Death Associated Protein Kinase (DAPK) -mediated neurodegenerative mechanisms in nematode excitotoxicity

BMC Neuroscience

Itzhak Mano⁵  Daniel Asemota³  Shirley Mei³  Maha Salama³  Tauhid Mahmud²  JunHyung An²  BakKeung Ko²  Uzair Amjad¹  Towfiq Ahmed²  Katherine Genevieve Feldmann⁵  John S Del Rosario⁴ 

[1] Undergraduate program in Biochemistry, CCNY, CUNY, New York, NY, USA;Undergraduate program in Biology, CCNY, CUNY, New York, NY, USA;Bs/MD program, Sophie Davis SBE, CCNY, CUNY, New York, NY, USA;MS program in Biology, CCNY, CUNY, New York, NY, USA;PhD program in Neuroscience, the CUNY Graduate Center, New York, NY, USA

关键词: Peptidyl prolyl isomerase Pin1;    Autophagy;    Death-Associated protein kinase;    Neurodegeneration;    Excitotoxicity;    Glutamate;    Ischemia;   

Others  :  1210194
DOI  :  10.1186/s12868-015-0158-2

 received in 2014-10-01, accepted in 2015-03-31,  发布年份 2015

【 摘 要 】

Background

Excitotoxicity (the toxic overstimulation of neurons by the excitatory transmitter Glutamate) is a central process in widespread neurodegenerative conditions such as brain ischemia and chronic neurological diseases. Many mechanisms have been suggested to mediate excitotoxicity, but their significance across diverse excitotoxic scenarios remains unclear. Death Associated Protein Kinase (DAPK), a critical molecular switch that controls a range of key signaling and cell death pathways, has been suggested to have an important role in excitotoxicity. However, the molecular mechanism by which DAPK exerts its effect is controversial. A few distinct mechanisms have been suggested by single (sometimes contradicting) studies, and a larger array of potential mechanisms is implicated by the extensive interactome of DAPK.

Results

Here we analyze a well-characterized model of excitotoxicity in the nematode C. elegans to show that DAPK is an important mediator of excitotoxic neurodegeneration across a large evolutionary distance. We further show that some proposed mechanisms of DAPK’s action (modulation of synaptic strength, involvement of the DANGER-related protein MAB-21, and autophagy) do not have a major role in nematode excitotoxicity. In contrast, Pin1/PINN-1 (a DAPK interaction-partner and a peptidyl-prolyl isomerase involved in chronic neurodegenerative conditions) suppresses neurodegeneration in our excitotoxicity model.

Conclusions

Our studies highlight the prominence of DAPK and Pin1/PINN-1 as conserved mediators of cell death processes in diverse scenarios of neurodegeneration.

【 授权许可】

   
2015 Del Rosario et al.; licensee BioMed Central.

【 图 表 】

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