheimer's disease genes and by Abeta amyloid, without effect on death by Q79 or superoxide dismutase-1 mutants. Transfected HN cDNA was transcribed to the corresponding polypeptide and then was secreted into the cultured medium. The rescue action clearly depended on the primary structure of HN. This polypeptide would serve as a molecular clue for the development of new therapeutics for Alzheimer's disease targeting neuroprotection.

SUBMITTER: Hashimoto Y

PROVIDER: S-EPMC33469 | biostudies-literature | 2001 May

REPOSITORIES: biostudies-literature

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A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Abeta.

Hashimoto Y Y Niikura T T Tajima H H Yasukawa T T Sudo H H Ito Y Y Kita Y Y Kawasumi M M Kouyama K K Doyu M M Sobue G G Koide T T Tsuji S S Lang J J Kurokawa K K Nishimoto I I

Proceedings of the National Academy of Sciences of the United States of America 20010501 11

Through functional expression screening, we identified a gene, designated Humanin (HN) cDNA, which encodes a short polypeptide and abolishes death of neuronal cells caused by multiple different types of familial Alzheimer's disease genes and by Abeta amyloid, without effect on death by Q79 or superoxide dismutase-1 mutants. Transfected HN cDNA was transcribed to the corresponding polypeptide and then was secreted into the cultured medium. The rescue action clearly depended on the primary structu ...[more]

PMID: 11371646

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Project description:Ubiquitin (Ub) C-terminal hydrolase L1 (UCHL1) is a multifunctional protein that is expressed in neurons throughout brain at high levels. UCHL1 deletion is associated with axonal degeneration, progressive sensory motor ataxia, and premature death in mice. UCHL1 has been hypothesized to play a role in the pathogenesis of neurodegenerative diseases and recovery after neuronal injury. UCHL1 hydrolyzes Ub from polyubiquitinated (poly-Ub) proteins, but also may ligate Ub to select neuronal proteins, and interact with cytoskeletal proteins. These and other mechanisms have been hypothesized to underlie UCHL1's role in neurodegeneration and response to brain injury. A UCHL1 knockin mouse containing a C90A mutation (C90A) devoid of hydrolase activity was constructed. The C90A mouse did not develop the sensory and motor deficits, degeneration of the gracile nucleus and tract, or premature death as seen in UCHL1 deficient mice. C90A and wild type (WT) mice were subjected to the controlled cortical impact (CCI) model of traumatic brain injury (TBI), and cell death, axonal injury and behavioral outcome were assessed. C90A mice exhibited decreased spared tissue volume, greater loss of CA1 hippocampal neurons and greater axonal injury as detected using anti-amyloid precursor protein (APP) antibody and anti- non-phosphorylated neurofilament H (SMI-32) antibody immunohistochemistry after CCI compared to WT controls. Poly-Ub proteins and Beclin-1 were elevated after CCI in C90A mice compared to WT controls. Vestibular motor deficits assessed using the beam balance test resolved by day 5 after CCI in WT mice but not in C90A mice. These results suggest that the hydrolase activity of UCHL1 does not account for the progressive neurodegeneration and premature death seen in mice that do not express full length UCHL1. The hydrolase activity of UCHL1 contributes to the function of the ubiquitin proteasome pathway (UPP), ameliorates activation of autophagy, and improves motor recovery after CCI. Thus, UCHL1 hydrolase activity plays an important role in acute injury response after TBI.

Dataset Information

A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Abeta.

Publications

A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Abeta.

Similar Datasets

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