Caenorhabditis elegans dnj-14, the orthologue of the DNAJC5 gene mutated in adult onset neuronal ceroid lipofuscinosis, provides a new platform for neuroprotective drug screening and identifies a SIR-2.1-independent action of resveratrol.
Caenorhabditis elegans dnj-14, the orthologue of the DNAJC5 gene mutated in adult onset neuronal ceroid lipofuscinosis, provides a new platform for neuroprotective drug screening and identifies a SIR-2.1-independent action of resveratrol.
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DOI：
10.1093/hmg/ddu316
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发表时间：
2014-11-15
影响因子：
3.5
通讯作者：
Morgan A
中科院分区：
文献类型：
--
作者：
Kashyap SS;Johnson JR;McCue HV;Chen X;Edmonds MJ;Ayala M;Graham ME;Jenn RC;Barclay JW;Burgoyne RD;Morgan A
Adult onset neuronal lipofuscinosis (ANCL) is a human neurodegenerative disorder characterized by progressive neuronal dysfunction and premature death. Recently, the mutations that cause ANCL were mapped to the DNAJC5 gene, which encodes cysteine string protein alpha. We show here that mutating dnj-14, the Caenorhabditis elegans orthologue of DNAJC5, results in shortened lifespan and a small impairment of locomotion and neurotransmission. Mutant dnj-14 worms also exhibited age-dependent neurodegeneration of sensory neurons, which was preceded by severe progressive chemosensory defects. A focussed chemical screen revealed that resveratrol could ameliorate dnj-14 mutant phenotypes, an effect mimicked by the cAMP phosphodiesterase inhibitor, rolipram. In contrast to other worm neurodegeneration models, activation of the Sirtuin, SIR-2.1, was not required, as sir-2.1; dnj-14 double mutants showed full lifespan rescue by resveratrol. The Sirtuin-independent neuroprotective action of resveratrol revealed here suggests potential therapeutic applications for ANCL and possibly other human neurodegenerative diseases.
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DOI：
10.1126/science.1231097
发表时间：
2013-03-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hubbard BP;Gomes AP;Dai H;Li J;Case AW;Considine T;Riera TV;Lee JE;E SY;Lamming DW;Pentelute BL;Schuman ER;Stevens LA;Ling AJ;Armour SM;Michan S;Zhao H;Jiang Y;Sweitzer SM;Blum CA;Disch JS;Ng PY;Howitz KT;Rolo AP;Hamuro Y;Moss J;Perni RB;Ellis JL;Vlasuk GP;Sinclair DA
通讯作者：
Sinclair DA
影响因子：
64.5
作者：
BARGMANN, CI;HARTWIEG, E;HORVITZ, HR
通讯作者：
HORVITZ, HR
影响因子：
3.7
作者：
Graham ME;Prescott GR;Johnson JR;Jones M;Walmesley A;Haynes LP;Morgan A;Burgoyne RD;Barclay JW
通讯作者：
Barclay JW
影响因子：
5.3
作者：
Garcia-Junco-Clemente, Pablo;Cantero, Gloria;Fernandez-Chacon, Rafael
通讯作者：
Fernandez-Chacon, Rafael
影响因子：
2.7
作者：
CHALFIE, M;SULSTON, J
通讯作者：
SULSTON, J