scholarly journals Rapid Induction of Dopaminergic Neuron Loss Accompanied by Lewy Body-Like Inclusions in A53T BAC-SNCA Transgenic Mice

2021 ◽  
Author(s):  
Shinya Okuda ◽  
Norihito Uemura ◽  
Masanori Sawamura ◽  
Tomoyuki Taguchi ◽  
Masashi Ikuno ◽  
...  
Keyword(s):  
Dopaminergic Neuron ◽  
Motor Dysfunction ◽  
Substantia Nigra Pars Compacta ◽  
Positive Density ◽  
Post Injection ◽  
Wild Type ◽  
Comparable Amount ◽  
Neuron Loss ◽  
Short Period ◽  
Dopaminergic Neuron Loss

Abstract BackgroundParkinson’s disease (PD) is the most common neurodegenerative movement disorder. Pathological features of PD include dopaminergic neuron loss in the substantia nigra pars compacta (SNpc) and intraneuronal α-Synuclein (α-Syn) inclusions called Lewy bodies (LBs). Since there is no treatment to either halt or slow the progression of PD, it is highly demanded to establish a rodent model that recapitulates the clinicopathological features of PD within a short period to efficiently investigate the pathological mechanisms and test disease-modifying therapies (DMTs).MethodsWe injected human and mouse α-Syn-preformed fibrils (hPFFs and mPFFs, respectively) into the hemilateral dorsal striatum of wild-type mice, wild-type human α-Syn bacterial artificial chromosome (BAC) transgenic (WT BAC-SNCA Tg) mice, and A53T human α-Syn BAC transgenic (A53T BAC-SNCA Tg) mice, and conducted pathological and behavioral analyses.ResultsWT BAC-SNCA Tg and A53T BAC-SNCA Tg mice expressed a comparable amount of α-Syn (2.9 and 2.7-fold more α-Syn, respectively, than wild-type mice) in the brains. mPFF injections induced more severe α-Syn pathology in most brain regions, including the ipsilateral SNpc, than hPFF injections in all genotypes at 1 month post-injection. Among the mPFF-injected mice, the A53T BAC-SNCA Tg mice exhibited the most severe α-Syn pathology as early as 0.5 month (2 weeks) post-injection. Consistent with these observations, in vitro fibrillization assay revealed that a mixture of A53T human α-Syn and mouse α-Syn seeded with mPFFs aggregated most rapidly among the conditions tested. The mPFF-injected A53T BAC-SNCA Tg mice showed a 38% reduction in tyrosine hydroxylase (TH)-positive neurons in the ipsilateral SNpc, apomorphine-induced rotational behavior, and motor dysfunction at 2 months post-injection. Notably, the reduction in TH-positive density in the striatum and microglial activation preceded the obvious TH-positive neuron loss in the SNpc.ConclusionsOur data indicate that the extent of α-Syn pathology induced by α-Syn PFF injection depends on the types of α-Syn PFFs and exogenously expressed α-Syn in Tg mice. The mPFF-injected A53T BAC-SNCA Tg mice recapitulate the pathological processes of PD more rapidly than previously reported mouse models, suggesting their usefulness for testing DMTs as well as analyzing the pathological mechanisms.

scholarly journals Norepinephrine depleting toxin DSP-4 and LPS alter gut microbiota and induce neurotoxicity in α-synuclein mutant mice

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Sheng Song ◽  
Jie Liu ◽  
Feng Zhang ◽  
Jau-Shyong Hong
Keyword(s):  
Gene Expression ◽  
Gut Microbiota ◽  
Dopaminergic Neuron ◽  
Critical Role ◽  
Genetic Mutation ◽  
Clinical Findings ◽  
Translocator Protein ◽  
Substantia Nigra Pars Compacta ◽  
Neuron Loss ◽  
Dopaminergic Neuron Loss

Abstract This study examined the genetic mutation and toxicant exposure in producing gut microbiota alteration and neurotoxicity. Homozygous α-synuclein mutant (SNCA) mice that overexpress human A53T protein and littermate wild-type mice received a single injection of LPS (2 mg/kg) or a selective norepinephrine depleting toxin DSP-4 (50 mg/kg), then the motor activity, dopaminergic neuron loss, colon gene expression and gut microbiome were examined 13 months later. LPS and DSP-4 decreased rotarod and wirehang activity, reduced dopaminergic neurons in substantia nigra pars compacta (SNpc), and SNCA mice were more vulnerable. SNCA mice had 1,000-fold higher human SNCA mRNA expression in the gut, and twofold higher gut expression of NADPH oxidase (NOX2) and translocator protein (TSPO). LPS further increased expression of TSPO and IL-6 in SNCA mice. Both LPS and DSP-4 caused microbiome alterations, and SNCA mice were more susceptible. The altered colon microbiome approximated clinical findings in PD patients, characterized by increased abundance of Verrucomicrobiaceae, and decreased abundance of Prevotellaceae, as evidenced by qPCR with 16S rRNA primers. The Firmicutes/Bacteroidetes ratio was increased by LPS in SNCA mice. This study demonstrated a critical role of α-synuclein and toxins interactions in producing gut microbiota disruption, aberrant gut pro-inflammatory gene expression, and dopaminergic neuron loss.

Electroacupuncture therapy ameliorates motor dysfunction via brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor in a mouse model of Parkinson's disease

2019 ◽  
Author(s):  
Malk Eun Pak ◽  
Sung Min Ahn ◽  
Da Hee Jung ◽  
Hong Ju Lee ◽  
Ki Tae Ha ◽  
...  
Keyword(s):  
Substantia Nigra ◽  
Mouse Model ◽  
Mouse Models ◽  
Neurotrophic Factor ◽  
Dopaminergic Neurons ◽  
Dopaminergic Neuron ◽  
Motor Dysfunction ◽  
Protective Effects ◽  
Neuron Loss ◽  
Dopaminergic Neuron Loss

Abstract Parkinson’s disease (PD) is characterized by dopaminergic neuron loss in the substantia nigra. However, specific sensory stimulation via electroacupuncture (EA) therapy may attenuate this loss by promoting the expression of endogenous neurotrophic factors in a manner similar to physical therapy. We investigated the potential protective effects of EA on dopaminergic neurons in a mouse model of PD and whether these effects are associated with the promotion of endogenous brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF). Mouse models of PD were generated using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine. Motor performance was assessed using behavioral tests, and Western blot experiments, enzyme-linked immunosorbent assays, and immunohistochemical assays were performed. In both mouse models, EA treatment ameliorated motor impairments and dopaminergic neuron loss; these changes were accompanied by increases in BDNF and GDNF. In the MPTP group, EA treatment improved motor dysfunction by attenuating dopaminergic neuron loss in the substantia nigra, similar to the effects of levodopa. EA treatment significantly upregulated BDNF and GDNF expression in both the substantia nigra and striatum. Moreover, EA treatment induced the expression of cAMP response element binding protein (CREB) as well as Akt and Pitx3 in dopaminergic neurons in the substantia nigra. However, levodopa treatment did not induce BDNF/GDNF activation or related signaling factors. Thus, EA therapy may exert protective effects on dopaminergic neurons by upregulating the expression of BDNF, GDNF, and related signaling factors, thereby improving motor function. Hence, EA may represent an effective adjuvant therapy for motor deficits in patients with PD.

scholarly journals Microbiome changes: an indicator of Parkinson’s disease?

2019 ◽  
Vol 8 (1) ◽  
Author(s):  
Caroline Haikal ◽  
Qian-Qian Chen ◽  
Jia-Yi Li
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Gut Microbiome ◽  
Dopaminergic Neuron ◽  
Alpha Synuclein ◽  
Neuron Loss ◽  
The Future ◽  
Dopaminergic Neuron Loss

AbstractParkinson’s disease is characterized by dopaminergic neuron loss and intracellular inclusions composed mainly of alpha synuclein (α-syn), but the mechanism of pathogenesis is still obscure. In recent years, more attention has been given to the gut as a key player in the initiation and progression of PD pathology. Several studies characterizing changes in the microbiome, particularly the gut microbiome, have been conducted. Although many studies found a decrease in the bacterial family Prevotellaceae and in butyrate-producing bacterial genera such as Roseburia and Faecalibacteria, and an increase in the genera Akkermansia many of the studies reported contradictory findings. In this review, we highlight the findings from the different studies and reflect on the future of microbiome studies in PD research.

Risk factors for dopaminergic neuron loss in human α-synuclein transgenic mice

2004 ◽  
Vol 19 (4) ◽  
pp. 845-854 ◽  
Author(s):  
M. J. Thiruchelvam ◽  
J. M. Powers ◽  
D. A. Cory-Slechta ◽  
E. K. Richfield
Keyword(s):  
Risk Factors ◽  
Transgenic Mice ◽  
Dopaminergic Neuron ◽  
Neuron Loss ◽  
Dopaminergic Neuron Loss

scholarly journals Rapamycin activation of 4E-BP prevents parkinsonian dopaminergic neuron loss

2009 ◽  
Vol 12 (9) ◽  
pp. 1129-1135 ◽  
Author(s):  
Luke S Tain ◽  
Heather Mortiboys ◽  
Ran N Tao ◽  
Elena Ziviani ◽  
Oliver Bandmann ◽  
...  
Keyword(s):  
Dopaminergic Neuron ◽  
Neuron Loss ◽  
Dopaminergic Neuron Loss
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