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

Del Rosario JS, Feldmann KG, Ahmed T, Amjad U, Ko B, An J, Mahmud T, Salama M, Mei S, Asemota D, Mano I - BMC Neurosci (2015)

Bottom Line: However, the molecular mechanism by which DAPK exerts its effect is controversial.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.Our studies highlight the prominence of DAPK and Pin1/PINN-1 as conserved mediators of cell death processes in diverse scenarios of neurodegeneration.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Pharmacology, and Neuroscience, Sophie Davis School of Biomedical Education (SBE), City College of New York (CCNY), The City University of New York (CUNY), New York, NY, USA. delrosariojohns@gmail.com.

ABSTRACT

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.

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Related in: MedlinePlus

pinn-1 is an important suppressor of nematode excitotoxicity that does not affect basic synaptic strength. A)pinn-1 mutation enhances excitotoxicity throughout development. **p < 0.01 B & C)pinn-1 does not affect the duration of spontaneous forward mobility or nose touch sensitivity, two sensitive measures of Glu synaptic strength.
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Fig5: pinn-1 is an important suppressor of nematode excitotoxicity that does not affect basic synaptic strength. A)pinn-1 mutation enhances excitotoxicity throughout development. **p < 0.01 B & C)pinn-1 does not affect the duration of spontaneous forward mobility or nose touch sensitivity, two sensitive measures of Glu synaptic strength.

Mentions: Pin1 is an isomerase that changes the conformation of proline residues located next to phosphorylated Ser or Thr residues, thus changing overall protein conformation and controlling the activity of many phosphoproteins [67,68]. In recent years this protein has gained recognition as a major regulator of many signaling cascades, involved in both normal cell physiology, pathology, and in neurodegenerative diseases [67,69-71]. Pin1 is expressed in dendrites, its activity is modulated by Glu signaling, and it regulates PKCζ and PKMζ [72,73]. Pin1 is also known for its regulation of neuronal cytoskeleton and Tau protein phosphorylation, and for modulating neurodegeneration [69,74,75]. Recently, Pin1 was shown to functionally interact with DAPK [76]. We find that pinn-1 ko [77] causes increased neurodegeneration in nematode excitotoxicity (Figure 5). Like dapk-1 ko, the effect of pinn-1 ko is seen in all developmental stages (Figure 5A), and does not seem to involve a change in Glu synaptic strength (Figure 5B and C), suggesting that they influence cell-death processes subsequent to- (and not at the level of-) GluR.Figure 5


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

Del Rosario JS, Feldmann KG, Ahmed T, Amjad U, Ko B, An J, Mahmud T, Salama M, Mei S, Asemota D, Mano I - BMC Neurosci (2015)

pinn-1 is an important suppressor of nematode excitotoxicity that does not affect basic synaptic strength. A)pinn-1 mutation enhances excitotoxicity throughout development. **p < 0.01 B & C)pinn-1 does not affect the duration of spontaneous forward mobility or nose touch sensitivity, two sensitive measures of Glu synaptic strength.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4414438&req=5

Fig5: pinn-1 is an important suppressor of nematode excitotoxicity that does not affect basic synaptic strength. A)pinn-1 mutation enhances excitotoxicity throughout development. **p < 0.01 B & C)pinn-1 does not affect the duration of spontaneous forward mobility or nose touch sensitivity, two sensitive measures of Glu synaptic strength.
Mentions: Pin1 is an isomerase that changes the conformation of proline residues located next to phosphorylated Ser or Thr residues, thus changing overall protein conformation and controlling the activity of many phosphoproteins [67,68]. In recent years this protein has gained recognition as a major regulator of many signaling cascades, involved in both normal cell physiology, pathology, and in neurodegenerative diseases [67,69-71]. Pin1 is expressed in dendrites, its activity is modulated by Glu signaling, and it regulates PKCζ and PKMζ [72,73]. Pin1 is also known for its regulation of neuronal cytoskeleton and Tau protein phosphorylation, and for modulating neurodegeneration [69,74,75]. Recently, Pin1 was shown to functionally interact with DAPK [76]. We find that pinn-1 ko [77] causes increased neurodegeneration in nematode excitotoxicity (Figure 5). Like dapk-1 ko, the effect of pinn-1 ko is seen in all developmental stages (Figure 5A), and does not seem to involve a change in Glu synaptic strength (Figure 5B and C), suggesting that they influence cell-death processes subsequent to- (and not at the level of-) GluR.Figure 5

Bottom Line: However, the molecular mechanism by which DAPK exerts its effect is controversial.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.Our studies highlight the prominence of DAPK and Pin1/PINN-1 as conserved mediators of cell death processes in diverse scenarios of neurodegeneration.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Pharmacology, and Neuroscience, Sophie Davis School of Biomedical Education (SBE), City College of New York (CCNY), The City University of New York (CUNY), New York, NY, USA. delrosariojohns@gmail.com.

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus