Blocking acid-sensing ion channel 1 alleviates Huntington's disease pathology via an ubiquitin-proteasome system-dependent mechanism

Wong, Hon Kit; Bauer, Peter; Kurosawa, Masaru; Goswami, Anand; Washizu, Chika; Machida, Yo; Tosaki, Asako; Yamada, Masako; Knöpfel, Thomas; Nakamura, Takemichi; Nukina, Nobuyuki

doi:10.1093/hmg/ddn218

Cited by 118 publications

(101 citation statements)

References 61 publications

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Section: Discussionmentioning

confidence: 99%

“…5,6,[39][40][41] Tissue acidosis is one of the common symptoms shared by these diseases 5,6,[39][40][41] and considered as the cause of ASIC1a-mediated neuronal damage. 5,6,[39][40][41] Notably, mitochondria play essential roles in all these diseases. 10,14,26,42 Taken ischemic stroke as an example, ASIC1a gene deletion has been shown to protect against ischemic brain damage in the rodent focal ischemia/ reperfusion model, middle cerebral artery occlusion.…”

Section: Discussionmentioning

confidence: 99%

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Intracellular ASIC1a regulates mitochondrial permeability transition-dependent neuronal death

et al. 2013

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Acid-sensing ion channel 1a (ASIC1a) is the key proton receptor in nervous systems, mediating acidosis-induced neuronal injury in many neurological disorders, such as ischemic stroke. Up to now, functional ASIC1a has been found exclusively on the plasma membrane. Here, we show that ASIC1a proteins are also present in mitochondria of mouse cortical neurons where they are physically associated with adenine nucleotide translocase. Moreover, purified mitochondria from ASIC1a À / À mice exhibit significantly enhanced Ca 2 þ retention capacity and accelerated Ca 2 þ uptake rate. When challenged with hydrogen peroxide (H 2 O 2 ), ASIC1a À / À neurons are resistant to cytochrome c release and inner mitochondrial membrane depolarization, suggesting an impairment of mitochondrial permeability transition (MPT) due to ASIC1a deletion. Consistently, H 2 O 2 -induced neuronal death, which is MPT dependent, is reduced in ASIC1a À / À neurons. Additionally, significant increases in mitochondrial size and oxidative stress levels are detected in ASIC1a À / À mouse brain, which also displays marked changes (42-fold) in the expression of mitochondrial proteins closely related to reactive oxygen species signal pathways, as revealed by two-dimensional difference gel electrophoresis followed by mass spectrometry analysis. Our data suggest that mitochondrial ASIC1a may serve as an important regulator of MPT pores, which contributes to oxidative neuronal cell death. The acid-sensing ion channels (ASICs) represent a subfamily of degenerin/epithelial Na þ channels that are activated by extracellular protons. 1 Homomeric ASIC1a channels are expressed throughout central and peripheral nervous systems and are implicated in learning/memory, pain sensation and neuronal death. 1-8 Among all these functions, mediating ischemic neuronal death was one of the most prominent pathological features of ASIC1a channels. [5][6][7] Although it has been established that severe extracellular acidosis in ischemic brain overactivated ASIC1a and caused neuronal death, 5,6 the death mechanisms remained largely unknown particularly considering that ASIC1a channels completely desensitize within a few seconds during persistent acidosis. 9 Thus, under such ischemic conditions, there might be other ASIC1a-associated mechanism(s) than acidosisinduced channel activation to explain the prominent effect against ischemic insult in the ASIC1a gene deletion mutant. 5 Indeed, ischemic neuronal death is a consequence of numerous ionic, biochemical and cellular events. 10,11 Multiple causes have been identified for neuronal demise such as excitotoxicity, acidotoxicity, oxidative stress and inflammation. [10][11][12] The ASIC1a channels may be involved in one or more of these mechanisms.Mitochondria are the key death executors in the cell, playing a central role in neuronal damages associated with neurological disorders such as ischemic stroke and neurodegenerative diseases. 13 Mitochondrial permeability transition (MPT) is a key event that occurs in most forms of cell demise ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Intracellular ASIC1a regulates mitochondrial permeability transition-dependent neuronal death

et al. 2013

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“…Neurodegenerative disorders: Ca2+ ion permeabili y of ASIC1a and tissue acidification is play a role in a handful number of neurodegenerative disease, including ischemic s roke [40], epileptic seizures [41][42][43] au oimmune encephalitis [44], Hunting on`s [45] and Parkinson`s disease [46][47]. I has been proposed ha blocking of ASICs gave a herapeutic time window of more han 5 h in ra models of focal ischemia and herefore makes hem a grea herapeutic arge for s roke rea men [48].…”

Section: Pathophysiological Role Of Acid-sensing Ion Channelsmentioning

confidence: 99%

Acid Sensing Ion Channels (Asics): Potential Targets for the Discovery of Novel Therapeutics in Disease Management

Roy¹

2018

IJCBR

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INTRODUCTIONThe acid-sensing ion channels or ASICs form a distinc branch of he degenerin superfamily (ENaC/DEG) of sodium channels. A leas four ASIC genes have been identified in humans so far, numbered 1-4, wi h a number of splice varian s encoding a o al of nine unique pro eins [1][2][3][4][5][6][7][8][9]. The channels formed by he ASIC pro eins are basically pro on-ga ed cation channels, opening rapidly in he presence of ex racellular acid. All ASIC subuni consis s of a large ex racellular domain, 2 ransmembrane helices, and shor cy oplasmic N and C ermini. Functional ASICs are homo or he ero rimers of ASIC1a, ASIC1bASIC2a, ASIC2b, and/ or ASIC3 subuni s [10][11]. ASIC2b is no functional as homomultimer bu form functional he eromeric channels in combination wi h o her subuni s [12]. The activi y of ASIC4 channel has been de ec ed very limi ed ye . I may participa e in regulating he membrane availabili y of o her ASIC subuni s [13]. ASIC1a and ASIC3 are activa ed by an acidi y range (pH 7.0-6.0) observed in several acu e and chronic pain conditions. ASIC3 is particularly sensitive o lactic acidosis and hus is considered o be an impor an componen of acid induced pain [14].Corresponding author: Debendra Nath Roy, Department of Pharmacy, Faculty of Biological Science and Technology, Jessore University of Science and Technology, Jessore-7408, Bangladesh. Email: roydn009@gmail.com I has been noticed ha he activation of ASIC in neurons induce action po entials. The ex en and duration of he ASIC-media ed depolarization depends bo h on ASIC ampli ude activi y and he number of charges he channels ranspor during heir opening [15][16]. Among all o hers, ASIC3 is he mos sensitive o increases in pro on concen ration, wi h half-maximal pH activation is 6.4 [17]. ASIC2 is he leas sensitive, requiring exposure o pH 4.5 for halfmaximal activation. ASICs have been de ec ed hroughou he nervous sys em, specifically in areas of high synaptic densi y, localizing primarily o he soma and processes of neurons [18][19]. Their expression pattern has sugges ed ha hese channels play a role in sensory perception and various neural processes [20][21]. ASICs have widespread dis ribution o many regions in he nervous sys em including dorsal roo ganglia, cor ex, hippocampus, basal ganglia, amygdale, olfac ory bulb, cerebrum and elsewhere [22 -24]. In erestingly, ASICs are increasingly being de eced in nonneuronal settings including cancer cells [25], bone [26], in estinal and bladder epi helium cells and smoo h muscle [27][28][29][30]. Because ASICs are permeable o Na+, heir activation leads o membrane depolarization, hus inducing action po entials in neurons ASICs often have an activation effec on neurons. A s rong ASIC-media ed depolarization, however, can inhibi an already actively signaling neuron. ASIC1a has a small permeabili y for Ca2+ in addition o i s Na+ permeabili y, and some of i s cellular functions, as for example neurodegeneration after ischem- ABSTRACTAcid sensing ion channels (ASIC) are Na+ channels activa ed by ex ernal pro o...

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“…Some HD models have been studied, where amiloride derivative benzamil (Ben), a chemical agent used to rescue acid-sensing ion channel (ASIC)-dependent acidotoxicity, was examined whether chronic acidosis is an important part of the HD pathomechanism and whether these drugs could be used as novel therapeutic agents. Ben markedly reduced the huntingtin-polyglutamine (htt-polyQ) aggregation in an inducible cellular system, and the therapeutic value of Ben was successfully recapitulated in the animal model of HD [294].…”

Section: Huntington's Diseasementioning

confidence: 99%

Ion Channels as Drug Targets in Central Nervous System Disorders

Waszkielewicz¹,

Gunia²,

Szkaradek³

et al. 2013

CMC

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Ion channel targeted drugs have always been related with either the central nervous system (CNS), the peripheral nervous system, or the cardiovascular system. Within the CNS, basic indications of drugs are: sleep disorders, anxiety, epilepsy, pain, etc. However, traditional channel blockers have multiple adverse events, mainly due to low specificity of mechanism of action. Lately, novel ion channel subtypes have been discovered, which gives premises to drug discovery process led towards specific channel subtypes. An example is Na + channels, whose subtypes 1.3 and 1.7-1.9 are responsible for pain, and 1.1 and 1.2 -for epilepsy. Moreover, new drug candidates have been recognized. This review is focusing on ion channels subtypes, which play a significant role in current drug discovery and development process. The knowledge on channel subtypes has developed rapidly, giving new nomenclatures of ion channels. For example, Ca 2+ channels are not any more divided to T, L, N, P/Q, and R, but they are described as Ca v 1.1-Ca v 3.3, with even newer nomenclature 1A-1I and 1S. Moreover, new channels such as P2X1-P2X7, as well as TRPA1-TRPV1 have been discovered, giving premises for new types of analgesic drugs.

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Blocking acid-sensing ion channel 1 alleviates Huntington's disease pathology via an ubiquitin-proteasome system-dependent mechanism

Cited by 118 publications

References 61 publications

Intracellular ASIC1a regulates mitochondrial permeability transition-dependent neuronal death

Intracellular ASIC1a regulates mitochondrial permeability transition-dependent neuronal death

Acid Sensing Ion Channels (Asics): Potential Targets for the Discovery of Novel Therapeutics in Disease Management

Ion Channels as Drug Targets in Central Nervous System Disorders

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