Ryanodine Receptors: A Potential Treatment Target in Various Neurodegenerative Disease
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REVIEW PAPER
Ryanodine Receptors: A Potential Treatment Target in Various Neurodegenerative Disease Liang Sun1,2 · Huafeng Wei1 Received: 9 February 2020 / Accepted: 5 August 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Progressive neuronal demise is a key contributor to the key pathogenic event implicated in many different neurodegenerative disorders (NDDs). There are several therapeutic strategies available; however, none of them are particularly effective. Targeted neuroprotective therapy is one such therapy, which seems a compelling option, yet remains challenging due to the internal heterogeneity of the mechanisms underlying various NDDs. An alternative method to treat NDDs is to exploit common modalities involving molecularly distinct subtypes and thus develop specialized drugs with broad-spectrum characteristics. There is mounting evidence which supports for the theory that dysfunctional ryanodine receptors (RyRs) disrupt intracellular Ca2+ homeostasis, contributing to NDDs significantly. This review aims to provide direct and indirect evidence on the intersection of NDDs and RyRs malfunction, and to shed light on novel strategies to treat RyRs-mediated disease, modifying pharmacological therapies such as the potential therapeutic role of dantrolene, a RyRs antagonist. Keywords Calcium · Ryanodine receptor · Apoptosis · Autophagy · Neurodegenerative disorders · Endoplasmic reticulum · Mitochondria · Dantrolene
Introduction Neurodegenerative disorders (NDDs) including Alzheimer’s disease (AD) (Liang and Wei 2015), Parkinson’s disease (PD) (Belvisi et al. 2019), amyotrophic lateral sclerosis (ALS) (Tedeschi et al. 2019), Huntington’s disease (HD) (Pini et al. 2020) and spinocerebellar ataxia (SCA) (Egorova and Bezprozvanny 2019), are typically characterized by persistent neuronal loss or death implicated in the central and peripheral nervous systems (Karagas and Venkatachalam 2019). NDDs are generally gradual and progressive, and there is presently no available cure; thus, these disorders remain a major socioeconomic burden worldwide, due to temporary treatments which can prolong lifespan. Though the ideal maneuver would be to fully exploit neuroprotective * Huafeng Wei [email protected] 1
Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, 305 John Morgan Building, 3610 Hamilton Walk, Philadelphia, PA 19104, USA
Department of Anesthesiology, Peking University People’s Hospital, Beijing 100044, China
2
methods, current treatments are only able to achieve partial symptom-relieving effects. In PD, symptomatic relief by dopamine replacement is transient and accompanied by unexpected adverse side effects (Masi et al. 2019). Similarly, in AD symptom relief is rarely obtainable (Tong et al. 2018). Though intensive research, referenced above, has been done towards achieving optimal neuroprotectivity, clinical trials have not shown results. In recent years there has been a push towards understand
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