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Polcyn et al. NSE in neural survival and death

Investigation into the neurotrophic activity of NSE in MAPK/ERK pathways and result in cell death. It would
a mouse model of the neurodegenerative condition be interesting to investigate the role of ENOblock in
AD has shown that NSE can be regulated by Cat regulating PI3K/Akt and MAPK/ERK pathways and
X, a lysosomal cysteine protease that cleaves the Cat X activity. Future studies to elucidate the role of
C-terminal end of the NSE enzyme under acidic PI3K/Akt and MAPK/ERK pathways in defining cell
[5]
conditions . The C-terminal peptide of NSE, which fate are warranted. Mediation of the Cat X activity in
is not involved in plasminogen binding (due to the association with these pathways could result in partial
absence of lysine) or glycolytic function, contains as opposed to total degradation of NSE, thus reducing
a PDZ-binding domain for the scaffold protein γ-1 NSE and Cat X mediated cell death and providing
syntrophin that enables NSE to relocate to the plasma a promising future therapeutic target for reversal of
membrane via actin filament, as evidenced by their co- secondary injury mechanisms in acute and chronic
[4]
localization . This C-terminal peptide has been shown SCI as well as other neurological conditions.
to have a pro-survival effect on PC12 cells [19] . The
cleavage of NSE at this site by Cat X severely affects In conclusion, several future avenues for research
its ability to function in neuronal cell differentiation on the mechanisms of NSE expression and
for pro-survival activity or cell death. Because of activity in neurons and glia and the process of
the known involvement of PI3K/Akt and MAPK/ERK neurodegeneration and regeneration following
signaling pathways in the activation of cathepsin B, a neurological impairment have been discussed. NSE,
similar cysteine protease, in glioma, Cat X activity is once migrated to the plasma membrane, takes part in
likely associated with these same pathways [20] . cellular activation, production of inflammatory cytokines
and chemokines, and induction of neuronal cell death
An additional cysteine protease, calpain, is involved (neurodegeneration) [1,3] . The regulated expression of
in the neuroinflammatory response to SCI [21] . Calpain NSE may promote neuronal survival (neuroprotection
is found in the cytosol and is active under neutral pH or regeneration) via cell survival pathways. Previous
2+
conditions upon Ca activation. The role of calpain research has focused on the harmful effects of NSE
in apoptosis has been clearly demonstrated, and its overexpression following neuronal damage. However,
activation in SCI conditions has been shown to lead to future studies should address the conditions leading
cytoskeletal and myelin protein cleavage. Calpeptin, to preferential differentiation into pro-survival activity
a calpain inhibitor, can exhibit neuroprotective effects or neuronal cell death and specific methods for
against excitotoxic apoptosis, reducing neuronal cell regulating NSE and Cat X activity to mediate the
death [22] . While inhibition of enolase by ENOblock secondary damages associated with SCI. The role of
alters cellular growth, cytokines/chemokines, and Cat X in secondary injury remains unknown, as does
inflammatory markers [2,23] , it is unknown if ENOblock the influence of SCI on Cat X expression and activity.
acts on Cat X and regulates its function. Our group Additionally, the direct and indirect targets of ENOblock
has found increased calpain activity and cell-specific treatment have yet to be determined. Calpeptin,
overexpression in astrocytes, microglia, macrophages which acts on calpain to reduce neuronal cell death,
and T cells in inf lammator y demyelinating may similarly act on Cat X to regulate NSE activity.
diseases [24-26] . However, the effects of calpain inhibition The effects of these inhibitors on neurodegeneration
(calpeptin) on NSE and Cat X functions remain to be and/or neuroprotection and their potential interaction
investigated. Calpeptin, which is a cysteine protease with the PI3K/Akt and MAPK/ERK pathways remain
inhibitor, could possibly target Cat X, leading to to be determined. This editorial has highlighted
inhibition of NSE-mediated inflammatory events and several potential intermediary effectors associated
with neurodegeneration and neuroprotection in SCI
promotion of neuronal cell survival. Since NSE is a and other neuropathological conditions. Significant
substrate of Cat X, evaluating both ENOblock and research is needed to further evaluate these possible
calpeptin as potential mediators of NSE expression mechanisms and their potential for translation into
and activity in neuronal cells following SCI and other future preclinical and clinical treatments.
neurological disorders.

At certain levels, NSE can support regeneration of DECLARATIONS
neuronal cells [1,5] . NSE-mediated activation of the
PI3K/Akt and MAPK/ERK pathways likely supports Authors’ contributions
cell survival and regeneration. On the other hand, Overall design and completion of the manuscript: A.
these pathways also likely activate Cat X, an enzyme Haque
that cleaves NSE. Cat X activity would likely result in a Performed original research on enolase and SCI,
reduction of NSE-mediated activation of PI3K/Akt and and analyzed data published in Neurochemical

256 Neuroimmunology and Neuroinflammation ¦ Volume 4 ¦ December 6, 2017