Nitrosative stress in Parkinson’s disease

Abstract

Parkinson’s Disease (PD) is a neurodegenerative disorder characterized, in part, by the loss of dopaminergic neurons within the nigral-striatal pathway. Multiple lines of evidence support a role for reactive nitrogen species (RNS) in degeneration of this pathway, specifically nitric oxide (NO). This review will focus on how RNS leads to loss of dopaminergic neurons in PD and whether RNS accumulation represents a central signal in the degenerative cascade. Herein, we provide an overview of how RNS accumulates in PD by considering the various cellular sources of RNS including nNOS, iNOS, nitrate, and nitrite reduction and describe evidence that these sources are upregulating RNS in PD. We document that over 1/3 of the proteins that deposit in Lewy Bodies, are post-translationally modified (S-nitrosylated) by RNS and provide a broad description of how this elicits deleterious effects in neurons. In doing so, we identify specific proteins that are modified by RNS in neurons which are implicated in PD pathogenesis, with an emphasis on exacerbation of synucleinopathy. How nitration of alpha-synuclein (aSyn) leads to aSyn misfolding and toxicity in PD models is outlined. Furthermore, we delineate how RNS modulates known PD-related phenotypes including axo-dendritic-, mitochondrial-, and dopamine-dysfunctions. Finally, we discuss successful outcomes of therapeutics that target S-nitrosylation of proteins in Parkinson’s Disease related clinical trials. In conclusion, we argue that targeting RNS may be of therapeutic benefit for people in early clinical stages of PD.

Post-fibrillization nitration of alpha-synuclein abolishes its seeding activity and pathology formation in primary neurons andin vivo

“…However, the relative contribution and differential role of oxidative stress at different stages of the development and progression of NDDs remains poorly understood 55 . One major hallmark of oxidative stress in NDDs is the preferential accumulation of nitrated misfolded proteins in the proteinaceous pathological inclusions found in the brains of affected patients 2, 7, 56 . This has led to the suggestion that oxidative modifications of aggregation-prone proteins may play causative roles in the initiation and/or progression of protein misfolding, aggregation, pathology spreading, or neurodegeneration in NDDs 20, 57 .…”

“…In these diseases, the production of reactive oxygen (ROS) and nitrogen (RNS) species overwhelms the antioxidant capacity of cells 5 , leading to a redox imbalance and ultimately to increased production of the nitrogen dioxide radical (NO 2 ˙), 3-nitrotyrosine, and dityrosine cross-linking formation 3,6 . Several neuropathological observations and recent rodent studies also suggest this to be the case in Parkinson's disease (PD) [7][8][9] , the second most common age-related NDD.…”

Unscrambling the Role of Redox-Active Biometals in Dopaminergic Neuronal Death and Promising Metal Chelation-Based Therapy for Parkinson’s Disease

“…Oxidative and nitrative stress in the mesencephalon, where dopaminergic neurons are located, is one of the main factors related to PD pathogenesis [ 20 , 21 ]. Dopamine is susceptible to auto-oxidization, producing toxic semiquinone species, H 2 O 2 , and a small amount of the neurotoxin 6-hydroxydopamine [ 22 , 23 ].…”

Mitochondrial Complex I as a Pathologic and Therapeutic Target for Parkinson’s Disease

“…The exact mechanism is not clear, but excess calcium produces superoxides, which in the presence of NO produce peroxy nitrates and inactivate MCI. 112,113 3.5. Endoplasmic Reticulum Stress, Calcium Overload, and MCI Dysfunction.…”

“…In PD, studies have shown increased nitrosative stress. The exact mechanism is not clear, but excess calcium produces superoxides, which in the presence of NO produce peroxy nitrates and inactivate MCI. , …”