α‐synuclein abnormalities trigger focal tau pathology, spreading to various brain areas in Parkinson disease

• Published in: Journal of neurochemistry 2021-05, Vol.157 (3), p.727-751
• Main Authors: Hadi, Fatemeh, Akrami, Hassan, Totonchi, Mehdi, Barzegar, Abdolrazagh, Nabavi, Seyed Massood, Shahpasand, Koorosh
• Format: Article
• Language: English
• Subjects: 6‐OHDA; Abnormalities; Brain; Cytokines; Dopamine receptors; Immunotherapy; Interferon; Monoclonal antibodies; Movement disorders; MPTP; Neurodegeneration; Neurodegenerative diseases; Neurons; Neurotoxins; Parkinson disease; Parkinson's disease; Pathogenicity; Pathogens; Pathology; Phosphorylation; P‐tau; P‐α‐synuclein; Synuclein; Tau protein; Therapeutic targets; Toxins
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.15257

Parkinson disease (PD) is the second most common neurodegenerative disorder, whose prevalence is 2~3% in the population over 65. α‐Synuclein aggregation is the major pathological hallmark of PD. However, recent studies have demonstrated enhancing evidence of tau pathology in PD. Despite extensive considerations, thus far, the actual spreading mechanism of neurodegeneration has remained elusive in a PD brain. This study aimed to further investigate the development of α‐synuclein and tau pathology. We employed various PD models, including cultured neurons treated with either 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) or with recombinant α‐synuclein. Also, we studied dopaminergic neurons of cytokine Interferon‐β knock‐out. Moreover, we examined rats treated with 6‐hydroxydopamine, Rhesus monkeys administrated with MPTP neurotoxin, and finally, human post‐mortem brains. We found the α‐synuclein phosphorylation triggers tau pathogenicity. Also, we observed more widespread phosphorylated tau than α‐synuclein with prion‐like nature in various brain areas. We optionally removed P‐tau or P‐α‐synuclein from cytokine interferon‐β knock out with respective monoclonal antibodies. We found that tau immunotherapy suppressed neurodegeneration more than α‐synuclein elimination. Our findings indicate that the pathogenic tau could be one of the leading causes of comprehensive neurodegeneration triggered by PD. Thus, we can propose an efficient therapeutic target to fight the devastating disorder. We herein examined the development of α‐synuclein and tau pathology in Parkinson's disease (PD). We employed PD models, including cultured neurons treated with either 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) or with recombinant α‐synuclein. Also, we studied dopaminergic neurons of Cytokine Interferon‐β (Infβ) knock‐out (KO). We examined rats treated with 6‐Hydroxydopamine, Rhesus monkeys who had been administered MPTP neurotoxin, and human post‐mortem brains. We found α‐synuclein phosphorylation triggers tau pathogenicity. Also, we observed more widespread phosphorylated tau than α‐synuclein in various brain areas. We optionally removed P‐tau or P‐α‐synuclein from Infβ KO with monoclonal antibodies and found that tau immunotherapy was more suppressive to neurodegeneration than α‐synuclein elimination.