Drosophila spaghetti and doubletime link the circadian clock and light to caspases, apoptosis and tauopathy.
Drosophila spaghetti and doubletime link the circadian clock and light to caspases, apoptosis and tauopathy.
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DOI：
10.1371/journal.pgen.1005171
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发表时间：
2015-05
期刊：
影响因子：
4.5
通讯作者：
Price JL
中科院分区：
文献类型：
--
作者：
Means JC;Venkatesan A;Gerdes B;Fan JY;Bjes ES;Price JL
While circadian dysfunction and neurodegeneration are correlated, the mechanism for this is not understood. It is not known if age-dependent circadian dysfunction leads to neurodegeneration or vice-versa, and the proteins that mediate the effect remain unidentified. Here, we show that the knock-down of a regulator (spag) of the circadian kinase Dbt in circadian cells lowers Dbt levels abnormally, lengthens circadian rhythms and causes expression of activated initiator caspase (Dronc) in the optic lobes during the middle of the day or after light pulses at night. Likewise, reduced Dbt activity lengthens circadian period and causes expression of activated Dronc, and a loss-of-function mutation in Clk also leads to expression of activated Dronc in a light-dependent manner. Genetic epistasis experiments place Dbt downstream of Spag in the pathway, and Spag-dependent reductions of Dbt are shown to require the proteasome. Importantly, activated Dronc expression due to reduced Spag or Dbt activity occurs in cells that do not express the spag RNAi or dominant negative Dbt and requires PDF neuropeptide signaling from the same neurons that support behavioral rhythms. Furthermore, reduction of Dbt or Spag activity leads to Dronc-dependent Drosophila Tau cleavage and enhanced neurodegeneration produced by human Tau in a fly eye model for tauopathy. Aging flies with lowered Dbt or Spag function show markers of cell death as well as behavioral deficits and shortened lifespans, and even old wild type flies exhibit Dbt modification and activated caspase at particular times of day. These results suggest that Dbt suppresses expression of activated Dronc to prevent Tau cleavage, and that the circadian clock defects confer sensitivity to expression of activated Dronc in response to prolonged light. They establish a link between the circadian clock factors, light, cell death pathways and Tau toxicity, potentially via dysregulation of circadian neuronal remodeling in the optic lobes. Alzheimer’s disease is the most common cause of dementia in the aging population. It is a progressive neurodegenerative disorder that attacks the brain neurons, resulting in loss of memory, thinking and behavioral changes. One pathological hallmark is aggregation of the microtubule-associated protein Tau. A growing body of evidence highlights the importance of caspase-dependent Tau truncation in initiation and potentiation of Tau aggregation. Here we use the fruit fly Drosophila to examine the links between circadian rhythms, aging, apoptosis and Alzheimer’s Disease. We identified a regulator (spag) of the circadian kinase Dbt that functions to stabilize Dbt during the middle of the day. In addition, the caspase Dronc is regulated by Dbt and Spag and, when activated by reduction of either, targets Tau for cleavage, leading to behavioral deficits and shortened lifespans. The expression of activated caspase occurs in several parts of the brain in a manner requiring signaling from a neuropeptide produced by circadian cells. Wild type flies with no genetic modifications eventually exhibit modified Dbt and expression of activated caspase at specific times of day, further demonstrating the links between the circadian clock, light and apoptosis.
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影响因子：
3.3
作者：
Fan, Jin-Yuan;Preuss, Fabian;Price, Jeffrey L.
通讯作者：
Price, Jeffrey L.
DOI：
10.1002/cne.22311
发表时间：
2010-06-01
期刊：
The Journal of comparative neurology
影响因子：
--
作者：
Im SH;Taghert PH
通讯作者：
Taghert PH
DOI：
10.1083/jcb.200708110
发表时间：
2008-02-11
期刊：
The Journal of cell biology
影响因子：
--
作者：
Boulon S;Marmier-Gourrier N;Pradet-Balade B;Wurth L;Verheggen C;Jády BE;Rothé B;Pescia C;Robert MC;Kiss T;Bardoni B;Krol A;Branlant C;Allmang C;Bertrand E;Charpentier B
通讯作者：
Charpentier B
影响因子：
3.7
作者：
Damulewicz, Milena;Pyza, Elzbieta
通讯作者：
Pyza, Elzbieta
DOI：
10.1073/pnas.1630428100
发表时间：
2003-08-19
影响因子：
11.1
作者：
Gamblin, TC;Chen, F;Cryns, VL
通讯作者：
Cryns, VL