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

John S Del Rosario,Maha Salama,Tauhid Mahmud,Shirley Mei,Bakkeung Ko,Towfiq Ahmed,Daniel Asemota,Katherine Genevieve Feldmann,Junhyung An,Uzair Amjad,Itzhak Mano

doi:10.1186/s12868-015-0158-2

Abstract

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

Highlights

Excitotoxicity is a central process in widespread neurodegenerative conditions such as brain ischemia and chronic neurological diseases
We observe that adding dapk-1 ko to this excitotoxicity strain causes a strong and statistically significant suppression of neurodegeneration throughout development (Figure 1A, an additional independent cross gave very similar results, not shown)
We considered the many other proteins that are known to interact with Death Associated Protein Kinase (DAPK) [18] as possible modulators of excitotoxicity, but we could not assign to many of them high priority because either there was no immediate obvious connection to neurodegeneration, there is no clear nematode homolog (e.g., NFκB), the nematode homolog is not known to be active in C. elegans neurons (e.g., p53), or the process in which this protein is involved has been shown by us to be not involved in nematode excitotoxicity

Summary

Introduction

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. The most cited suggestion in the field attributes the involvement of DAPK in excitotoxicity to the potentiation of Ca2+ currents through NR2B/GluN2B subunit-containing complexes of the NMDA- receptor (NMDA-Rs) family of GluRs [24] This suggestion fits well with a proposed leading role for extrasynaptic NR2B/GluN2B –containing NMDA-Rs in excitotoxicity [25]. Some cases of excitotoxicity are mediated by another family of GluRs, the Ca2+ -Permeable AMPA Receptors (CPARs) [30,31,32] These observations suggest that if DAPK is widely involved in excitotoxicity, including in cases where NR2B/GluN2B is not a main determinant of neurodegeneration, it might act through additional mechanisms to exert its effect

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