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Parkinson disease and stem cell

Kenneth Maiese
As a result of the advancing age of the global population and the progressive increase in lifespan, neurodegenerative disorders continue to increase in incidence throughout the world. New strategies for neurodegenerative disorders involve the novel pathways of the mechanistic target of rapamycin (mTOR) and the silent mating-type information regulation 2 homolog 1 ( Saccharomyces cerevisiae ) (SIRT1) that can modulate pathways of apoptosis and autophagy. The pathways of mTOR and SIRT1 are closely integrated...
March 9, 2018: Biochemical Society Transactions
Lara Marrone, Christine Bus, David Schöndorf, Julia Catherine Fitzgerald, Manuela Kübler, Benjamin Schmid, Peter Reinhardt, Lydia Reinhardt, Michela Deleidi, Tanya Levin, Andrea Meixner, Barbara Klink, Michael Glatza, Christian Johannes Gloeckner, Thomas Gasser, Jared Sterneckert
Induced pluripotent stem cells (iPSCs) have recapitulated several aspects of Parkinson's disease (PD), but most iPSCs are derived from familial cases, which account for only about 15% of patients. Thus, while the emphasis has justifiably been on using iPSCs to model rare familial cases, models for the most common forms of PD are critically lacking. Here, we report the generation of an iPSC-based model of idiopathic PD (iPD) with or without RS1491923, which is a common risk variant in the LRRK2 locus. Consistent with GWA studies, we found large variability in our datasets...
2018: PloS One
Maroof M Adil, David V Schaffer
Human pluripotent stem cell (hPSC)-derived midbrain dopaminergic (mDA) neurons may facilitate the development of therapies for Parkinson's disease via disease modeling, drug screening, and cell replacement therapy. However, large numbers of cells are typically needed for these applications, and 2-D culture-based approaches typically used for mDA differentiation are difficult to scale up and require a long time for mDA maturation. Here we present a protocol to rapidly generate functional mDA neurons in a fully defined, scalable, thermoresponsive 3-D biomaterial...
February 28, 2018: Current Protocols in Stem Cell Biology
Yujing Gao, Gabrielle R Wilson, Kiymet Bozaoglu, Andrew G Elefanty, Edouard G Stanley, Mirella Dottori, Paul J Lockhart
Mutations in RAB39B are a known cause of X-linked early onset Parkinson's disease. Isogenic human embryonic stem cell lines carrying two independent deletions of RAB39B were generated using CRISPR/Cas9 genome editing tool. The deletions were confirmed by PCR and direct sequence analysis in two edited stem cell lines. Both cell lines showed pluripotency and displayed a normal karyotype. Further, they were able to form embryoid bodies in vitro, and express markers indicative of differentiation to the three germ layers...
February 21, 2018: Stem Cell Research
Gabrielle Shall, Megan Menosky, Sarah Decker, Priya Nethala, Ryan Welchko, Xavier Leveque, Ming Lu, Michael Sandstrom, Ute Hochgeschwender, Julien Rossignol, Gary Dunbar
Multiple studies have demonstrated the ability of mesenchymal stem cells (MSCs) to differentiate into dopamine-producing cells, in vitro and in vivo, indicating their potential to be used in the treatment of Parkinson's disease (PD). However, there are discrepancies among studies regarding the optimal time (i.e., passage number) and method for dopaminergic induction, in vitro. In the current study, we compared the ability of early (P4) and later (P40) passaged bone marrow-derived MSCs to differentiate into dopaminergic neurons using two growth-factor-based approaches...
March 2, 2018: International Journal of Molecular Sciences
Francesca L'Episcopo, Cataldo Tirolo, Maria F Serapide, Salvatore Caniglia, Nunzio Testa, Loredana Leggio, Silvia Vivarelli, Nunzio Iraci, Stefano Pluchino, Bianca Marchetti
Neuroinflammatory processes are recognized key contributory factors in Parkinson's disease (PD) physiopathology. While the causes responsible for the progressive loss of midbrain dopaminergic (mDA) neuronal cell bodies in the subtantia nigra pars compacta are poorly understood, aging, genetics, environmental toxicity, and particularly inflammation, represent prominent etiological factors in PD development. Especially, reactive astrocytes, microglial cells, and infiltrating monocyte-derived macrophages play dual beneficial/harmful effects, via a panel of pro- or anti-inflammatory cytokines, chemokines, neurotrophic and neurogenic transcription factors...
2018: Frontiers in Aging Neuroscience
Tammy Ryan, Vladimir V Bamm, Morgan G Stykel, Carla L Coackley, Kayla M Humphries, Rhiannon Jamieson-Williams, Rajesh Ambasudhan, Dick D Mosser, Stuart A Lipton, George Harauz, Scott D Ryan
Neuronal loss in Parkinson's disease (PD) is associated with aberrant mitochondrial function and impaired proteostasis. Identifying the mechanisms that link these pathologies is critical to furthering our understanding of PD pathogenesis. Using human pluripotent stem cells (hPSCs) that allow comparison of cells expressing mutant SNCA (encoding α-synuclein (α-syn)) with isogenic controls, or SNCA-transgenic mice, we show that SNCA-mutant neurons display fragmented mitochondria and accumulate α-syn deposits that cluster to mitochondrial membranes in response to exposure of cardiolipin on the mitochondrial surface...
February 26, 2018: Nature Communications
Han Gao, Lianrong Dou, Liang Shan, Yan Sun, Wentao Li
Neural stem cells (NSCs) are important cellular sources of transplantation therapies for Parkinson's disease. This study aimed to determine the effects of extracts of radix astragali on the proliferation and differentiation into dopamine (DA) neurons in NSCs. NSCs were dealt with astragaloside IV (ASI), astragalus polysaccharide (APS), and astraisoflavan (ASF), the main active ingredients of radix astragali. First, the results from cell-count kit-8 (CCK-8) assay showed that ASI, ASF, and APS had positive effects on the proliferation of NSCs...
February 23, 2018: Neuroreport
Tatsiana Aneichyk, William T Hendriks, Rachita Yadav, David Shin, Dadi Gao, Christine A Vaine, Ryan L Collins, Aloysius Domingo, Benjamin Currall, Alexei Stortchevoi, Trisha Multhaupt-Buell, Ellen B Penney, Lilian Cruz, Jyotsna Dhakal, Harrison Brand, Carrie Hanscom, Caroline Antolik, Marisela Dy, Ashok Ragavendran, Jason Underwood, Stuart Cantsilieris, Katherine M Munson, Evan E Eichler, Patrick Acuña, Criscely Go, R Dominic G Jamora, Raymond L Rosales, Deanna M Church, Stephen R Williams, Sarah Garcia, Christine Klein, Ulrich Müller, Kirk C Wilhelmsen, H T Marc Timmers, Yechiam Sapir, Brian J Wainger, Daniel Henderson, Naoto Ito, Neil Weisenfeld, David Jaffe, Nutan Sharma, Xandra O Breakefield, Laurie J Ozelius, D Cristopher Bragg, Michael E Talkowski
X-linked Dystonia-Parkinsonism (XDP) is a Mendelian neurodegenerative disease that is endemic to the Philippines and is associated with a founder haplotype. We integrated multiple genome and transcriptome assembly technologies to narrow the causal mutation to the TAF1 locus, which included a SINE-VNTR-Alu (SVA) retrotransposition into intron 32 of the gene. Transcriptome analyses identified decreased expression of the canonical cTAF1 transcript among XDP probands, and de novo assembly across multiple pluripotent stem-cell-derived neuronal lineages discovered aberrant TAF1 transcription that involved alternative splicing and intron retention (IR) in proximity to the SVA that was anti-correlated with overall TAF1 expression...
February 22, 2018: Cell
Anand Rane, Subramanian Rajagopalan, Manuj Ahuja, Bobby Thomas, Shankar J Chinta, Julie K Andersen
The heat shock factor 90 (hsp90) complex has long been associated with neuropathological phenotypes linked to Parkinson's disease (PD) and its inhibition is neuroprotective in disease models. Hsp90 is conventionally believed to act by suppressing induction of hsp70. Here, we report a novel hsp70-independent mechanism by which Hsp90 may also contribute to PD-associated neuropathology. We previously reported that inhibition of the enzyme prolyl hydroxylase domain 2 (PHD2) in conjunction with increases in hypoxia-inducible factor 1 alpha (HIF1α) results in protection of vulnerable dopaminergic substantia nigra pars compacta (DAergic SNpc) neurons in in vitro and in vivo models of PD...
February 19, 2018: Neurotoxicology
Samuela Cataldi, Cataldo Arcuri, Stéphane Hunot, Carmen Mecca, Michela Codini, Maria E Laurenti, Ivana Ferri, Elisabetta Loreti, Mercedes Garcia-Gil, Giovanna Traina, Carmela Conte, Francesco S Ambesi-Impiombato, Tommaso Beccari, Francesco Curcio, Elisabetta Albi
It has long been proven that neurogenesis continues in the adult brains of mammals in the dentatus gyrus of the hippocampus due to the presence of neural stem cells. Although a large number of studies have been carried out to highlight the localization of vitamin D receptor in hippocampus, the expression of vitamin D receptor in neurogenic dentatus gyrus of hippocampus in Parkinson's disease (PD) and the molecular mechanisms triggered by vitamin D underlying the production of differentiated neurons from embryonic cells remain unknown...
2018: Frontiers in Cellular Neuroscience
Yukari Suda, Naoko Kuzumaki, Takefumi Sone, Michiko Narita, Kenichi Tanaka, Yusuke Hamada, Chizuru Iwasawa, Masahiro Shibasaki, Aya Maekawa, Miri Matsuo, Wado Akamatsu, Nobutaka Hattori, Hideyuki Okano, Minoru Narita
Ghrelin exerts a wide range of physiological actions throughout the body and appears to be a promising target for disease therapy. Endogenous ghrelin receptors (GHSRs) are present in extrahypothalamic sites including the substantia nigra pars compacta (SNc), which is related to phenotypic dysregulation or frank degeneration in Parkinson's disease (PD). Here we found a dramatic decrease in the expression of GHSR in PD-specific induced pluripotent stem cell (iPSC)-derived dopaminergic (DAnergic) neurons generated from patients carrying parkin gene (PARK2) mutations compared to those from healthy controls...
February 20, 2018: Molecular Brain
Xiaoxiang Chen, Yuan Qian, Xiangpeng Wang, Zhiwei Tang, Jiaotian Xu, Hai Lin, Zhiyong Yang, Xiaobin Song, Di Lu, Jiazhi Guo, Ligong Bian, Yu Li, Lei Zhou, Xingli Deng
INTRODUCTION: Neural stem cells (NSCs) are the most promising cells for cell replacement therapy for Parkinson's disease (PD). However, a majority of the transplanted NSCs differentiated into glial cells, thereby limiting the clinical application. Previous studies indicated that chronic neuroinflammation plays a vital role in the degeneration of midbrain DA (mDA) neurons, which suggested the developing potential of therapies for PD by targeting the inflammatory processes. Thus, Nurr1 (nuclear receptor-related factor 1), a transcription factor, has been referred to play a pivotal role in both the differentiation of dopaminergic neurons in embryonic stages and the maintenance of the dopaminergic phenotype throughout life...
February 15, 2018: CNS Neuroscience & Therapeutics
Zubair Ahmed Nizamudeen, Lisa Chakrabarti, Virginie Sottile
Fasudil is a clinically approved Rho-associated protein kinase (ROCK) inhibitor that has been used widely to treat cerebral consequences of subarachnoid hemorrhage. It is known to have a positive effect on animal models of neurological disorders including Parkinson's disease and stroke. However, its cellular effect on progenitor populations and differentiation is not clearly understood. While recent studies suggest that fasudil promotes the mobilization of neural stem cells (NSCs) from the subventricular zone in vivo and promotes the differentiation of the C17...
February 6, 2018: Stem Cell Research
Shi-Lung Lin
Pluripotent stem cells are a resourceful treasure box for regenerative medicine. They contain a large variety of novel materials useful for designing and developing new medicines and therapies directed against many aging-associated degenerative disorders, including Alzheimer's disease, Parkinson's disease, stroke, diabetes, osteoporosis, and cancers. Currently, identification of these novel stem cell-specific materials is one of major breakthroughs in the field of stem cell research. Particularly, since the discovery of induced pluripotent stem cells (iPSC) in year 2006, the methods of iPSC derivation further provide an unlimited resource for screening, isolating, and even producing theses novel stem cell-specific materials in vitro...
2018: Methods in Molecular Biology
Evan E Santo, Jihye Paik
The evolutionarily conserved FOXO family of transcription factors has emerged as a significant arbiter of neural cell fate and function in mammals. From the neural stem cell (NSC) state through mature neurons under both physiological and pathological conditions, they have been found to modulate neural cell survival, stress responses, lineage commitment, and neuronal signaling. Lineage-specific FOXO knockout mice have provided an invaluable tool for the dissection of FOXO biology in the nervous system. Within the NSC compartments of the brain, FOXOs are required for the maintenance of NSC quiescence and for the clearance of reactive oxygen species...
2018: Current Topics in Developmental Biology
Laura de Boni, Gilles Gasparoni, Carolin Haubenreich, Sascha Tierling, Ina Schmitt, Michael Peitz, Philipp Koch, Jörn Walter, Ullrich Wüllner, Oliver Brüstle
Background: Genetic predisposition and epigenetic alterations are both considered to contribute to sporadic neurodegenerative diseases (NDDs) such as Parkinson's disease (PD). Since cell reprogramming and the generation of induced pluripotent stem cells (iPSCs) are themselves associated with major epigenetic remodeling, it remains unclear to what extent iPSC-derived neurons lend themselves to model epigenetic disease-associated changes. A key question to be addressed in this context is whether iPSC-derived neurons exhibit epigenetic signatures typically observed in neurons derived from non-reprogrammed human embryonic stem cells (hESCs)...
2018: Clinical Epigenetics
Oumei Cheng, Xiaoyan Tian, Ying Luo, Shaoshan Mai, Yang Yang, Shengnan Kuang, Qi Chen, Jie Ma, Beibei Chen, Rong Li, Lu Yang, Huan Li, Congli Hu, Jiahua Zhang, Zhihao Chen, Yuke Li, Hui Xia, Ying Xu, Junqing Yang
Dopaminergic (DA) neurons derived from bone marrow derived mesenchymal stem cells (BMSCs) maybe a valuable source for cell replacement therapy in Parkinson disease. Recent studies showed that new functions of LXR and their ligands have been proposed to prevent PD in the adult nervous system. The present study was designed to observe the effect of liver X receptors (LXR) agonist on differentiation of rat BMSCs into DA neurons. Expressions of the neuronal markers (Tuj1 and Nestin), the specific marker of DA neurons (tyrosine hydroxylase, TH), LXR α and LXR β were measured by immunocytochemical assay and TH/Tuj1 positive cells were determined by quantitative cell count analyses...
January 2, 2018: Oncotarget
Jens Christian Schwamborn
Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease. The incidence of PD cases increases with age, accordingly classically PD is considered to be an age associated neurodegenerative disease. In this review the hypothesis that PD is actually a neurodevelopmental disorder that is compensated for long time, will be discussed. However, patients who suffer from Parkinson's disease typically do not show symptoms early in their live. This implies that, if the hypothesis that PD has a significant neurodevelopmental component is correct, the developmental defects are compensated for long time...
February 7, 2018: Stem Cells and Development
Ana Marote, Yuriy Pomeshchik, Anna Collin, Stefano Goldwurm, Nuno J Lamas, Luísa Pinto, António J Salgado, Laurent Roybon
The leucine-rich repeat kinase 2 (LRRK2) p.G2019S mutation is the most common genetic cause of Parkinson's disease (PD). An induced pluripotent stem cell (iPSC) line CSC-41 was generated from a 75-year old patient diagnosed with PD caused by a p.G2019S mutation in LRRK2. Skin fibroblasts were reprogrammed using a non-integrating Sendai virus-based technology to deliver OCT3/4, SOX2, c-MYC and KLF4 transcription factors. The generated iPSC line exhibits expression of common pluripotency markers, differentiates into the three germ layers and has a normal karyotype...
February 2, 2018: Stem Cell Research
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