S-Nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration

Abstract

Stress proteins located in the cytosol or endoplasmic reticulum (ER) maintain cell homeostasis and afford tolerance to severe insults. In neurodegenerative diseases, several chaperones ameliorate the accumulation of misfolded proteins triggered by oxidative or nitrosative stress, or of mutated gene products. Although severe ER stress can induce apoptosis, the ER withstands relatively mild insults through the expression of stress proteins or chaperones such as glucose-regulated protein (GRP) and protein-disulphide isomerase (PDI), which assist in the maturation and transport of unfolded secretory proteins. PDI catalyses thiol-disulphide exchange, thus facilitating disulphide bond formation and rearrangement reactions. PDI has two domains that function as independent active sites with homology to the small, redox-active protein thioredoxin. During neurodegenerative disorders and cerebral ischaemia, the accumulation of immature and denatured proteins results in ER dysfunction, but the upregulation of PDI represents an adaptive response to protect neuronal cells. Here we show, in brains manifesting sporadic Parkinson's or Alzheimer's disease, that PDI is S-nitrosylated, a reaction transferring a nitric oxide (NO) group to a critical cysteine thiol to affect protein function. NO-induced S-nitrosylation of PDI inhibits its enzymatic activity, leads to the accumulation of polyubiquitinated proteins, and activates the unfolded protein response. S-nitrosylation also abrogates PDI-mediated attenuation of neuronal cell death triggered by ER stress, misfolded proteins or proteasome inhibition. Thus, PDI prevents neurotoxicity associated with ER stress and protein misfolding, but NO blocks this protective effect in neurodegenerative disorders through the S-nitrosylation of PDI.

Redox-based regulation of signal transduction: Principles, pitfalls, and promises

“…PDI is also surface associated, where it may play a role in transport of NO from S-nitrosothiols across membranes (whether directly or by maintaining surfact thiols in the reduced state is not clear) [160,161]. Interestingly, S-nitrosylation of PDI [162,163] has been linked to neurodegenerative disease [162]. Interestingly, PDI itself can mediate its own denitrosylation [163].…”

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

“…46,47 Our group first identified the physiological relevance of S-nitrosylation by showing that NO and related RNS exert paradoxical effects via redox-based mechanisms -NO is neuroprotective via S-nitrosylation of NMDA receptors (as well as other subsequently discovered targets, including caspases), and yet can also be neurodestructive by formation of peroxynitrite (or, as later discovered, reaction with additional molecules such as parkin, PDI, GAPDH, and MMP-9) (Figure 1). 6,8,9,12,14,16,17,[19][20][21][22]48 Over the past decade, accumulating evidence has suggested that S-nitrosylation can regulate the biological activity of a great variety of proteins, in some ways akin to phosphorylation. 10,[49][50][51][52][53][54] Chemically, NO is often a good 'leaving group,' facilitating further oxidation of critical thiol to disulfide bonds among neighboring (vicinal) cysteine residues or, via reaction with ROS, to sulfenic (ÀSOH), sulfinic (ÀSO 2 H), or sulfonic (ÀSO 3 H) acid derivatization of the protein.…”

“…10,[49][50][51][52][53][54] Chemically, NO is often a good 'leaving group,' facilitating further oxidation of critical thiol to disulfide bonds among neighboring (vicinal) cysteine residues or, via reaction with ROS, to sulfenic (ÀSOH), sulfinic (ÀSO 2 H), or sulfonic (ÀSO 3 H) acid derivatization of the protein. 19,20,22,55 Alternatively, S-nitrosylation may possibly produce a nitroxyl disulfide, in which the NO group is shared by close cysteine thiols. 19,56 Although the involvement of NO in neurodegeneration has been widely accepted, the chemical relationship between nitrosative stress and neuronal cell death has remained obscure.…”

“…(a) S-nitrosylation of NMDA receptors can positively influence neuronal survival; 6,8-11 (b) S-nitrosylation of cysteine protease caspase blocks apoptotic cell death; [12][13][14][15][16] (c) S-nitrosylation of parkin (a ubiquitin E3 ligase) and protein-disulfide isomerase (PDI, an endoplasmic reticulum (ER) chaperone) can be injurious by effecting accumulation of misfolded proteins in neurodegenerative diseases such as PD, AD, and other conditions; [17][18][19][20] (d) S-nitrosylation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) formed in the cytoplasm transduces an apoptotic signal into the nucleus of neuronal cells; 21 and (e) S-nitrosylation of matrix metalloproteinase (MMP)-2/9 leads to a unique extracellular pathway contributing to excitotoxic neuronal cell damage. 22 NMDA Receptor-Mediated Glutamatergic Signaling Pathways Induce Ca 2 þ Influx…”

“…37,38 Pesticide and other environmental toxins that inhibit mitochondrial complex I result in oxidative and nitrosative stress, and consequent aberrant protein accumulation. 17,19,20,39 Administration to animal models of complex I inhibitors, such as MPTP, 6-hydroxydopamine, rotenone, or paraquat, which result in overproduction of ROS/RNS, reproduces many of the features of sporadic PD, such as dopaminergic neuron degeneration, upregulation and aggregation of a-synuclein, Lewy body-like intraneuronal inclusions, and behavioral impairment. 37,38 Additionally, it has recently been proposed that mitochondrial cytochrome oxidase can produce NO in a nitrite (NO 2 À )-and pH-dependent but non-Ca 2 þ -dependent manner.…”