scholarly journals In vivo phenotyping of Parkinson-specific stem cells reveals increased a-Synuclein levels but no spreading

2017 ◽  
Author(s):  
Kathrin Hemmer ◽  
Lisa M. Smits ◽  
Silvia Bolognin ◽  
Jens C. Schwamborn
Keyword(s):  
Parkinson’S Disease ◽  
Stem Cells ◽  
Parkinson's Disease ◽  
Mouse Brain ◽  
Disease Modeling ◽  
Disease Patient ◽  
Alpha Synuclein ◽  
Patient Specific ◽  
Species Barrier

AbstractParkinson′s disease is a progressive age-associated neurological disorder. One of the major neuropathological hallmarks of Parkinson’s disease is the appearance of protein aggregates, mainly consisting of the protein alpha-Synuclein. These aggregates have been described both in genetic as well as idiopathic forms of the disease. Currently, Parkinson’s disease patient-specific induced pluripotent stem cells (iPSCs) are mainly used for in vitro disease modeling or for experimental cell replacement approaches. Here, we demonstrate that these cells can be used for in vivo disease modeling. We show that Parkinson’s disease patient-specific, iPSC-derived neurons carrying the LRRK2-G2019S mutation show an upregulation of alpha-Synuclein after transplantation in the mouse brain. However, further investigations indicate that the increased human alpha-Synuclein levels fail to induce spreading or aggregation in the mouse brain. We therefore conclude that grafting of these cells into the mouse brain is suitable for cell autonomous in vivo disease modeling but has strong limitations beyond that. Furthermore, our results support the hypothesis that there might be a species barrier between human to mouse concerning alpha-Synuclein spreading.

Conditional control of human wild-type and Parkinson's disease-associated mutant alpha-synuclein in transgenic mouse brain

2004 ◽  
Vol 31 (S 1) ◽  
Author(s):  
S Nuber ◽  
T Schmidt ◽  
D Berg ◽  
M Neumann ◽  
C Holzmann ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Transgenic Mouse ◽  
Mouse Brain ◽  
Alpha Synuclein ◽  
Wild Type ◽  
Conditional Control ◽  
Human Wild Type

scholarly journals Age-related pathological impairments in induced neurons derived from patients with idiopathic Parkinson’s disease

2021 ◽  
Author(s):  
Janelle Drouin-Ouellet ◽  
Karolina Pircs ◽  
Emilie M. Legault ◽  
Marcella Birtele ◽  
Fredrik Nilsson ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Alpha Synuclein ◽  
Specific Model ◽  
Dermal Fibroblasts ◽  
Patient Specific ◽  
Idiopathic Parkinson’S Disease ◽  
Age Related ◽  
Idiopathic Parkinson's Disease ◽  
Induced Neurons

AbstractUnderstanding the pathophysiology of Parkinson’s disease has been hampered by the lack of models that recapitulate all the critical factors underlying its development. Here, we generated functional induced dopaminergic neurons (iDANs) that were directly reprogrammed from adult human dermal fibroblasts of patients with idiopathic Parkinson’s disease to investigate diseaserelevant pathology. We show that iDANs derived from Parkinson’s disease patients exhibit lower basal chaperone-mediated autophagy as compared to iDANs of healthy donors. Furthermore, stress-induced autophagy resulted in an accumulation of macroautophagic structures in induced neurons (iNs) derived from Parkinson’s disease patients, independently of the specific neuronal subtype but dependent on the age of the donor. Finally, we found that these impairments in patient-derived iNs lead to an accumulation of phosphorylated alpha-synuclein, a hallmark of Parkinson’s disease pathology. Taken together, our results demonstrate that direct neural reprogramming provides a patient-specific model to study aged neuronal features relevant to idiopathic Parkinson’s disease.

scholarly journals Modeling the pathophysiology of Parkinson’s disease in patient-specific neurons

2020 ◽  
pp. 153537022096178
Author(s):  
Jian Feng
Keyword(s):  
Parkinson’S Disease ◽  
Stem Cells ◽  
Parkinson's Disease ◽  
Stem Cell ◽  
Basal Ganglia ◽  
Pluripotent Stem Cells ◽  
Patient Specific ◽  
Mechanistic Studies ◽  
Induced Pluripotent ◽  
Further Development

The 30 trillion cells that self-assemble into a human being originate from the pluripotent stem cells in the inner cell mass of a human blastocyst. The discovery of induced pluripotent stem cells (iPSCs) makes it possible to approximate various aspects of this natural developmental process artificially by generating materials that can be used in invasive mechanistic studies of virtually all human conditions. In Parkinson’s disease, instructions computed by the basal ganglia to control voluntary motor functions break down, leading to widespread rhythmic bursting activities in the basal ganglia and beyond. It is thought that these oscillatory neuronal activities, which disrupt aperiodic neurotransmission in a normal brain, may reduce information content in the instructions for motor control. Using midbrain neuronal cultures differentiated from iPSCs of Parkinson’s disease patients with parkin mutations, we find that parkin mutations cause oscillatory neuronal activities when dopamine D1-class receptors are activated. This system makes it possible to study the molecular basis of rhythmic bursting activities in Parkinson’s disease. Further development of stem cell models of Parkinson’s disease will enable better approximation of the situation in the brain of Parkinson’s disease patients. In this review, I will discuss what has been found in the past about the pathophysiology of motor dysfunction in Parkinson’s disease, especially oscillatory neuronal activities and how stem cell technologies may transform our abilities to understand the pathophysiology of Parkinson’s disease. Impact statement Research on the pathophysiology of Parkinson’s disease (PD) has generated effective therapies such as deep brain stimulation. A better understanding of PD pathophysiology calls for patient-specific materials amenable for invasive mechanistic studies. In this minireview, I discuss our recent work on oscillatory neuronal activities in midbrain neurons differentiated from induced pluripotent stem cells (iPSCs) of PD patients with parkin mutations. These patient-specific neurons enable a variety of studies previously not feasible in the human system. Further development in stem cell technologies may generate more realistic models for us to decipher PD pathophysiology. These new developments will transform research and development in Parkinson’s disease.

scholarly journals Modeling Parkinson’s Disease Using Induced Pluripotent Stem Cells

2020 ◽  
Vol 2020 ◽  
pp. 1-15
Author(s):  
Xinchao Hu ◽  
Chengyuan Mao ◽  
Liyuan Fan ◽  
Haiyang Luo ◽  
Zhengwei Hu ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Stem Cells ◽  
Parkinson's Disease ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Molecular Mechanisms ◽  
Cellular Level ◽  
Patient Specific ◽  
Ubiquitin Protein Ligase ◽  
Induced Pluripotent

Parkinson’s disease (PD) is the second most common neurodegenerative disease. The molecular mechanisms of PD at the cellular level involve oxidative stress, mitochondrial dysfunction, autophagy, axonal transport, and neuroinflammation. Induced pluripotent stem cells (iPSCs) with patient-specific genetic background are capable of directed differentiation into dopaminergic neurons. Cell models based on iPSCs are powerful tools for studying the molecular mechanisms of PD. The iPSCs used for PD studies were mainly from patients carrying mutations in synuclein alpha (SNCA), leucine-rich repeat kinase 2 (LRRK2), PTEN-induced putative kinase 1 (PINK1), parkin RBR E3 ubiquitin protein ligase (PARK2), cytoplasmic protein sorting 35 (VPS35), and variants in glucosidase beta acid (GBA). In this review, we summarized the advances in molecular mechanisms of Parkinson’s disease using iPSC models.

3.122 A NOVEL SERIES OF HUMAN ALPHA-SYNUCLEIN BAC TRANSGENIC MOUSE MODELS TO DISSECT IN VIVO PATHOGENIC MECHANISMS IN PARKINSON'S DISEASE (PD)

2012 ◽  
Vol 18 ◽  
pp. S194
Author(s):  
T. Murphy Weitz ◽  
S.M. Fleming ◽  
S. Ren ◽  
Y. Wang ◽  
M.-F. Chesselet ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Transgenic Mouse ◽  
Mouse Models ◽  
Alpha Synuclein ◽  
Transgenic Mouse Models ◽  
Pathogenic Mechanisms ◽  
Bac Transgenic Mouse

scholarly journals Modeling Parkinson’s Disease Using Patient-specific Induced Pluripotent Stem Cells

2018 ◽  
Vol 8 (4) ◽  
pp. 479-493 ◽  
Author(s):  
Hong Li ◽  
Houbo Jiang ◽  
Boyang Zhang ◽  
Jian Feng
Keyword(s):  
Parkinson’S Disease ◽  
Stem Cells ◽  
Parkinson's Disease ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Patient Specific ◽  
Induced Pluripotent
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