Introduction Halogenative and nitrosative stress are two types of oxidative stress that have been proposed as pathogenic mechanisms in Parkinson’s disease (PD). They can be caused by overstimulation of phagocytes. This hypothesis discusses serum protein halogenation and nitrosylation as traits of maintained overstimulation of blood phagocytes in sporadic Parkinson’s disease. Hypothesis I hypothesize that maintained phagocyte overstimulation leads to both halogenative and nitrosative stress in PD, which are present in the serum and cerebrospinal fluid of patients. These types of oxidative stress could modify proteins related to the pathogenesis of PD. Evaluation of hypothesis It has been detected that the presence of halogenative stress in the serum and, to a lesser extent, cerebrospinal fluid of Parkinsonian patients leads to excess of advanced oxidized protein products. On the other hand, nitrosative stress is also present in serum and cerebrospinal fluid of patients with early PD, characterized by the selective increase of 3-nitrotyrosine proteins other than nitroalbumin and free 3-nitrotyrosine. Nitrosylation stress accompanies modification of the sites of nitrosylation of αsynuclein in these patients, characterized by dominant nitrosylation of tyrosine 125/136 residues. Conclusion Since metabolism of advanced oxidized protein products and 3nitrotyrosine proteins has been associated with phagocytic overstimulation, this pathological alteration could play a pathogenic role in sporadic PD. Our observations also lead to the hypothesis that serum level of advanced oxidized protein products is a prognostic marker for PD duration, and these oxidized proteins could participate in neuroinflammation. Besides, the evaluation of nitrosative stress through enhanced levels of 3-nitrotyrosine proteins in serum and cerebrospinal fluid without changes in nitroalbumin, together with the profile of tyrosine nitrosylation of serum α-synuclein characterized by dominant nitrosylation of Tyr125/136, could serve for the diagnosis of sporadic PD. Nitroα-synuclein is a main component of Lewy bodies, hallmarks of the disease, and serum nitro-α-synuclein could represent a pathogenic factor in PD. Introduction Oxidative stress is defined as an imbalance between the production of reactive oxygen and nitrogen species (ROS/RNS) and antioxidant mechanisms, and it is considered as an important pathogenic mechanism in Parkinson’s disease (PD)1–4. Halogenation is a type of oxidative stress induced by phagocytic overstimulation, leading to excess of several molecules such as advanced oxidized protein products (AOPPs). These products originate as a result of the action of free radicals such as chloramines and hypochlorous acid (HOCl) on proteins, and they are augmented in several diseases5. This halogenative process could also modify free amines such as tyrosine, leading to the formation of free 3chlorotyrosine, as shown in Figure 1. Another type of oxidative stress is nitrosylation, where oxidative modifications of proteins are secondary to excess of nitric oxide. Nitrosylation of tyrosine leading to 3-nitrotyrosine proteins or free 3-nitrotyrosine is the most prominent change, and this type of oxidative stress has been associated with human pathologies6, and it is recognized as a salient feature of diverse α-synucleinopathies such as PD and Lewy body dementia7. In PD, protein tyrosine nitrosylation has been demonstrated to represent a pathogenic mechanism, and nitrosylated tyrosine residues of diverse proteins such as neurofilaments or α-synuclein are detected in the brain proteinaceous aggregates or Lewy bodies, hallmarks of the disease8. Moreover, nitrating agents generated by dopamine are known to promote α-synuclein aggregation9, a critical step for the formation of Lewy bodies. Biochemically, nitrosylated proteins and amines can be formed through different pathways (Figure 1). The formation of peroxynitrite (ONOO–) through nitric oxide and superoxide anion is the main pathway10. However, other nitrating pathways related to phagocyte overstimulation exist. For instance, myeloperoxidase (MPO) activity and nitric oxide excess from macrophages or brain microglia yield nitrosylated proteins and nitrotyrosines11. This hypothesis discusses if protein halogenation * Corresponding author Email: efespejo@us.es University of Seville, Department of Medical Physiology, Laboratory of Molecular Neurology and Neurophysiology, E-41009 Seville, Spain