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Single Cell ADNP Predictive of Human Muscle Disorders: Mouse Knockdown Results in Muscle Wasting

Activity-dependent neuroprotective protein (ADNP) mutations are linked with cognitive dysfunctions characterizing the autistic-like ADNP syndrome patients, who also suffer from delayed motor maturation. We thus hypothesized that ADNP is deregulated in versatile myopathies and that local ADNP muscle...

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Autores principales: Kapitansky, Oxana, Karmon, Gidon, Sragovich, Shlomo, Hadar, Adva, Shahoha, Meishar, Jaljuli, Iman, Bikovski, Lior, Giladi, Eliezer, Palovics, Robert, Iram, Tal, Gozes, Illana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603382/
https://www.ncbi.nlm.nih.gov/pubmed/33086621
http://dx.doi.org/10.3390/cells9102320
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author Kapitansky, Oxana
Karmon, Gidon
Sragovich, Shlomo
Hadar, Adva
Shahoha, Meishar
Jaljuli, Iman
Bikovski, Lior
Giladi, Eliezer
Palovics, Robert
Iram, Tal
Gozes, Illana
author_facet Kapitansky, Oxana
Karmon, Gidon
Sragovich, Shlomo
Hadar, Adva
Shahoha, Meishar
Jaljuli, Iman
Bikovski, Lior
Giladi, Eliezer
Palovics, Robert
Iram, Tal
Gozes, Illana
author_sort Kapitansky, Oxana
collection PubMed
description Activity-dependent neuroprotective protein (ADNP) mutations are linked with cognitive dysfunctions characterizing the autistic-like ADNP syndrome patients, who also suffer from delayed motor maturation. We thus hypothesized that ADNP is deregulated in versatile myopathies and that local ADNP muscle deficiency results in myopathy, treatable by the ADNP fragment NAP. Here, single-cell transcriptomics identified ADNP as a major constituent of the developing human muscle. ADNP transcript concentrations further predicted multiple human muscle diseases, with concentrations negatively correlated with the ADNP target interacting protein, microtubule end protein 1 (EB1). Reverting back to modeling at the single-cell level of the male mouse transcriptome, Adnp mRNA concentrations age-dependently correlated with motor disease as well as with sexual maturation gene transcripts, while Adnp expressing limb muscle cells significantly decreased with aging. Mouse Adnp heterozygous deficiency exhibited muscle microtubule reduction and myosin light chain (Myl2) deregulation coupled with motor dysfunction. CRISPR knockdown of adult gastrocnemius muscle Adnp in a Cas9 mouse resulted in treadmill (male) and gait (female) dysfunctions that were specifically ameliorated by treatment with the ADNP snippet, microtubule interacting, Myl2—regulating, NAP (CP201). Taken together, our studies provide new hope for personalized diagnosis/therapeutics in versatile myopathies.
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spelling pubmed-76033822020-11-01 Single Cell ADNP Predictive of Human Muscle Disorders: Mouse Knockdown Results in Muscle Wasting Kapitansky, Oxana Karmon, Gidon Sragovich, Shlomo Hadar, Adva Shahoha, Meishar Jaljuli, Iman Bikovski, Lior Giladi, Eliezer Palovics, Robert Iram, Tal Gozes, Illana Cells Article Activity-dependent neuroprotective protein (ADNP) mutations are linked with cognitive dysfunctions characterizing the autistic-like ADNP syndrome patients, who also suffer from delayed motor maturation. We thus hypothesized that ADNP is deregulated in versatile myopathies and that local ADNP muscle deficiency results in myopathy, treatable by the ADNP fragment NAP. Here, single-cell transcriptomics identified ADNP as a major constituent of the developing human muscle. ADNP transcript concentrations further predicted multiple human muscle diseases, with concentrations negatively correlated with the ADNP target interacting protein, microtubule end protein 1 (EB1). Reverting back to modeling at the single-cell level of the male mouse transcriptome, Adnp mRNA concentrations age-dependently correlated with motor disease as well as with sexual maturation gene transcripts, while Adnp expressing limb muscle cells significantly decreased with aging. Mouse Adnp heterozygous deficiency exhibited muscle microtubule reduction and myosin light chain (Myl2) deregulation coupled with motor dysfunction. CRISPR knockdown of adult gastrocnemius muscle Adnp in a Cas9 mouse resulted in treadmill (male) and gait (female) dysfunctions that were specifically ameliorated by treatment with the ADNP snippet, microtubule interacting, Myl2—regulating, NAP (CP201). Taken together, our studies provide new hope for personalized diagnosis/therapeutics in versatile myopathies. MDPI 2020-10-19 /pmc/articles/PMC7603382/ /pubmed/33086621 http://dx.doi.org/10.3390/cells9102320 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kapitansky, Oxana
Karmon, Gidon
Sragovich, Shlomo
Hadar, Adva
Shahoha, Meishar
Jaljuli, Iman
Bikovski, Lior
Giladi, Eliezer
Palovics, Robert
Iram, Tal
Gozes, Illana
Single Cell ADNP Predictive of Human Muscle Disorders: Mouse Knockdown Results in Muscle Wasting
title Single Cell ADNP Predictive of Human Muscle Disorders: Mouse Knockdown Results in Muscle Wasting
title_full Single Cell ADNP Predictive of Human Muscle Disorders: Mouse Knockdown Results in Muscle Wasting
title_fullStr Single Cell ADNP Predictive of Human Muscle Disorders: Mouse Knockdown Results in Muscle Wasting
title_full_unstemmed Single Cell ADNP Predictive of Human Muscle Disorders: Mouse Knockdown Results in Muscle Wasting
title_short Single Cell ADNP Predictive of Human Muscle Disorders: Mouse Knockdown Results in Muscle Wasting
title_sort single cell adnp predictive of human muscle disorders: mouse knockdown results in muscle wasting
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603382/
https://www.ncbi.nlm.nih.gov/pubmed/33086621
http://dx.doi.org/10.3390/cells9102320
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