The Role of Deimination as a Response to Trauma and Hypoxic Injury in the Developing CNS

Ferretti, Patrizia; Lange, Sigrun; U, Kin Pong; Raivich, Gennadij

doi:10.1007/978-1-4614-8317-5_15

Cited by 2 publications

(4 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…AIF-mediated cell death depends on the cell type and nature of the apoptotic insult, which may determine the mechanisms of AIF release from the mitochondria [56–59] . Significantly, AIF has been reported to play a role in neural tissue damage following hypoxia ischemia in neonates, and there is some evidence of neural damage reduction in the neonatal hypoxic–ischemic model upon PAD inhibition [7,60] .…”

Section: Discussionmentioning

confidence: 99%

“…Inhibition of citrullination can reduce disease onset or severity in mouse models of multiple sclerosis, rheumatoid arthritis and ulcerative colitis [23–25] . Significantly, the PAD inhibitor Cl-amidine reduces neural damage in a chick spinal cord injury model and in a neonatal mouse hypoxia model [6,7,26] . In the chick, PAD3 appears to be the main PAD involved in secondary injury response, that includes increased intracellular Ca 2 + , leading to apoptosis and consequent neural tissue loss.…”

Section: Introductionmentioning

confidence: 99%

“…The importance of citrullination/deimination, the hydrolysis of protein-bound arginine to citrulline, in several neural pathologies is becoming increasingly apparent [1–7] . These include traumatic injury, hypoxia and neurodegenerative diseases, such as Alzheimer's disease and multiple sclerosis, where an increase in Ca 2 + levels is considered to play a relevant role in neural tissue loss [8–11] .…”

Section: Introductionmentioning

confidence: 99%

“…Ca 2 + -dependent cell death is not executed by caspase 3, and translocation to the nucleus of the mitochondrial protein, apoptosis inducing factor (AIF), mediates apoptosis in injured brains [29,30] . AIF down-regulation appears to be neuroprotective; hence effective targeting of this pathway could be valuable in pathologies involving Ca 2 + homeostasis dysregulation either during embryonic development or post-natally, such as traumatic injuries, hypoxia–ischemia and damage to neural precursors caused by radiotherapy in young brains [7,30–35] .…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Modulation of calcium-induced cell death in human neural stem cells by the novel peptidylarginine deiminase–AIF pathway

U¹,

Subramanian

Nicholas

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

Self Cite

View full text Add to dashboard Cite

PADs (peptidylarginine deiminases) are calcium-dependent enzymes that change protein-bound arginine to citrulline (citrullination/deimination) affecting protein conformation and function. PAD up-regulation following chick spinal cord injury has been linked to extensive tissue damage and loss of regenerative capability. Having found that human neural stem cells (hNSCs) expressed PAD2 and PAD3, we studied PAD function in these cells and investigated PAD3 as a potential target for neuroprotection by mimicking calcium-induced secondary injury responses. We show that PAD3, rather than PAD2 is a modulator of cell growth/death and that PAD activity is not associated with caspase-3-dependent cell death, but is required for AIF (apoptosis inducing factor)-mediated apoptosis. PAD inhibition prevents association of PAD3 with AIF and AIF cleavage required for its translocation to the nucleus. Finally, PAD inhibition also hinders calcium-induced cytoskeleton disassembly and association of PAD3 with vimentin, that we show to be associated also with AIF; together this suggests that PAD-dependent cytoskeleton disassembly may play a role in AIF translocation to the nucleus. This is the first study highlighting a role of PAD activity in balancing hNSC survival/death, identifying PAD3 as an important upstream regulator of calcium-induced apoptosis, which could be targeted to reduce neural loss, and shedding light on the mechanisms involved.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%