Dose-related biphasic effect of the Parkinson’s disease neurotoxin MPTP, on the spread, accumulation, and toxicity of α-synuclein

• Published in: Neurotoxicology (Park Forest South) 2021-05, Vol.84, p.41-52
• Main Authors: Merghani, Madiha Mohieldin, Ardah, Mustafa T., Al Shamsi, Mariam, Kitada, Tohru, Haque, M. Emdadul
• Format: Article
• Language: English
• Subjects: Accumulation; Antibodies; Axons; Brain; Cell activation; Conformation; Coordination; Dopamine receptors; Dosage; Endopeptidase K; Fibrils; Glial cells; Hydroxylase; Inclusions; Injection; Inoculation; Lewy bodies; Lewy body; Mitochondria; Motor ability; Movement disorders; MPTP; Muscle strength; Neostriatum; Neurodegeneration; Neurodegenerative diseases; Neurons; Neurotoxicity; Neurotoxins; Parkinson's disease; Parkinson’s disease (PD); Preformed fibril (PFF); Propagation; Proteinase; Reduction; Substantia nigra; Synuclein; Toxicity; Toxins; Tyrosine; α-synuclein
• ISSN: 0161-813X; 1872-9711
• DOI: 10.1016/j.neuro.2021.02.001

•Single injection of α-syn PFF in the mice striatum induced the spreading of α-syn.•Low dose of MPTP (10 mg/kg.b.wt) further enhanced this spreading and neuronal death.•Low dose of MPTP in α-syn PFF injected mice causes significant motor deficit.•High dose of MPTP (25 mg/kg.b.wt.) reduced the spreading of α-syn.•High dose of MPTP caused nuclear translocation of α-syn. Parkinson’s disease (PD), the second most common progressive neurodegenerative disorder, is characterized by the abnormal accumulation of intraneuronal inclusions enriched in aggregated α-synuclein (α-syn), known as Lewy bodies (LBs) and Lewy neurites (LNs), and significant loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) of the brain. Recent evidence suggests that the intrastriatal inoculation of α-syn preformed fibrils (PFF) in mice brain triggers endogenous α-syn in interconnected brain regions. 1-methyl, 4-phenyl, 1,2,3,6 tetrahydropyridine (MPTP), a mitochondrial neurotoxin, has been used previously to generate a PD mouse model. However, the common methods of MPTP exposure do not induce LB or α-syn aggregation in mice. In the present study, we evaluated the effect of different doses of MPTP (10 mg/kg.b.wt and/or 25 mg/kg.b.wt) on the spread, accumulation, and toxicity of endogenous α-syn in mice administered an intrastriatal injection of human α-syn PFF. We inoculated human WT α-syn PFF in mouse striatum. At 6 weeks post PFF injection, we challenged the animal with two different doses of MPTP (10 mg/kg.b.wt and 25 mg/kg.b.wt) once daily for five consecutive days. At 2 weeks from the start of the MPTP regimen, we collected the mice brain and performed immunohistochemical analysis, and Rotarod test to assess motor coordination and muscle strength before and after MPTP injection. A single injection of human WT α-syn PFF in the mice striatum induced the propagation of α-syn, occurring as phosphorylated α-synuclein (pS129), towards the SNpc, within a very short time. Injection of a low dose of MPTP (10 mg/kg.b.wt) at 6 weeks post α-syn PFF inoculation further enhanced the spread, whereas a high dose of MPTP (25 mg/kg.b.wt.) reduced the spread. Majority of the accumulated α-syn were proteinase K resistant, as recognized using a conformation-specific α-syn antibody. Injection of α-syn PFF alone caused 12 % reduction in the number of tyrosine hydroxylase positive neurons while α-syn PFF + a low dose of MPTP caused 33 % reduction (loss), compared to the control mice