scholarly journals Excess Lipin enzyme activity contributes to TOR1A recessive disease and DYT-TOR1A dystonia

Brain ◽  
2020 ◽  
Vol 143 (6) ◽  
pp. 1746-1765 ◽  
Author(s):  
Ana Cascalho ◽  
Joyce Foroozandeh ◽  
Lise Hennebel ◽  
Jef Swerts ◽  
Christine Klein ◽  
...  

Abstract TOR1A/TorsinA mutations cause two incurable diseases: a recessive congenital syndrome that can be lethal, and a dominantly-inherited childhood-onset dystonia (DYT-TOR1A). TorsinA has been linked to phosphatidic acid lipid metabolism in Drosophila melanogaster. Here we evaluate the role of phosphatidic acid phosphatase (PAP) enzymes in TOR1A diseases using induced pluripotent stem cell-derived neurons from patients, and mouse models of recessive Tor1a disease. We find that Lipin PAP enzyme activity is abnormally elevated in human DYT-TOR1A dystonia patient cells and in the brains of four different Tor1a mouse models. Its severity also correlated with the dosage of Tor1a/TOR1A mutation. We assessed the role of excess Lipin activity in the neurological dysfunction of Tor1a disease mouse models by interbreeding these with Lpin1 knock-out mice. Genetic reduction of Lpin1 improved the survival of recessive Tor1a disease-model mice, alongside suppressing neurodegeneration, motor dysfunction, and nuclear membrane pathology. These data establish that TOR1A disease mutations cause abnormal phosphatidic acid metabolism, and suggest that approaches that suppress Lipin PAP enzyme activity could be therapeutically useful for TOR1A diseases.

2020 ◽  
Vol 6 (46) ◽  
pp. eabc1428
Author(s):  
A. Nakano-Kobayashi ◽  
A. Fukumoto ◽  
A. Morizane ◽  
D. T. Nguyen ◽  
T. M. Le ◽  
...  

Neurodegenerative disorders are caused by progressive neuronal loss, and there is no complete treatment available yet. Neuroinflammation is a common feature across neurodegenerative disorders and implicated in the progression of neurodegeneration. Dysregulated activation of microglia causes neuroinflammation and has been highlighted as a treatment target in therapeutic strategies. Here, we identified novel therapeutic candidate ALGERNON2 (altered generation of neurons 2) and demonstrate that ALGERNON2 suppressed the production of proinflammatory cytokines and rescued neurodegeneration in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)–induced Parkinson’s disease model. ALGERNON2 stabilized cyclinD1/p21 complex, leading to up-regulation of nuclear factor erythroid 2–related factor 2 (Nrf2), which contributes to antioxidative and anti-inflammatory responses. Notably, ALGERNON2 enhanced neuronal survival in other neuroinflammatory conditions such as the transplantation of induced pluripotent stem cell–derived dopaminergic neurons into murine brains. In conclusion, we present that the microglial potentiation of the p21-Nrf2 pathway can contribute to neuronal survival and provide novel therapeutic potential for neuroinflammation-triggered neurodegeneration.


2020 ◽  
Vol 1 ◽  
pp. 254
Author(s):  
Katherine E. Hekman ◽  
Kyle Koss ◽  
David Z. Ivancic ◽  
Congcong He ◽  
Jason A. Wertheim

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Alondra Schweizer Burguete ◽  
Sandra Almeida ◽  
Fen-Biao Gao ◽  
Robert Kalb ◽  
Michael R Akins ◽  
...  

Microsatellite expansions are the leading cause of numerous neurodegenerative disorders. Here we demonstrate that GGGGCC and CAG microsatellite repeat RNAs associated with C9orf72 in amyotrophic lateral sclerosis/frontotemporal dementia and with polyglutamine diseases, respectively, localize to neuritic granules that undergo active transport into distal neuritic segments. In cultured mammalian spinal cord neurons, the presence of neuritic GGGGCC repeat RNA correlates with neuronal branching defects, and the repeat RNA localizes to granules that label with fragile X mental retardation protein (FMRP), a transport granule component. Using a Drosophila GGGGCC expansion disease model, we characterize dendritic branching defects that are modulated by FMRP and Orb2. The human orthologs of these modifiers are misregulated in induced pluripotent stem cell-differentiated neurons (iPSNs) from GGGGCC expansion carriers. These data suggest that expanded repeat RNAs interact with the messenger RNA transport and translation machinery, causing transport granule dysfunction. This could be a novel mechanism contributing to the neuronal defects associated with C9orf72 and other microsatellite expansion diseases.


2018 ◽  
Vol 360 ◽  
pp. 88-98 ◽  
Author(s):  
Liang Guo ◽  
Sandy Eldridge ◽  
Michael Furniss ◽  
Jodie Mussio ◽  
Myrtle Davis

2020 ◽  
Vol 21 (19) ◽  
pp. 6997 ◽  
Author(s):  
Davide Rovina ◽  
Elisa Castiglioni ◽  
Francesco Niro ◽  
Sara Mallia ◽  
Giulio Pompilio ◽  
...  

The ultimate goal of precision disease modeling is to artificially recreate the disease of affected people in a highly controllable and adaptable external environment. This field has rapidly advanced which is evident from the application of patient-specific pluripotent stem-cell-derived precision therapies in numerous clinical trials aimed at a diverse set of diseases such as macular degeneration, heart disease, spinal cord injury, graft-versus-host disease, and muscular dystrophy. Despite the existence of semi-adequate treatments for tempering skeletal muscle degeneration in dystrophic patients, nonischemic cardiomyopathy remains one of the primary causes of death. Therefore, cardiovascular cells derived from muscular dystrophy patients’ induced pluripotent stem cells are well suited to mimic dystrophin-associated cardiomyopathy and hold great promise for the development of future fully effective therapies. The purpose of this article is to convey the realities of employing precision disease models of dystrophin-associated cardiomyopathy. This is achieved by discussing, as suggested in the title echoing William Shakespeare’s words, the settlements (or “leagues”) made by researchers to manage the constraints (“betwixt mine eye and heart”) distancing them from achieving a perfect precision disease model.


2019 ◽  
Vol 115 (5) ◽  
pp. 949-959 ◽  
Author(s):  
Nazish Sayed ◽  
Mohamed Ameen ◽  
Joseph C Wu

Abstract Treatment of cancer has evolved in the last decade with the introduction of new therapies. Despite these successes, the lingering cardiotoxic side-effects from chemotherapy remain a major cause of morbidity and mortality in cancer survivors. These effects can develop acutely during treatment, or even years later. Although many risk factors can be identified prior to beginning therapy, unexpected toxicity still occurs, often with lasting consequences. Specifically, cardiotoxicity results in cardiac cell death, eventually leading to cardiomyopathy and heart failure. Certain risk factors may predispose an individual to experiencing adverse cardiovascular effects, and when unexpected cardiotoxicity occurs, it is generally managed with supportive care. Animal models of chemotherapy-induced cardiotoxicity have provided some mechanistic insights, but the precise mechanisms by which these drugs affect the heart remains unknown. Moreover, the genetic rationale as to why some patients are more susceptible to developing cardiotoxicity has yet to be determined. Many genome-wide association studies have identified genomic variants that could be associated with chemotherapy-induced cardiotoxicity, but the lack of validation has made these studies more speculative rather than definitive. With the advent of human induced pluripotent stem cell (iPSC) technology, researchers not only have the opportunity to model human diseases, but also to screen drugs for their efficacy and toxicity using human cell models. Furthermore, it allows us to conduct validation studies to confirm the role of genomic variants in human diseases. In this review, we discuss the role of iPSCs in modelling chemotherapy-induced cardiotoxicity.


2021 ◽  
Vol 8 (11) ◽  
pp. 148
Author(s):  
Jee Eun Oh ◽  
Cholomi Jung ◽  
Young-sup Yoon

Human induced pluripotent stem cells (hiPSCs) hold great promise for cardiovascular regeneration following ischemic injury. Considerable effort has been made toward the development and optimization of methods to differentiate hiPSCs into vascular cells, such as endothelial and smooth muscle cells (ECs and SMCs). In particular, hiPSC-derived ECs have shown robust potential for promoting neovascularization in animal models of cardiovascular diseases, potentially achieving significant and sustained therapeutic benefits. However, the use of hiPSC-derived SMCs that possess high therapeutic relevance is a relatively new area of investigation, still in the earlier investigational stages. In this review, we first discuss different methodologies to derive vascular cells from hiPSCs with a particular emphasis on the role of key developmental signals. Furthermore, we propose a standardized framework for assessing and defining the EC and SMC identity that might be suitable for inducing tissue repair and regeneration. We then highlight the regenerative effects of hiPSC-derived vascular cells on animal models of myocardial infarction and hindlimb ischemia. Finally, we address several obstacles that need to be overcome to fully implement the use of hiPSC-derived vascular cells for clinical application.


Sign in / Sign up

Export Citation Format

Share Document