S-Nitrosylation and uncompetitive/fast off-rate (UFO) drug therapy in neurodegenerative disorders of protein misfolding

Abstract

Although activation of glutamate receptors is essential for normal brain function, excessive activity leads to a form of neurotoxicity known as excitotoxicity. Key mediators of excitotoxic damage include overactivation of N-methyl-D-aspartate (NMDA) receptors, resulting in excessive Ca 2 þ influx with production of free radicals and other injurious pathways. Overproduction of free radical nitric oxide (NO) contributes to acute and chronic neurodegenerative disorders. NO can react with cysteine thiol groups to form S-nitrosothiols and thus change protein function. S-nitrosylation can result in neuroprotective or neurodestructive consequences depending on the protein involved. Many neurodegenerative diseases manifest conformational changes in proteins that result in misfolding and aggregation. Our recent studies have linked nitrosative stress to protein misfolding and neuronal cell death. Molecular chaperones -such as protein-disulfide isomerase, glucose-regulated protein 78, and heat-shock proteins -can provide neuroprotection by facilitating proper protein folding. Here, we review the effect of S-nitrosylation on protein function under excitotoxic conditions, and present evidence that NO contributes to degenerative conditions by S-nitrosylating-specific chaperones that would otherwise prevent accumulation of misfolded proteins and neuronal cell death. In contrast, we also review therapeutics that can abrogate excitotoxic damage by preventing excessive NMDA receptor activity, in part via S-nitrosylation of this receptor to curtail excessive activity.

Mitochondrial ubiquitin ligase MITOL blocks S-nitrosylated MAP1B-light chain 1-mediated mitochondrial dysfunction and neuronal cell death

“…NO can lead to protective or damaging actions in the central nervous system. For example, there is a protective feedback mechanism via down-regulation of NMDA receptor by S-nitrosylation (35,36). Similarly, S-nitrosylation of LC1 may protect from NMDA-induced toxicity via stabilization of microtubules.…”

Slow Excitotoxicity in Alzheimer's Disease

“…More recently, second generation memantines (NitroMemantine) have been synthesized, which use memantine as a homing signal to target NO to hyperactivated NMDA receptors, in order to avoid systemic side-effects of NO such as hypotension. The NitroMemantines have enhanced neuroprotective efficacy in vitro, and in animal models of neurological disorders [261,262].…”

Janus a god with two faces: death and survival utilise same mechanisms conserved by evolution

“…These guiding concepts have inspired the articles presented in this issue of Cell Death & Differentiation. [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] This collection of reviews, dealing with mechanisms of cells and tissue damage and repair, is based on the invited lectures given at an international conference on this broad topic. This conference, which was organized jointly by Academia Europaea and The Klaus Tschira Foundation, took place in Heidelberg, Germany in March 2007 (Figure 1).…”