Date of Award
Master of Science in Medical Sciences (MSMS)
Md. Emdadul Haque
Parkinson’s disease (PD) is the second most common progressive neurodegenerative disorder, characterized by abnormal accumulation of interneuronal inclusions of α-synuclein (α-syn) known as Lewy bodies (LBs) and Lewy neurites (LNs), and significant loss of dopamine neurons in the substantia nigra pars compacta (SNc) region of the brain. Recent evidence suggests that intrastriatal inoculation of α-syn Preformed Fibril (PFF) into mice induces PD-like LBs and LNs pathology formed by aggregated α-syn in anatomically interconnected brain regions which needs several months of incubation to develop the pathology. In the present study, we have evaluated the effect of different doses of 1-methyl, 4-phenyl, 1,2,3,6 tetrahydropyridine (MPTP) in triggering endogenous alpha-synuclein spreading when inoculated with human wild type (WT) α-syn preformed fibrils. We have found that a single injection of human WT α-syn preformed fibrils into the striatum region of the brain induces the propagation of phosphorylated α-syn (pS129) to the SNpc within a short period of time. Interestingly, injection of the low dose of MPTP (10 mg/kg.b.wt) 6 weeks after postinoculation of α-syn preformed fibrils further enhances the spreading where a high dose of MPTP (25 mg/kg.b.wt.) reduces the spreading. After intrastriatal injection of α-Syn preformed fibrils, a low dose of MPTP enhanced the pathological accumulation of phosphorylated α-syn (pS129) in the ipsilateral side. The majority of the accumulated α-syn were proteinase k resistant which was recognized by a conformational specific antibody of α-syn. Furthermore, we have found that injection of α-syn preformed fibrils alone causes only 12% dopaminergic neuronal loss while in presence of a low dose of MPTP it causes 33% in comparison to saline-injected control mice (100%). A combination of α-synuclein preformed fibril and a low dose of MPTP also causes a deficit in motor coordination. Noteworthy to mention that a low dose of MPTP alone does not cause significant dopaminergic cells death when comparing to the saline-treated group. Interestingly, animals that receive a combination of α-synuclein preformed fibril and a high dose of MPTP show a massive activation of glial cells. However, they show a decrease in α-synuclein spreading, and the majority of the detectable α-syn was found in the nucleus.
Therefore, our results suggest that human WT α-synuclein preformed fibrils in combination with a low dose of MPTP increase the pathological conversion and the propagation of endogenous α-syn as well as neurodegeneration within a very short period of time. Our presented model may be used to study the mechanism of α-syn propagation and for screening of potential drugs for PD.
Merghani, Madiha Mohieldin, "EFFECT OF MPTP ON α-SYNUCLEIN SPREADING, ACCUMULATION AND TOXICITY IN MICE WITH INTRASTRIATAL INNOCULATION OF HUMAN α-SYNUCLEIN PREFORMED FIBRIL" (2020). Theses. 797.