Phosphorylated α-Synuclein Accumulations and Lewy Body-like Pathology Distributed in Parkinson’s Disease-Related Brain Areas of Aged Rhesus Monkeys Treated with MPTP

Huang, Bo; Wu, Shihao; Wang, Zhengbo; Ge, Longjiao; Rizak, Joshua D.; Wu, Jing; Li, Jiali; Xu, Lin; Lv, Lei; Yin, Yan; Hu, Xintian; Li, Hao

doi:10.1016/j.neuroscience.2018.03.026

Cited by 30 publications

(23 citation statements)

References 45 publications

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“…Casein kinase-2 and G-protein-coupled receptor are two main kinases which influence the phosphorylation of α-syn ( 59 , 60 ). Circumstance poisons such as MPTP and paraquat can also cause S129 of α-syn ( 61 ). Approximately 90% of α-syn in Lewy bodies is phosphorylated at S129 in PD in the brain, while it is relatively rare in human normal brain tissue (~4%).…”

Section: Pathogenic Protein Function In Autoimmunity-associated Pdmentioning

confidence: 99%

The Challenge of the Pathogenesis of Parkinson's Disease: Is Autoimmunity the Culprit?

Jiang

et al. 2018

Front. Immunol.

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The role of autoimmunity in Parkinson's disease (PD), as one of the most popular research subjects, has been intensively investigated in recent years. Although the ultimate cause of PD is unknown, one major area of interest remains identifying new therapeutic targets and options for patients suffering from PD. Herein, we present a comprehensive review of the impacts of autoimmunity in neurodegenerative diseases, especially PD, and we have composed a logical argument to substantiate that autoimmunity is actively involved in the pathogenesis of PD through several proteins, including α-synuclein, DJ-1, PINK1, and Parkin, as well as immune cells, such as dendritic cells, microglia, T cells, and B cells. Furthermore, a detailed analysis of the relevance of autoimmunity to the clinical symptoms of PD provides strong evidence for the close correlation of autoimmunity with PD. In addition, the previously identified relationships between other autoimmune diseases and PD help us to better understand the disease pattern, laying the foundation for new therapeutic solutions to PD. In summary, this review aims to integrate and present currently available data to clarify the pathogenesis of PD and discuss some controversial but innovative research perspectives on the involvement of autoimmunity in PD, as well as possible novel diagnostic methods and treatments based on autoimmunity targets.

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Section: Pathogenic Protein Function In Autoimmunity-associated Pdmentioning

confidence: 99%

The Challenge of the Pathogenesis of Parkinson's Disease: Is Autoimmunity the Culprit?

Jiang

et al. 2018

Front. Immunol.

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“…In the two individuals, the dopaminergic neuron loss was approximately 64% in Old 1 and approximately 58% in Middle age 1. Importantly, dopaminergic neurons on the AAV9-SaCas9-SgControl side of the two monkeys were not significantly different from those in the two age-matched normal control monkeys used in our previous studies [26,30] either in Fig. 3 Quantification of functional deficits in the nigrostriatal dopaminergic system by PINK1 and DJ-1 gene-editing in the adult monkey SN using the apomorphine (Apo)-induced rotational behavior test, and quantification of the fine motor skill deficits caused by the PINK1 and DJ-1 gene-editing using a food-grasping task.…”

Section: Assessment Of Pathological Hallmarkmentioning

confidence: 73%

“…Another four were included in the current study in which both the PINK1 and DJ-1 genes were edited together. The remaining two monkeys were age-matched normal controls (without any procedures) for tyrosine hydroxylase (TH) immunostaining used in our previous studies [ 26 , 30 ]. Detailed information for all the monkeys is listed in Table 1 .…”

Section: Methodsmentioning

confidence: 99%

Co-editing PINK1 and DJ-1 Genes Via Adeno-Associated Virus-Delivered CRISPR/Cas9 System in Adult Monkey Brain Elicits Classical Parkinsonian Phenotype

et al. 2021

Neurosci. Bull.

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Whether direct manipulation of Parkinson’s disease (PD) risk genes in the adult monkey brain can elicit a Parkinsonian phenotype remains an unsolved issue. Here, we used an adeno-associated virus serotype 9 (AAV9)-delivered CRISPR/Cas9 system to directly co-edit PINK1 and DJ-1 genes in the substantia nigras (SNs) of two monkey groups: an old group and a middle-aged group. After the operation, the old group exhibited all the classic PD symptoms, including bradykinesia, tremor, and postural instability, accompanied by key pathological hallmarks of PD, such as severe nigral dopaminergic neuron loss (>64%) and evident α-synuclein pathology in the gene-edited SN. In contrast, the phenotype of their middle-aged counterparts, which also showed clear PD symptoms and pathological hallmarks, were less severe. In addition to the higher final total PD scores and more severe pathological changes, the old group were also more susceptible to gene editing by showing a faster process of PD progression. These results suggested that both genetic and aging factors played important roles in the development of PD in the monkeys. Taken together, this system can effectively develop a large number of genetically-edited PD monkeys in a short time (6–10 months), and thus provides a practical transgenic monkey model for future PD studies.

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“…However, since MPTP was potent also in young adult mice [ 71 , 72 ], this indicates that MPTP also targets dopaminergic neurons lacking NM, at least at higher doses. MPTP/MPP + induces LBs in humans, but often not in animals (also often not in monkeys), although one study found that more LBs are formed in older MPTP-injected monkeys [ 73 ].…”

Section: Chemically-induced Pd-resembling Animal Modelsmentioning

confidence: 99%

Interaction of Neuromelanin with Xenobiotics and Consequences for Neurodegeneration; Promising Experimental Models

et al. 2021

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Neuromelanin (NM) accumulates in catecholamine long-lived brain neurons that are lost in neurodegenerative diseases. NM is a complex substance made of melanic, peptide and lipid components. NM formation is a natural protective process since toxic endogenous metabolites are removed during its formation and as it binds excess metals and xenobiotics. However, disturbances of NM synthesis and function could be toxic. Here, we review recent knowledge on NM formation, toxic mechanisms involving NM, go over NM binding substances and suggest experimental models that can help identifying xenobiotic modulators of NM formation or function. Given the high likelihood of a central NM role in age-related human neurodegenerative diseases such as Parkinson’s and Alzheimer’s, resembling such diseases using animal models that do not form NM to a high degree, e.g., mice or rats, may not be optimal. Rather, use of animal models (i.e., sheep and goats) that better resemble human brain aging in terms of NM formation, as well as using human NM forming stem cellbased in vitro (e.g., mid-brain organoids) models can be more suitable. Toxicants could also be identified during chemical synthesis of NM in the test tube.

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Phosphorylated α-Synuclein Accumulations and Lewy Body-like Pathology Distributed in Parkinson’s Disease-Related Brain Areas of Aged Rhesus Monkeys Treated with MPTP

Cited by 30 publications

References 45 publications

The Challenge of the Pathogenesis of Parkinson's Disease: Is Autoimmunity the Culprit?

The Challenge of the Pathogenesis of Parkinson's Disease: Is Autoimmunity the Culprit?

Co-editing PINK1 and DJ-1 Genes Via Adeno-Associated Virus-Delivered CRISPR/Cas9 System in Adult Monkey Brain Elicits Classical Parkinsonian Phenotype

Interaction of Neuromelanin with Xenobiotics and Consequences for Neurodegeneration; Promising Experimental Models

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