scholarly journals Amplifying the heat shock response ameliorates pathology in mouse and human models of ALS and FTD.

2021 ◽  
Author(s):  
Mhoriam Ahmed ◽  
Charlotte Spicer ◽  
Jasmine Harley ◽  
Nikolaj Petersen ◽  
Paul Taylor ◽  
...  
Keyword(s):  
Heat Shock ◽  
Motor Neurons ◽  
Heat Shock Response ◽  
Therapeutic Potential ◽  
Experimental Models ◽  
Pathological Changes ◽  
Beneficial Effects ◽  
Disease Spectrum ◽  
Shock Response ◽  
Lateral Sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are now widely considered to be part of a disease spectrum with the identification of common pathological features and genetic causes. However, despite these advances, there remains no effective therapy for these conditions. In this study we demonstrate that mice expressing mutant valosin containing protein (VCP) develop an ALS/FTD-like phenotype in the spinal cord and brain, and treatment with arimoclomol, a pharmacological amplifier of the cytoprotective heat shock response ameliorates this phenotype. Moreover, the beneficial effects of arimoclomol are seen in both fibroblasts and iPSC-derived motor neurons from patients. Importantly, we show the pathological changes targeted by arimoclomol in our experimental models are present in post-mortem FTD patient tissue. Together with previous data demonstrating the efficacy of arimoclomol in SOD1-ALS models, our findings suggest that arimoclomol may have therapeutic potential not only in non-SOD1 ALS but also for the treatment of FTD.

Heat Shock Response Regulates Insulin Sensitivity and Glucose Homeostasis: Pathophysiological Impact and Therapeutic Potential

2011 ◽  
Vol 7 (4) ◽  
pp. 264-269 ◽  
Author(s):  
Tatsuya Kondo ◽  
Saori Koga ◽  
Rina Matsuyama ◽  
Katsutoshi Miyagawa ◽  
Rieko Goto ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Heat Shock ◽  
Glucose Homeostasis ◽  
Heat Shock Response ◽  
Therapeutic Potential ◽  
Shock Response

scholarly journals Therapeutic Potential of Polyphenols in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Antioxidants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1328
Author(s):  
Valentina Novak ◽  
Boris Rogelj ◽  
Vera Župunski
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Frontotemporal Dementia ◽  
Therapeutic Potential ◽  
Treatment Options ◽  
Common Disease ◽  
Beneficial Effects ◽  
Disease Spectrum ◽  
New Compounds ◽  
And Oxidative Stress ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are severe neurodegenerative disorders that belong to a common disease spectrum. The molecular and cellular aetiology of the spectrum is a highly complex encompassing dysfunction in many processes, including mitochondrial dysfunction and oxidative stress. There is a paucity of treatment options aside from therapies with subtle effects on the post diagnostic lifespan and symptom management. This presents great interest and necessity for the discovery and development of new compounds and therapies with beneficial effects on the disease. Polyphenols are secondary metabolites found in plant-based foods and are well known for their antioxidant activity. Recent research suggests that they also have a diverse array of neuroprotective functions that could lead to better treatments for neurodegenerative diseases. We present an overview of the effects of various polyphenols in cell line and animal models of ALS/FTD. Furthermore, possible mechanisms behind actions of the most researched compounds (resveratrol, curcumin and green tea catechins) are discussed.

scholarly journals Depending on the stress, histone deacetylase inhibitors act as heat shock protein co-inducers in motor neurons and potentiate arimoclomol, exerting neuroprotection through multiple mechanisms in ALS models

2020 ◽  
Vol 25 (1) ◽  
pp. 173-191 ◽  
Author(s):  
Rachel Kuta ◽  
Nancy Larochelle ◽  
Mario Fernandez ◽  
Arun Pal ◽  
Sandra Minotti ◽  
...  
Keyword(s):  
Heat Shock ◽  
Histone Deacetylase ◽  
Motor Neurons ◽  
Heat Shock Response ◽  
Hdac Inhibitors ◽  
Dependent Manner ◽  
Hdac Inhibition ◽  
Proteotoxic Stress ◽  
Shock Response ◽  
Stress Dependent

AbstractUpregulation of heat shock proteins (HSPs) is an approach to treatment of neurodegenerative disorders with impaired proteostasis. Many neurons, including motor neurons affected in amyotrophic lateral sclerosis (ALS), are relatively resistant to stress-induced upregulation of HSPs. This study demonstrated that histone deacetylase (HDAC) inhibitors enable the heat shock response in cultured spinal motor neurons, in a stress-dependent manner, and can improve the efficacy of HSP-inducing drugs in murine spinal cord cultures subjected to thermal or proteotoxic stress. The effect of particular HDAC inhibitors differed with the stress paradigm. The HDAC6 (class IIb) inhibitor, tubastatin A, acted as a co-inducer of Hsp70 (HSPA1A) expression with heat shock, but not with proteotoxic stress induced by expression of mutant SOD1 linked to familial ALS. Certain HDAC class I inhibitors (the pan inhibitor, SAHA, or the HDAC1/3 inhibitor, RGFP109) were HSP co-inducers comparable to the hydroxyamine arimoclomol in response to proteotoxic stress, but not thermal stress. Regardless, stress-induced Hsp70 expression could be enhanced by combining an HDAC inhibitor with either arimoclomol or with an HSP90 inhibitor that constitutively induced HSPs. HDAC inhibition failed to induce Hsp70 in motor neurons expressing ALS-linked mutant FUS, in which the heat shock response was suppressed; yet SAHA, RGFP109, and arimoclomol did reduce loss of nuclear FUS, a disease hallmark, and HDAC inhibition rescued the DNA repair response in iPSC-derived motor neurons carrying the FUSP525Lmutation, pointing to multiple mechanisms of neuroprotection by both HDAC inhibiting drugs and arimoclomol.

scholarly journals Histamine Is an Inducer of the Heat Shock Response in SOD1-G93A Models of ALS

2019 ◽  
Vol 20 (15) ◽  
pp. 3793 ◽  
Author(s):  
Savina Apolloni ◽  
Francesca Caputi ◽  
Annabella Pignataro ◽  
Susanna Amadio ◽  
Paola Fabbrizio ◽  
...  
Keyword(s):  
Heat Shock ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Heat Shock Response ◽  
Type I ◽  
Spine Density ◽  
Shock Response ◽  
Anti Inflammatory

(1) Background: Amyotrophic lateral sclerosis (ALS) is a multifactorial non-cell autonomous disease where activation of microglia and astrocytes largely contributes to motor neurons death. Heat shock proteins have been demonstrated to promote neuronal survival and exert a strong anti-inflammatory action in glia. Having previously shown that the pharmacological increase of the histamine content in the central nervous system (CNS) of SOD1-G93A mice decreases neuroinflammation, reduces motor neuron death, and increases mice life span, here we examined whether this effect could be mediated by an enhancement of the heat shock response. (2) Methods: Heat shock protein expression was analyzed in vitro and in vivo. Histamine was provided to primary microglia and NSC-34 motor neurons expressing the SOD1-G93A mutation. The brain permeable histamine precursor histidine was chronically administered to symptomatic SOD1-G93A mice. Spine density was measured by Golgi-staining in motor cortex of histidine-treated SOD1-G93A mice. (3) Results: We demonstrate that histamine activates the heat shock response in cultured SOD1-G93A microglia and motor neurons. In SOD1-G93A mice, histidine augments the protein content of GRP78 and Hsp70 in spinal cord and cortex, where the treatment also rescues type I motor neuron dendritic spine loss. (4) Conclusion: Besides the established histaminergic neuroprotective and anti-inflammatory effects, the induction of the heat shock response in the SOD1-G93A model by histamine confirms the importance of this pathway in the search for successful therapeutic solutions to treat ALS.

scholarly journals The heat shock response plays an important role in TDP-43 clearance: evidence for dysfunction in amyotrophic lateral sclerosis

Brain ◽  
2016 ◽  
Vol 139 (5) ◽  
pp. 1417-1432 ◽  
Author(s):  
Han-Jou Chen ◽  
Jacqueline C. Mitchell ◽  
Sergey Novoselov ◽  
Jack Miller ◽  
Agnes L. Nishimura ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Heat Shock ◽  
Heat Shock Response ◽  
Shock Response ◽  
Lateral Sclerosis

scholarly journals Mesenchymal Stem Cells: A Potential Therapeutic Approach for Amyotrophic Lateral Sclerosis?

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Agnese Gugliandolo ◽  
Placido Bramanti ◽  
Emanuela Mazzon
Keyword(s):  
Stem Cells ◽  
Clinical Trials ◽  
Amyotrophic Lateral Sclerosis ◽  
Mesenchymal Stem Cells ◽  
Motor Neurons ◽  
Experimental Models ◽  
Partial Recovery ◽  
Rodent Models ◽  
Beneficial Effects ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the degeneration of both upper and lower motor neurons. Patients show both motor and extra-motor symptoms. A cure is not available at this time, and the disease leads to death within 3–5 years, mainly due to respiratory failure. Stem cell therapy is arising as a new promising approach for the treatment of neurodegenerative disorders. In particular, mesenchymal stem cells (MSCs) seem the most suitable type of stem cells, thanks to their demonstrated beneficial effects in different experimental models, to the easy availability, and to the lack of ethical problems. In this review, we focused on the studies involving ALS rodent models and clinical trials in order to understand the potential beneficial effects of MSC transplantation. In different ALS rodent models, the administration of MSCs induced a delay in disease progression and at least a partial recovery of the motor function. In addition, clinical trials evidenced the feasibility and safety of MSC transplantation in ALS patients, given that no major adverse events were recorded. However, only partial improvements were shown. For this reason, more studies and trials are needed to clarify the real effectiveness of MSC-based therapy in ALS.

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