Abstract
BackgroundParkinson’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. MethodsWe 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. ResultsA 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 injected with saline. This combination also reduced the motor coordination. Interestingly, a low dose of MPTP alone did not cause any significant reduction in the number of tyrosine hydroxylase positive neurons compared to saline treatment. Animals that received α-syn PFF and a high dose of MPTP showed massive activation of glial cells and decreased spread of α-syn, majority of which were detected in the nucleus. ConclusionOur results suggest that a combination of human WT α-syn PFF and a low dose of MPTP increases the pathological conversion and propagation of endogenous α-syn, and neurodegeneration, within a very short time. Our model can be used to study the mechanisms of α-syn propagation and screen for potential drugs against PD.
Highlights
Parkinson’s disease (PD) is a progressive multifactorial neurodegenerative disorder that is characterized by the progressive loss of a selective population of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc), which results in the depletion of dopamine neurotransmitters in the striatum
Our results suggest that a combination of human wild type (WT) α-syn preformed fibrils (PFF) and a low dose of MPTP increases the pathological conversion and propagation of endogenous α-syn, and neurodegeneration, within a very short time
We found that pS129 synuclein was detected at the site of injection, in significant amounts, in the animal injected with wild type α-syn PFF in the presence of saline or MPTP (Fig. 1)
Summary
Parkinson’s disease (PD) is a progressive multifactorial neurodegenerative disorder that is characterized by the progressive loss of a selective population of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc), which results in the depletion of dopamine neurotransmitters in the striatum. The major constituent of LBs are α-synuclein (α-syn), a protein with a molecular weight of 14 kDa. The vast majority of PD cases appear to be sporadic; several familial forms of PD cases have been identified in which α-syn, Parkin, DJ-1, LRRK2, PINK1 genes, and other candidate loci have been implicated [1]. Mutations in α-syn gene (SNCA) have been found in familial PD cases suggesting that α-syn protein plays an important role in the progression of PD pathogenesis, in sporadic, and in familial PD cases. Α-syn pathology is present in virtually all sporadic and familial PD patients [2], and its distribution is correlated with motor/cognitive dysfunction. Transgenic mice with ectopic expression of WT or mutant α-syn have been shown to cause an age-associated reduction in dopamine neurotransmitters and behavioral defects [3]
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