scholarly journals Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson’s disease

Nature ◽  
2011 ◽  
Vol 480 (7378) ◽  
pp. 547-551 ◽  
Author(s):  
Sonja Kriks ◽  
Jae-Won Shim ◽  
Jinghua Piao ◽  
Yosif M. Ganat ◽  
Dustin R. Wakeman ◽  
...  
2015 ◽  
Vol 113 (1) ◽  
pp. 200-205 ◽  
Author(s):  
Kenneth T. Kishida ◽  
Ignacio Saez ◽  
Terry Lohrenz ◽  
Mark R. Witcher ◽  
Adrian W. Laxton ◽  
...  

In the mammalian brain, dopamine is a critical neuromodulator whose actions underlie learning, decision-making, and behavioral control. Degeneration of dopamine neurons causes Parkinson’s disease, whereas dysregulation of dopamine signaling is believed to contribute to psychiatric conditions such as schizophrenia, addiction, and depression. Experiments in animal models suggest the hypothesis that dopamine release in human striatum encodes reward prediction errors (RPEs) (the difference between actual and expected outcomes) during ongoing decision-making. Blood oxygen level-dependent (BOLD) imaging experiments in humans support the idea that RPEs are tracked in the striatum; however, BOLD measurements cannot be used to infer the action of any one specific neurotransmitter. We monitored dopamine levels with subsecond temporal resolution in humans (n = 17) with Parkinson’s disease while they executed a sequential decision-making task. Participants placed bets and experienced monetary gains or losses. Dopamine fluctuations in the striatum fail to encode RPEs, as anticipated by a large body of work in model organisms. Instead, subsecond dopamine fluctuations encode an integration of RPEs with counterfactual prediction errors, the latter defined by how much better or worse the experienced outcome could have been. How dopamine fluctuations combine the actual and counterfactual is unknown. One possibility is that this process is the normal behavior of reward processing dopamine neurons, which previously had not been tested by experiments in animal models. Alternatively, this superposition of error terms may result from an additional yet-to-be-identified subclass of dopamine neurons.


Author(s):  
Alexander F. Hoffman ◽  
Meleik A. Hebert ◽  
Barry J. Hoffer ◽  
Zhiming Zhang ◽  
Wayne A. Cass ◽  
...  

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Abeer Dagra ◽  
Douglas R. Miller ◽  
Min Lin ◽  
Adithya Gopinath ◽  
Fatemeh Shaerzadeh ◽  
...  

AbstractPathophysiological damages and loss of function of dopamine neurons precede their demise and contribute to the early phases of Parkinson’s disease. The presence of aberrant intracellular pathological inclusions of the protein α-synuclein within ventral midbrain dopaminergic neurons is one of the cardinal features of Parkinson’s disease. We employed molecular biology, electrophysiology, and live-cell imaging to investigate how excessive α-synuclein expression alters multiple characteristics of dopaminergic neuronal dynamics and dopamine transmission in cultured dopamine neurons conditionally expressing GCaMP6f. We found that overexpression of α-synuclein in mouse (male and female) dopaminergic neurons altered neuronal firing properties, calcium dynamics, dopamine release, protein expression, and morphology. Moreover, prolonged exposure to the D2 receptor agonist, quinpirole, rescues many of the alterations induced by α-synuclein overexpression. These studies demonstrate that α-synuclein dysregulation of neuronal activity contributes to the vulnerability of dopaminergic neurons and that modulation of D2 receptor activity can ameliorate the pathophysiology. These findings provide mechanistic insights into the insidious changes in dopaminergic neuronal activity and neuronal loss that characterize Parkinson’s disease progression with significant therapeutic implications.


2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Keya Li ◽  
Xinyue Li ◽  
Guiying Shi ◽  
Xuepei Lei ◽  
Yiying Huang ◽  
...  

AbstractAnimal models provide an opportunity to assess the optimal treatment way and the underlying mechanisms of direct clinical application of adipose-derived stem cells (ADSCs). Previous studies have evaluated the effects of primitive and induced ADSCs in animal models of Parkinson’s disease (PD). Here, eight databases were systematically searched for studies on the effects and in vivo changes caused by ADSC intervention. Quality assessment was conducted using a 10-item risk of bias tool. For the subsequent meta-analysis, study characteristics were extracted and effect sizes were computed. Ten out of 2324 published articles (n = 169 animals) were selected for further meta-analysis. After ADSC therapy, the rotation behavior (10 experiments, n = 156 animals) and rotarod performance (3 experiments, n = 54 animals) were improved (P < 0.000 01 and P = 0.000 3, respectively). The rotation behavior test reflected functional recovery, which may be due to the neurogenesis from neuronally differentiated ADSCs, resulting in a higher pooled effect size of standard mean difference (SMD) (− 2.59; 95% CI, − 3.57 to − 1.61) when compared to that of primitive cells (− 2.18; 95% CI, − 3.29 to − 1.07). Stratified analyses by different time intervals indicated that ADSC intervention exhibited a long-term effect. Following the transplantation of ADSCs, tyrosine hydroxylase-positive neurons recovered in the lesion area with pooled SMD of 13.36 [6.85, 19.86]. Transplantation of ADSCs is a therapeutic option that shows long-lasting effects in animal models of PD. The potential mechanisms of ADSCs involve neurogenesis and neuroprotective effects. The standardized induction of neural form of transplanted ADSCs can lead to a future application in clinical practice.


2021 ◽  
pp. 1-10
Author(s):  
Vera Kovaleva ◽  
Mart Saarma

Parkinson’s disease (PD) pathology involves progressive degeneration and death of vulnerable dopamine neurons in the substantia nigra. Extensive axonal arborisation and distinct functions make this type of neurons particularly sensitive to homeostatic perturbations, such as protein misfolding and Ca2 + dysregulation. Endoplasmic reticulum (ER) is a cell compartment orchestrating protein synthesis and folding, as well as synthesis of lipids and maintenance of Ca2 +-homeostasis in eukaryotic cells. When misfolded proteins start to accumulate in ER lumen the unfolded protein response (UPR) is activated. UPR is an adaptive signalling machinery aimed at relieving of protein folding load in the ER. When UPR is chronic, it can either boost neurodegeneration and apoptosis or cause neuronal dysfunctions. We have recently discovered that mesencephalic astrocyte-derived neurotrophic factor (MANF) exerts its prosurvival action in dopamine neurons and in animal model of PD through the direct binding to UPR sensor inositol-requiring protein 1 alpha (IRE1α) and attenuation of UPR. In line with this, UPR targeting resulted in neuroprotection and neurorestoration in various preclinical PD animal models. Therefore, growth factors (GFs), possessing both neurorestorative activity and restoration of protein folding capacity are attractive as drug candidates for PD treatment especially their blood-brain barrier penetrating analogs and small molecule mimetics. In this review, we discuss ER stress as a therapeutic target to treat PD; we summarize the existing preclinical data on the regulation of ER stress for PD treatment. In addition, we point out the crucial aspects for successful clinical translation of UPR-regulating GFs and new prospective in GFs-based treatments of PD, focusing on ER stress regulation.


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