ADAM22 and ADAM23 modulate the targeting of the Kv1 channel-associated protein LGI1 to the axon initial segment

Hivert, Bruno; Marien, Laurene; Agbam, Komlan Nassirou; Faivre‐Sarrailh, Catherine

doi:10.1101/311365

Cited by 2 publications

(1 citation statement)

References 42 publications

(53 reference statements)

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“…The KCNA2 gene encodes the voltage-gated K + channel Kv1.2, and the mutations in it can cause progressive myoclonus epilepsy and epileptic encephalopathy (35). Additionally, the voltage-gated potassium channel Kv1.1/1.2-subunit is related to cell adhesion molecules (CAM), which includes Caspr2 and LGI1 (42). The interaction of LGI1 with ADAM22 and ADAM23 makes an important impact on the molecular mechanism of autosomal dominant lateral temporal lobe epilepsy (ADLTE).…”

Section: Discussionmentioning

confidence: 99%

Brain Proteomic Profiling in Intractable Epilepsy Caused by TSC1 Truncating Mutations: A Small Sample Study

Liu

et al. 2020

Front. Neurol.

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Tuberous sclerosis complex (TSC) is a genetic disease characterized by seizures, mental deficiency, and abnormalities of the skin, brain, kidney, heart, and lungs. TSC is inherited in an autosomal dominant manner and is caused by variations in either the TSC1 or TSC2 gene. TSC-related epilepsy (TRE) is the most prevalent and challenging clinical feature of TSC, and more than half of the patients have refractory epilepsy. In clinical practice, we found several patients of intractable epilepsy caused by TSC1 truncating mutations. To study the changes of protein expression in the brain, three cases of diseased brain tissue with TSC1 truncating mutation resected in intractable epilepsy operations and three cases of control brain tissue resected in craniocerebral trauma operations were collected to perform protein spectrum detection, and then the data-independent acquisition (DIA) workflow was used to analyze differentially expressed proteins. As a result, there were 55 up-and 55 down-regulated proteins found in the damaged brain tissue with TSC1 mutation compared to the control. Further bioinformatics analysis revealed that the differentially expressed proteins were mainly concentrated in the synaptic membrane between the patients with TSC and the control. Additionally, TSC1 truncating mutations may affect the pathway of amino acid metabolism. Our study provides a new idea to explore the brain damage mechanism caused by TSC1 mutations.

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Section: Discussionmentioning

confidence: 99%

Brain Proteomic Profiling in Intractable Epilepsy Caused by TSC1 Truncating Mutations: A Small Sample Study

Liu

et al. 2020

Front. Neurol.

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Global ribosome profiling reveals that mutant huntingtin stalls ribosomes and represses protein synthesis independent of fragile X mental retardation protein

Eshraghi

Karunadharma

Blin

et al. 2019

Preprint

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The regulators that stall ribosome translocation are poorly understood. We find that polyglutamine-expanded mutant Huntingtin (mHtt), the Huntington's disease (HD) causing protein, promotes ribosome stalling and physiologically suppresses protein synthesis. A comprehensive, genome-wide analysis of ribosome footprint profiling (Ribo-Seq) revealed widespread ribosome stalling on mRNA transcripts and a shift in the distribution of ribosomes toward the 5' end, with single-codon unique pauses on selected mRNAs in HD cells. In Ribo-Seq, we found fragile X mental retardation protein (FMRP), a known regulator of ribosome stalling, translationally upregulated and it coimmunoprecipitated with mHtt in HD cells and postmortem brain. Depletion of FMRP gene, Fmr1, however, did not affect the mHtt-mediated suppression of protein synthesis or ribosome stalling in HD cells. Consistent with this, heterozygous deletion of Fmr1 in Q175FDN-Het mouse model, Q175FDN-Het; Fmr1 +/-, showed no discernable phenotype, but a subtle deficit in motor skill learning. On the other hand, depletion of mHtt, which binds directly to ribosomes in an RNase-sensitive manner, enhanced global protein synthesis, increased ribosome translocation and decreased stalling. This mechanistic knowledge advances our understanding of the inhibitory role of mHtt in ribosome translocation and may lead to novel target(s) identification and therapeutic approaches that modulate ribosome stalling in HD. One Sentence Summary:Huntington's disease (HD) protein, mHtt, binds to ribosomes and affects their translocation and promotes stalling independent of the fragile X mental retardation protein.Main Text:

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ADAM22 and ADAM23 modulate the targeting of the Kv1 channel-associated protein LGI1 to the axon initial segment

Cited by 2 publications

References 42 publications

Brain Proteomic Profiling in Intractable Epilepsy Caused by TSC1 Truncating Mutations: A Small Sample Study

Brain Proteomic Profiling in Intractable Epilepsy Caused by TSC1 Truncating Mutations: A Small Sample Study

Global ribosome profiling reveals that mutant huntingtin stalls ribosomes and represses protein synthesis independent of fragile X mental retardation protein

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