Protein S-nitrosylation and oxidation contribute to protein misfolding in neurodegeneration

Abstract

Neurodegenerative disorders like Alzheimer's disease and Parkinson's disease are characterized by progressive degeneration of synapses and neurons. Accumulation of misfolded/aggregated proteins represents a pathological hallmark of most neurodegenerative diseases, potentially contributing to synapse loss and neuronal damage. Emerging evidence suggests that misfolded proteins accumulate in the diseased brain at least in part as a consequence of excessively generated reactive oxygen species (ROS) and reactive nitrogen species (RNS). Mechanistically, not only disease-linked genetic mutations but also known risk factors for neurodegenerative diseases, such as aging and exposure to environmental toxins, can accelerate production of ROS/RNS, which contribute to protein misfolding - in many cases mimicking the effect of rare genetic mutations known to be linked to the disease. This review will focus on the role of RNS-dependent post-translational modifications, such as S-nitrosylation and tyrosine nitration, in protein misfolding and aggregation. Specifically, we will discuss molecular mechanisms whereby RNS disrupt the activity of the cellular protein quality control machinery, including molecular chaperones, autophagy/lysosomal pathways, and the ubiquitin-proteasome system (UPS). Because chronic accumulation of misfolded proteins can trigger mitochondrial dysfunction, synaptic damage, and neuronal demise, further characterization of RNS-mediated protein misfolding may establish these molecular events as therapeutic targets for intervention in neurodegenerative diseases.

Keywords: Autophagy; Molecular chaperones; Protein S-nitrosylation; Protein misfolding; Tyrosine nitration; Ubiquitin-proteasome system.

Fig. 1.

Proposed mechanisms of SNO-TDP-43-mediated neurodegeneration. Genetic mutations or various environmental stimuli can cause an elevation in intracellular NO levels that increase S-nitrosylated TDP-43. SNO-TDP43 triggers intra-molecular disulfide bond formation that alters its protein conformation, contributing to aggregation of TDP-43. SNO-TDP-43 can spread to adjoining cells, leading to neurotoxicity.

Fig. 2.

S-Nitrosylation of PDI impairs its chaperone and disulfide isomerase activity that modulates protein folding. When an excessive amount of NO is present under pathological conditions, PDI is S-nitrosylated at its active site cysteines, thus inhibiting its protein folding and chaperone activity, resulting in accumulation of misfolded proteins with increased cell damage and death.

Fig. 3.

S-Nitrosylation of parkin and Uch-L1 impairs UPS activity. Aberrant S-nitrosylation of parkin disrupts its ubiquitin E3 ligase activity. S-Nitrosylated Uch-L1 manifests decreased deubiquitinase activity and increased transnitrosylation activity. Aberrant protein S-nitrosylation eventually impairs the function of the UPS, contributing to the accumulation of misfolded and aggregated proteins.

Fig. 4.

Regulation of autophagy by pathologically-elevated levels of NO-related species in neurodegenerative diseases. Pathologically increased levels of RNS inhibit autophagy under neuropathological conditions. Considering macroautophagy pathways, S-nitrosylation inhibits JNK1 and IKKβ kinase activity. As a consequence, downstream Bcl-2/Beclin 1 and mTOR pathways are altered, suppressing the initiation of autophagy. In mitophagy, S-nitrosylation of PINK1 decreases its kinase activity, thereby inhibiting phosphorylation of ubiquitin and parkin to suppress mitophagy. Considering CMA pathways, tyrosine nitration (denoted by the presence of NO₂ and detected as 3-nitrotyrosine) triggers a conformational change in αSyn that decreases its clearance through CMA. Overall, NO-mediated impairment in autophagy pathways contributes to accumulation of toxic oligomers/aggregates and damaged mitochondria. The inability to clear these proteins and damaged organelles leads to formation of inclusion bodies and contributes to neurodegeneration.