Progress in generating iPSC-derived dopaminergic neurons as accurate models of neurodegenerative disease

2021 ◽  
pp. 181-203
Author(s):  
Richard Sam ◽  
Tae-Un Han ◽  
Ellen Sidransky ◽  
Yu Chen
Keyword(s):  
Neurodegenerative Disease ◽  
Dopaminergic Neurons

TER94 , the Drosophila Homologue of the ALS-related VCP gene, Influences Lifespan and Leads to a Decline in Motor Function

2020 ◽  
Author(s):  
Emily Priscilla Hurley ◽  
Brian Ernest Staveley
Keyword(s):  
Neurodegenerative Disease ◽  
Motor Neurons ◽  
Dopaminergic Neurons ◽  
Altered Expression ◽  
Locomotor Function ◽  
Aaa Atpase ◽  
Median Lifespan ◽  
Novel Model ◽  
Locomotor Ability ◽  
Over Time

Abstract Background: Valosin-Containing Protein (VCP) is an essential AAA+ ATPase with diverse functions within the cell. Mutations in the VCP gene have been detected in patients with familial amyotrophic lateral sclerosis (ALS). The aim of this study is to create a novel model of human neurodegenerative disease in Drosophila melanogaster by altering the expression of TER94, the Drosophila orthologue of the human VCP gene. TER94 expression was altered in all neurons, the dopaminergic neurons and in the motor neurons, with longevity and locomotor function assessed over time. Altered TER94 expression in combination with the altered expression of known Parkinson Disease (PD) genes was examined to investigate potential interactions.Results: Inhibition of TER94 altered median lifespan in a manner dependent upon the transgene selected for use and the tissue-specific expression directed by the Gal4 transgene selected. Locomotor ability was significantly reduced in all cases of TER94 inhibition tested. The inhibition of TER94 by two TER94-RNAi inhibitory transgenes, in the motor neurons via D42-Gal4 lead to increases in median lifespan, with one inhibitory transgene generating a slightly reduced lifespan. Inhibition of TER94 in the dopaminergic neurons resulted in a severe reduction in lifespan. The co-inhibition of TER94 and parkin in the neurons resulted in a major decline in lifespan by approximately 30%. While the inhibition of TER94 and the co-expression of alpha-synuclein in the neurons resulted in an increase in lifespan by approximately 28%. Conclusions: The inhibition of TER94 in the motor neurons is an interesting model of ALS, due to the small, but reduced lifespan coupled with a strong decline in locomotor function. The inhibition of TER94 in the dopaminergic neurons is a potential model of ALS, due to the reduction of both lifespan and locomotor function over time. The co-inhibition of TER94 and parkin in the neurons provides a promising novel model of neurodegenerative disease, displaying a great reduction in lifespan and in locomotor ability over time.

scholarly journals Therapeutic Potential of Repeated Intravenous Transplantation of Human Adipose-Derived Stem Cells in Subchronic MPTP-Induced Parkinson’s Disease Mouse Model

2020 ◽  
Vol 21 (21) ◽  
pp. 8129
Author(s):  
Hyunjun Park ◽  
Keun-A Chang
Keyword(s):  
Parkinson’S Disease ◽  
Stem Cells ◽  
Parkinson's Disease ◽  
Neurodegenerative Disease ◽  
Neurotrophic Factor ◽  
Dopaminergic Neurons ◽  
Therapeutic Potential ◽  
Adipose Derived Stem Cells ◽  
Nigrostriatal Pathway

Parkinson’s disease (PD) is the second most common neurodegenerative disease, which is clinically and pathologically characterized by motor dysfunction and the loss of dopaminergic neurons in the substantia nigra, respectively. PD treatment with stem cells has long been studied by researchers; however, no adequate treatment strategy has been established. The results of studies so far have suggested that stem cell transplantation can be an effective treatment for PD. However, PD is a progressively deteriorating neurodegenerative disease that requires long-term treatment, and this has been insufficiently studied. Thus, we aimed to investigate the therapeutic potential of human adipose-derived stem cells (hASC) for repeated vein transplantation over long-term in an animal model of PD. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model mice, hASCs were administered on the tail vein six times at two-week intervals. After the last injection of hASCs, motor function significantly improved. The number of dopaminergic neurons present in the nigrostriatal pathway was recovered using hASC transplantation. Moreover, the administration of hASC restored altered dopamine transporter expression and increased neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF), in the striatum. Overall, this study suggests that repeated intravenous transplantation of hASC may exert therapeutic effects on PD by restoring BDNF and GDNF expressions, protecting dopaminergic neurons, and maintaining the nigrostriatal pathway.

scholarly journals Genetic Rat Models of Parkinson's Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Ryan M. Welchko ◽  
Xavier T. Lévêque ◽  
Gary L. Dunbar
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disease ◽  
Dopaminergic Neurons ◽  
Transgenic Rat ◽  
Leucine Rich Repeat ◽  
Transgenic Rats ◽  
Specific Loss ◽  
Rat Models ◽  
Early Stages

Parkinson’s disease (PD) is a neurodegenerative disease characterized by a specific loss of dopaminergic neurons. Although the vast majority of PD cases are idiopathic in nature, there is a subset that contains genetic links. Of the genes that have been linked to PD, α-synuclein and leucine-rich repeat kinase 2 have been used to develop transgenic rat models of the disease. In this paper we focused on the various transgenic rat models of PD in terms of their ability to mimic key symptoms of PD in a progressive manner. In general, we found that most of these models provided useful tools for the early stages of PD, but the development of new transgenic rats that present significant neuropathologic and motoric deficits in a progressive manner that more accurately mimics PD is needed.

Extract of Tripterygium wilfordii Hook F Protect Dopaminergic Neurons Against Lipopolysaccharide-Induced Inflammatory Damage

2010 ◽  
Vol 38 (04) ◽  
pp. 801-814 ◽  
Author(s):  
Yuxin Liu ◽  
Hui-Ling Chen ◽  
Gengliang Yang
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disease ◽  
Dopaminergic Neurons ◽  
Chinese Herbs ◽  
No Production ◽  
Tripterygium Wilfordii ◽  
Tripterygium Wilfordii Hook F ◽  
Activated Microglia ◽  
Tripterygium Wilfordii Hook

Activation of microglia is a critical pathological marker of Parkinson's disease. Activated microglia produces proinflammatory and neurotoxic factors, which cause neurons to induce neurodegeneration. Although it is believed that Chinese herbs, such as Tripterygium wilfordii Hook F, can ease inflammatory diseases, little is known about its benefit to neurodegenerative disease, like Parkinson's disease. In this study, we report the extract of Tripterygium wilfordii Hook F with a novel extraction method significantly protected dopaminergic neurons from LPS-induced degeneration in rat mesencephalic neuron-glia cultures. Cells pretreated with the extract have shown dose-dependent inhibition of LPS-induced TNFα and excessive NO production. More importantly, the total number of activated microglia was greatly reduced in these pretreated cells. Our results suggest that the extract of Tripterygium wilfordii Hook F has a strong bioactive function to diminish the pro-inflammatory factors, such as TNFα and NO. These data might also shed light for future neurodegenerative disease therapy.

scholarly journals p21 inhibitor UC2288 ameliorates MPTP induced Parkinson’s disease progression through inhibition of oxidative stress and neuroinflammation

2020 ◽  
Author(s):  
Jun Hyung Im ◽  
In Jun Yeo ◽  
Seong Hee Jeon ◽  
Dong Hun Lee ◽  
Hyeon Joo Ham ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Neurodegenerative Disease ◽  
Dopaminergic Neurons ◽  
Kinase Inhibitor ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Cultured Neurons ◽  
Dopamine Depletion ◽  
Erk Kinase

Abstract BackgroundParkinson's disease (PD) is a neurodegenerative disease characterized by the early prominent death of dopaminergic neurons and a decrease of dopamine levels. Dopamine depletion leads to several motor dysfunctions, including resting tremor, muscular rigidity, bradykinesia and postural instability. Our previous study determined that knockout of parkin, a gene of PD degrade p21, suppresses neurogenesis which is critical for a neurodegenerative disease. MethodsThus, we investigated the effect of UC2288, an inhibitor of p21, for its therapeutic effect on PD. We found that UC2288 attenuated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced behavioral impairment in Rota-rod and Pole test as well as dopamine depletion.ResultsMoreover, UC2288 recovered the number of TH positive cells, but decreased the number of GFAP and Iba-1 positive cells accompanied the decrease of BAX and cleaved caspase3 as well as iNOS and COX-2 expression. In cultured neurons, UC2288 recovered MPP+-induced neuronal cell death in a concentration dependent manner. We also found that UC2288 decreased the p21 reactive cell number, oxidative neuronal damages, cytokines product in vivo and cultured neurons. In a mechanism study, we found that UC2288 significantly decreased the activation of ERK and p38 kinase pathway in the mitogen-activated protein kinase (MAPK) pathway. In addition, 1-10 μM concentration of ERK kinase inhibitor U0126 recovered MPP+-induced neuronal cell death. However, ERK kinase inhibitor U0126 further decreased cell viability with the increase of H2O2.ConclusionThese results indicated that the administration of UC2288 exerted neuroprotective effects on the death of dopaminergic neurons through the suppression of oxidative stress and neuroinflammation via ERK pathway inhibition.

scholarly journals L-Dopa release from mesoporous silica nanoparticles engineered through the concept of drug-structure-directing agents for Parkinson’s disease

2021 ◽  
Author(s):  
Victoria Morales ◽  
Joseph McConnell ◽  
Manuel Pérez-Garnes ◽  
Nuria Almendro ◽  
Raúl Sanz ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mesoporous Silica ◽  
Neurodegenerative Disease ◽  
Silica Nanoparticles ◽  
Dopaminergic Neurons ◽  
Mesoporous Silica Nanoparticles ◽  
Main Effect ◽  
Structure Directing Agents

Parkinson’s disease (PD) is a progressive neurodegenerative disease, the 2nd most common behind Alzheimer´s, the main effect of which is the loss of dopaminergic neurons. Levodopa or L-Dopa is an...

Memory Processes, Aging, Cognitive Decline, and Neurodegenerative Diseases

2006 ◽  
Vol 11 (4) ◽  
pp. 304-311 ◽  
Author(s):  
Lars-Göran Nilsson
Keyword(s):  
Cognitive Impairment ◽  
Cognitive Decline ◽  
Neurodegenerative Disease ◽  
Genetic Markers ◽  
Brain Activity ◽  
Memory Performance ◽  
Modeling And Simulations ◽  
Aging And Health ◽  
Explained Variance ◽  
Different Levels

This paper presents four domains of markers that have been found to predict later cognitive impairment and neurodegenerative disease. These four domains are (1) data patterns of memory performance, (2) cardiovascular factors, (3) genetic markers, and (4) brain activity. The critical features of each domain are illustrated with data from the longitudinal Betula Study on memory, aging, and health ( Nilsson et al., 1997 ; Nilsson et al., 2004 ). Up to now, early signs regarding these domains have been examined one by one and it has been found that they are associated with later cognitive impairment and neurodegenerative disease. However, it was also found that each marker accounts for only a very small part of the total variance, implying that single markers should not be used as predictors for cognitive decline or neurodegenerative disease. It is discussed whether modeling and simulations should be used as tools to combine markers at different levels to increase the amount of explained variance.

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