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The failure of endogenous repair mechanisms is a key characteristic of neurological diseases, leading to the inability to restore damaged nerves and resulting in functional impairments. Since the endogenously regenerative capacity of damaged nerves is limited, the enhancement of regenerative potential of quiescent neural stem cells (NSCs) presents as a therapeutic option for neural diseases. Our previous studies have shown exciting progress in treating sciatic nerve injury in mice and rats using NSCs in conjunction with neurotrophic factors such as fibroblast growth factor 1 (FGF1). Additionally, a recently discovered neurotrophic factor, IL12p80, has shown significant therapeutic effects in sciatic nerve injury repair via myelinating oligodendrocytes. IL12p80 induces oligodendrocyte differentiation from NSCs through phosphorylation of Stat3. Therefore, it might be possible to alleviate the myelination defects of oligodendrocytes in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and even schizophrenia through the administration of IL12p80. These applications could shed light on IL12p80 and FGF1, not only in damaged nerve repair, but also in rectifying the oligodendrocytes' defects in neurodegenerative diseases, such as ALS and MS. Finally, the synergistic effects of neurogenesis-induced FGF1 and myelination-induced IL12 might be able to supplant the need of NSCs for nerve repair and neuroregeneration. [ABSTRACT FROM AUTHOR]

Hyperekplexia is a neurological disorder associated primarily with mutations in the α1 subunit of glycine receptors (GlyRs) that lead to dysfunction of glycinergic inhibitory transmission. To date, most of the identified mutations result in disruption of surface expression or altered channel properties of α1-containing GlyRs. Little evidence has emerged to support an involvement of allosteric GlyR modulation in human hyperekplexia. Here, we report that recombinant human GlyRs containing α1 or α1β subunits with a missense mutation in the α1 subunit (W170S), previously identified from familial hyperekplexia, caused remarkably reduced potentiation and enhanced inhibition by Zn(2+). Interestingly, mutant α1(W170S)β GlyRs displayed no significant changes in potency or maximum response to glycine, taurine, or β-alanine. By temporally separating the potentiating and the inhibitory effects of Zn(2+), we found that the enhancement of Zn(2+) inhibition resulted from a loss of Zn(2+)-mediated potentiation. The W170S mutation on the background of H107N, which was previously reported to selectively disrupt Zn(2+) inhibition, showed remarkable attenuation of Zn(2+)-mediated potentiation and thus indicated that W170 is an important residue for the Zn(2+)-mediated GlyR potentiation. Moreover, overexpressing the α1(W170S) subunit in cultured rat neurons confirmed the results from heterologous expression. Together, our results reveal a new zinc potentiation site on α1 GlyRs and a strong link between Zn(2+) modulation and human disease.