Early Parkinson's disease symptoms in  -synuclein transgenic monkeys

Niu, Yuyu; Guo, Xiangyu; Chen, Yongchang; Wang, Chuan En; Gao, Jinquan; Yang, Wenli; Kang, Yu; Si, Wei; Wang, Hong; Yang, Shang Hsun; Li, Shihua; Ji, Weizhi; Li, Xiao Jiang

doi:10.1093/hmg/ddu748

Cited by 83 publications

(59 citation statements)

References 28 publications

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“…To quantify neurons expressing transgenic A53T in transgenic monkey fetus brain (Niu et al, 2015), we used 5-8 images obtained with a 20ϫ numerical aperture (NA) 0.8 objective per section and 5 sections per group (3 or more animals per group). Neurons that were clearly labeled by anti-␣-syn were counted to obtain the mean values Ϯ SEM per image.…”

Section: Methodsmentioning

confidence: 99%

“…4A). Because A53T overexpression can mediate neuropathology in transgenic animal models (Eslamboli et al, 2007;Lin et al, 2009;Dawson et al, 2010;Magen and Chesselet, 2011;Niu et al, 2015), we examined reactive astrocytes, which reflect early neuronal damage, to assess neuropathology in the injected brain regions. Using antibody to GFAP, an astrocyte-specific protein, we also found more reactive astrocytes in the older monkey brain region after injection with lentiviral A53T (Fig.…”

Section: Age-dependent Increase In Lewy Neurites and Neuropathology Imentioning

confidence: 99%

“…We recently generated transgenic A53T monkeys and obtained a stillborn monkey brain to analyze the expression of transgenic A53T (Niu et al, 2015). Although this stillborn monkey provided us with a limited number of brain slices containing the striatum, we wanted to see whether neurons expressing transgenic A53T show any defective morphology.…”

Section: Protective Effect Of Neurofascin On A53t Neurotoxicitymentioning

confidence: 99%

“…However, mutations in ␣-syn may facilitate its accumulation and misfolding, resulting in Lewy bodies and neurodegeneration that are age dependent (Goedert, 2001;Neumann et al, 2002;Chung et al, 2013). Consistent with this idea, transgenic expression of mutant ␣-syn in various animal models has proved to be toxic to neuronal cells and cause neurological symptoms (Lin et al, 2009;Dawson et al, 2010;Magen and Chesselet, 2011;Niu et al, 2015).…”

Section: Introductionmentioning

confidence: 95%

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Mutant Alpha-Synuclein Causes Age-Dependent Neuropathology in Monkey Brain

Yang

Wang

et al. 2015

J. Neurosci.

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Parkinson's disease (PD) is an age-dependent neurodegenerative disease that often occurs in those over age 60. Although rodents and small animals have been used widely to model PD and investigate its pathology, their short life span makes it difficult to assess the aging-related pathology that is likely to occur in PD patient brains. Here, we used brain tissues from rhesus monkeys at 2-3, 7-8, and Ͼ15 years of age to examine the expression of Parkin, PINK1, and ␣-synuclein, which are known to cause PD via loss-or gain-of-function mechanisms. We found that ␣-synuclein is increased in the older monkey brains, whereas Parkin and PINK1 are decreased or remain unchanged. Because of the gain of toxicity of ␣-synuclein, we performed stereotaxic injection of lentiviral vectors expressing mutant ␣-synuclein (A53T) into the substantia nigra of monkeys and found that aging also increases the accumulation of A53T in neurites and its associated neuropathology. A53T also causes more extensive reactive astrocytes and axonal degeneration in monkey brain than in mouse brain. Using monkey brain tissues, we found that A53T interacts with neurofascin, an adhesion molecule involved in axon subcellular targeting and neurite outgrowth. Aged monkey brain tissues show an increased interaction of neurofascin with A53T. Overexpression of A53T causes neuritic toxicity in cultured neuronal cells, which can be attenuated by transfected neurofascin. These findings from nonhuman primate brains reveal age-dependent pathological and molecular changes that could contribute to the age-dependent neuropathology in PD.

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Section: Methodsmentioning

confidence: 99%

Section: Age-dependent Increase In Lewy Neurites and Neuropathology Imentioning

confidence: 99%

Section: Protective Effect Of Neurofascin On A53t Neurotoxicitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

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Mutant Alpha-Synuclein Causes Age-Dependent Neuropathology in Monkey Brain

Yang

Wang

et al. 2015

J. Neurosci.

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“…Niu et al (2015) have used a lentivirus to develop a transgenic rhesus monkey model expressing A53T a-synuclein under human ubiquitin (hUBC) promotor. This vector was injected into the perivitelline space of 113 MII oocytes, which were then fertilized by intracytoplasmic sperm injection and cultured for developing embryos in vitro.…”

Section: Transgenic Nhpsmentioning

confidence: 99%

α-Synuclein nonhuman primate models of Parkinson’s disease

Marmion

Kordower

2017

J Neural Transm

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Proper understanding of the mechanism(s) by which α-synuclein misfolds and propagates may hold the key to unraveling the complex pathophysiology of Parkinson's disease. A more complete understanding of the disease itself, as well as establishing animal models that fully recapitulate pathological and functional disease progression, are needed to develop treatments that will delay, halt or reverse the disease course. Traditional neurotoxin-based animal models fail to mimic crucial aspects of Parkinson's and thus are not relevant for the study of neuroprotection and disease-modifying therapies. Therefore, a new era of animal models centered on α-synuclein has emerged with the utility of nonhuman primates in these studies beginning to become important. Indeed, disease modeling in nonhuman primates offers a more similar anatomical and genetic background to humans, and the ability to assess complex behavioral impairments that are difficult to test in rodents. Furthermore, results obtained from monkey studies translate better to applications in humans. In this review, we highlight the importance of α-synuclein in Parkinson's disease and discuss the development of α-synuclein based nonhuman primate models.

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Generation of genetically engineered non‐human primate models of brain function and neurological disorders

Park

Silva

2018

American J Primatol

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Research with non-human primates (NHP) has been essential and effective in increasing our ability to find cures for a large number of diseases that cause human suffering and death. Extending the availability and use of genetic engineering techniques to NHP will allow the creation and study of NHP models of human disease, as well as broaden our understanding of neural circuits in the primate brain. With the recent development of efficient genetic engineering techniques that can be used for NHP, there’s increased hope that NHP will significantly accelerate our understanding of the etiology of human neurological and neuropsychiatric disorders. In this article, we review the present state of genetic engineering tools used in NHP, from the early efforts to induce exogeneous gene expression in macaques and marmosets, to the latest results in producing germline transmission of different transgenes and the establishment of knockout lines of specific genes. We conclude with future perspectives on the further development and employment of these tools to generate genetically engineered NHP.

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Early Parkinson's disease symptoms in -synuclein transgenic monkeys

Cited by 83 publications

References 28 publications

Mutant Alpha-Synuclein Causes Age-Dependent Neuropathology in Monkey Brain

Mutant Alpha-Synuclein Causes Age-Dependent Neuropathology in Monkey Brain

α-Synuclein nonhuman primate models of Parkinson’s disease

Generation of genetically engineered non‐human primate models of brain function and neurological disorders

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