Nitrosative stress linked to sporadic Parkinson's disease: S-nitrosylation of parkin regulates its E3 ubiquitin ligase activity

Abstract

Many hereditary and sporadic neurodegenerative disorders are characterized by the accumulation of aberrant proteins. In sporadic Parkinson's disease, representing the most prevalent movement disorder, oxidative and nitrosative stress are believed to contribute to disease pathogenesis, but the exact molecular basis for protein aggregation remains unclear. In the case of autosomal recessive-juvenile Parkinsonism, mutation in the E3 ubiquitin ligase protein parkin is linked to death of dopaminergic neurons. Here we show both in vitro and in vivo that nitrosative stress leads to S-nitrosylation of wild-type parkin and, initially, to a dramatic increase followed by a decrease in the E3 ligase-ubiquitin-proteasome degradative pathway. The initial increase in parkin's E3 ubiquitin ligase activity leads to autoubiquitination of parkin and subsequent inhibition of its activity, which would impair ubiquitination and clearance of parkin substrates. These findings may thus provide a molecular link between free radical toxicity and protein accumulation in sporadic Parkinson's disease

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.…”

“…Recent findings, however, have shed light on molecular events underlying this relationship. Specifically, we and other groups have recently mounted physiological and chemical evidence that S-nitrosylation enhances (1) neuronal survival by inhibiting the activities of (a) NMDA receptors and (b) caspases, or (2) neuronal cell injury by regulating the (a) ubiquitin E3 ligase activity of parkin, 17,18,20 (b) chaperone and isomerase activities of PDI, 19 (c) nuclear translocation of GAPDH, 21 and (d) activity of MMP-9. 22 In particular, S-nitrosylation of PDI and parkin can regulate protein misfolding and neurotoxicity in models of neurodegenerative disorders, and SNO-PDI, or SNO-parkin has been found in human postmortem brain tissue from patients with neurodegenerative conditions.…”

“…(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.…”