Increase of hyperpolarization‐activated cyclic nucleotide‐gated current in the aberrant excitability of spinal muscular atrophy

Lai, Hsing-Jung; Chen, Chien‐Lin; Tsai, Li-Kai

doi:10.1002/ana.25168

Cited by 4 publications

(3 citation statements)

References 45 publications

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“…SMN-independent approaches are also able to partially rescue SMA phenotype, targeting different pathways (as autophagy, Piras et al, 2017 ) or proteins, like ROCK (Bowerman et al, 2010 , 2012 ), Plastin3 (Oprea et al, 2008 ) and the zinc finger protein ZPR1 (Ahmad et al, 2016 ). Moreover, some therapeutic strategies are aimed at ameliorating SMA phenotype by acting on endplates and improving neuromuscular transmission (Wyatt and Keirstead, 2010 ; Wadman et al, 2012 ; Nishimune et al, 2014 ; Boido et al, 2018 ; Lai et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Pharmacological c-Jun NH2-Terminal Kinase (JNK) Pathway Inhibition Reduces Severity of Spinal Muscular Atrophy Disease in Mice

Schellino

Boido

Borsello

et al. 2018

Front. Mol. Neurosci.

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Spinal muscular atrophy (SMA) is a severe neurodegenerative disorder that occurs in early childhood. The disease is caused by the deletion/mutation of the survival motor neuron 1 (SMN1) gene resulting in progressive skeletal muscle atrophy and paralysis, due to the degeneration of spinal motor neurons (MNs). Currently, the cellular and molecular mechanisms underlying MN death are only partly known, although recently it has been shown that the c-Jun NH2-terminal kinase (JNK)-signaling pathway might be involved in the SMA pathogenesis. After confirming the activation of JNK in our SMA mouse model (SMN2+/+; SMNΔ7+/+; Smn−/−), we tested a specific JNK-inhibitor peptide (D-JNKI1) on these mice, by chronic administration from postnatal day 1 to 10, and histologically analyzed the spinal cord and quadriceps muscle at age P12. We observed that D-JNKI1 administration delayed MN death and decreased inflammation in spinal cord. Moreover, the inhibition of JNK pathway improved the trophism of SMA muscular fibers and the size of the neuromuscular junctions (NMJs), leading to an ameliorated innervation of the muscles that resulted in improved motor performances and hind-limb muscular tone. Finally, D-JNKI1 treatment slightly, but significantly increased lifespan in SMA mice. Thus, our results identify JNK as a promising target to reduce MN cell death and progressive skeletal muscle atrophy, providing insight into the role of JNK-pathway for developing alternative pharmacological strategies for the treatment of SMA.

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Section: Discussionmentioning

confidence: 99%

Pharmacological c-Jun NH2-Terminal Kinase (JNK) Pathway Inhibition Reduces Severity of Spinal Muscular Atrophy Disease in Mice

Schellino

Boido

Borsello

et al. 2018

Front. Mol. Neurosci.

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“…In agreement with these findings, HCN channel dysfunction has been implicated in PD and AD (Chan et al, 2011; Saito et al, 2012). Changes of HCN channels are also observed in ALS and SMA (Lai et al, 2018; Silbernagel et al, 2018). Therefore, in this review, we focus on the roles of HCN channels in the pathogenesis of PD, AD, and other neurodegenerative diseases.…”

Section: Introductionmentioning

confidence: 93%

“…Recently, a marked enhancement of I h amplitude as well as HCN channel expression was observed in the spinal cord and sciatic nerves of SMA mice. Furthermore, treatment with ZD7288 appeared to reduce early mortality, improve motor function, and restore neuromuscular junction architecture in SMA mice (Lai et al, 2018). These results provide initial evidence that HCN channels may play a role in SMA pathophysiology and could be a novel target for SMA treatment.…”

Section: Role Of Hcn Channels In Other Neurodegenerative Diseasesmentioning

confidence: 99%

Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels: An Emerging Role in Neurodegenerative Diseases

Chang

Wang

Jiang

et al. 2019

Front. Mol. Neurosci.

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Neurodegenerative diseases such as Parkinson’s disease (PD), Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and spinal muscular atrophy (SMA) are chronic, progressive, and age-associated neurological disorders characterized by neuronal deterioration in specific brain regions. Although the specific pathological mechanisms underlying these disorders have remained elusive, ion channel dysfunction has become increasingly accepted as a potential mechanism for neurodegenerative diseases. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are encoded by the HCN1-4 gene family and conduct the hyperpolarization-activated current ( I h ). These channels play important roles in modulating cellular excitability, rhythmic activity, dendritic integration, and synaptic transmission. In the present review, we first provide a comprehensive picture of the role of HCN channels in PD by summarizing their role in the regulation of neuronal activity in PD-related brain regions. Dysfunction of I h may participate in 1-methyl-4-phenylpyridinium (MPP + )-induced toxicity and represent a pathogenic mechanism in PD. Given current reports of the critical role of HCN channels in neuroinflammation and depression, we also discussed the putative contribution of HCN channels in inflammatory processes and non-motor symptoms in PD. In the second section, we summarize how HCN channels regulate the formation of β-amyloid peptide in AD and the role of these channels in learning and memory. Finally, we briefly discuss the effects of HCN channels in ALS and SMA based on existing discoveries.

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Expression of the pacemaker channel HCN4 in excitatory interneurons in the dorsal horn of the murine spinal cord

et al. 2020

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In the central nervous system, hyperpolarization-activated, cyclic nucleotide-gated (HCN1–4) channels have been implicated in neuronal excitability and synaptic transmission. It has been reported that HCN channels are expressed in the spinal cord, but knowledge about their physiological roles, as well as their distribution profiles, appear to be limited. We generated a transgenic mouse in which the expression of HCN4 can be reversibly knocked down using a genetic tetracycline-dependent switch and conducted genetically validated immunohistochemistry for HCN4. We found that the somata of HCN4-immunoreactive (IR) cells were largely restricted to the ventral part of the inner lamina II and lamina III. Many of these cells were either parvalbumin- or protein kinase Cγ (PKCγ)-IR. By using two different mouse strains in which reporters are expressed only in inhibitory neurons, we determined that the vast majority of HCN4-IR cells were excitatory neurons. Mechanical and thermal noxious stimulation did not induce c-Fos expression in HCN4-IR cells. PKCγ-neurons in this area are known to play a pivotal role in the polysynaptic pathway between tactile afferents and nociceptive projection cells that contributes to tactile allodynia. Therefore, pharmacological and/or genetic manipulations of HCN4-expressing neurons may provide a novel therapeutic strategy for the pain relief of tactile allodynia.

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Increase of hyperpolarization‐activated cyclic nucleotide‐gated current in the aberrant excitability of spinal muscular atrophy

Abstract: This study shows that increased HCN current underlies the pathophysiology of SMA and can be a novel non-SMN target for SMA therapy. Ann Neurol 2018;83:494-507.

Cited by 4 publications

References 45 publications

Pharmacological c-Jun NH2-Terminal Kinase (JNK) Pathway Inhibition Reduces Severity of Spinal Muscular Atrophy Disease in Mice

Pharmacological c-Jun NH2-Terminal Kinase (JNK) Pathway Inhibition Reduces Severity of Spinal Muscular Atrophy Disease in Mice

Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels: An Emerging Role in Neurodegenerative Diseases

Expression of the pacemaker channel HCN4 in excitatory interneurons in the dorsal horn of the murine spinal cord

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