Synaptic disruption and CREB-regulated transcription are restored by K+ channel blockers in ALS

被引：26

作者：

Catanese, Alberto ^{[1
]}

Rajkumar, Sandeep ^{[1
]}

Sommer, Daniel ^{[1
]}

Freisem, Dennis ^{[1
]}

Wirth, Alexander ^{[1
]}

Aly, Amr ^{[1
]}

Massa-Lopez, David ^{[2
]}

Olivieri, Andrea ^{[1
]}

Torelli, Federica ^{[1
]}

Ioannidis, Valentin ^{[1
]}

Lipecka, Joanna ^{[3
]}

Guerrera, Ida Chiara ^{[3
]}

Zytnicki, Daniel ^{[4
]}

Ludolph, Albert ^{[2
,5
]}

Kabashi, Edor ^{[6
]}

Mulaw, Medhanie A. ^{[7
,8
]}

Roselli, Francesco ^{[1
,2
,5
]}

Boeckers, Tobias M. ^{[1
,2
]}

机构：

[1] Ulm Univ, Sch Med, Inst Anat & Cell Biol, Ulm, Germany

[2] Deutsch Zentrum Neurodegenerat Erkrankungen DZNE, Ulm Site, Ulm, Germany

[3] Univ Paris Struct Federat Rech Necker, CNRS, INSERM, Prote Platform Necker,US24,UMS3633, Paris, France

[4] Univ Paris, CNRS, SPPIN St Peres Paris Inst Neurosci, Paris, France

[5] Ulm Univ, Sch Med, Dept Neurol, Ulm, Germany

[6] INSERM, UMR 1163, Inst Translat Res Neurol Disorders, Imagine Inst, Paris, France

[7] Univ Ulm Univ, Univ Hosp Ulm, Med Fac, Internal Med 1, Ulm, Germany

[8] Univ Ulm Univ, Univ Hosp Ulm, Med Fac, Inst Mol Med & Stem Cell Aging, Ulm, Germany

来源：

EMBO MOLECULAR MEDICINE | 2021年 / 13卷 / 07期

关键词：

ALS; CREB; hiPSC; motoneuron; synapse; SPINAL MOTONEURONS; FIRING PROPERTIES; MOTOR-NEURONS; PHOSPHORYLATION; EXCITABILITY; HYPEREXCITABILITY; CHARYBDOTOXIN; DYSFUNCTION; INHIBITION; CALMODULIN;

D O I：

10.15252/emmm.202013131

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, which is still missing effective therapeutic strategies. Although manipulation of neuronal excitability has been tested in murine and human ALS models, it is still under debate whether neuronal activity might represent a valid target for efficient therapies. In this study, we exploited a combination of transcriptomics, proteomics, optogenetics and pharmacological approaches to investigate the activity-related pathological features of iPSC-derived C9orf72-mutant motoneurons (MN). We found that human ALS(C9orf72) MN are characterized by accumulation of aberrant aggresomes, reduced expression of synaptic genes, loss of synaptic contacts and a dynamic "malactivation" of the transcription factor CREB. A similar phenotype was also found in TBK1-mutant MN and upon overexpression of poly(GA) aggregates in primary neurons, indicating a strong convergence of pathological phenotypes on synaptic dysregulation. Notably, these alterations, along with neuronal survival, could be rescued by treating ALS-related neurons with the K+ channel blockers Apamin and XE991, which, respectively, target the SK and the Kv7 channels. Thus, our study shows that restoring the activity-dependent transcriptional programme and synaptic composition exerts a neuroprotective effect on ALS disease progression.

引用

页数：16

共 69 条

[1]

Alaburda A, 2002, J PHYSIOL-LONDON, V540, P875

[2] Synaptic restoration by cAMP/PKA drives activity-dependent neuroprotection to motoneurons in ALS [J].