Cargando…

Wild type human TDP-43 potentiates ALS-linked mutant TDP-43 driven progressive motor and cortical neuron degeneration with pathological features of ALS

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disorder, and cytoplasmic inclusions containing transactive response (TAR) DNA binding protein (TDP-43) are present in ~90 % of cases. Here we report detailed pathology in human TDP-43 transgenic mice t...

Descripción completa

Detalles Bibliográficos
Autores principales: Mitchell, Jacqueline C, Constable, Remy, So, Eva, Vance, Caroline, Scotter, Emma, Glover, Leanne, Hortobagyi, Tibor, Arnold, Eveline S., Ling, Shuo-Chien, McAlonis, Melissa, Da Cruz, Sandrine, Polymenidou, Magda, Tessarolo, Lino, Cleveland, Don W, Shaw, Christopher E
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4479086/
https://www.ncbi.nlm.nih.gov/pubmed/26108367
http://dx.doi.org/10.1186/s40478-015-0212-4
_version_ 1782377972976582656
author Mitchell, Jacqueline C
Constable, Remy
So, Eva
Vance, Caroline
Scotter, Emma
Glover, Leanne
Hortobagyi, Tibor
Arnold, Eveline S.
Ling, Shuo-Chien
McAlonis, Melissa
Da Cruz, Sandrine
Polymenidou, Magda
Tessarolo, Lino
Cleveland, Don W
Shaw, Christopher E
author_facet Mitchell, Jacqueline C
Constable, Remy
So, Eva
Vance, Caroline
Scotter, Emma
Glover, Leanne
Hortobagyi, Tibor
Arnold, Eveline S.
Ling, Shuo-Chien
McAlonis, Melissa
Da Cruz, Sandrine
Polymenidou, Magda
Tessarolo, Lino
Cleveland, Don W
Shaw, Christopher E
author_sort Mitchell, Jacqueline C
collection PubMed
description INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disorder, and cytoplasmic inclusions containing transactive response (TAR) DNA binding protein (TDP-43) are present in ~90 % of cases. Here we report detailed pathology in human TDP-43 transgenic mice that recapitulate key features of TDP-43-linked ALS. RESULTS: Expression of human wild-type TDP-43 (TDP-43(WT)) caused no clinical or pathological phenotype, while expression of Q331K mutant (TDP-43(Q331K)) resulted in a non-lethal age-dependent motor phenotype, accompanied by cytoplasmic TDP-43 aggregation, mild neuronal loss, with astroglial and microglial activation in the motor cortex and spinal cord at 24 months. However, co-expression of WT and Q331K mutant (TDP-43(WTxQ331K)) resulted in an extremely aggressive motor phenotype with tremor from 3 weeks and progressive hind-limb paralysis necessitating euthanasia by 8–10 weeks of age. Neuronal loss and reactive gliosis was observed in the spinal cord and layer V region of the cortex, with TDP-43, ubiquitin and p62 cytoplasmic inclusions and an increase in insoluble TDP-43. Nuclear clearance of TDP-43 was not observed in TDP-43(Q331K) mice but was seen in 65 % of aggregate containing spinal cord motor neurons in TDP-43(WTxQ331K) mice. CONCLUSIONS: We hypothesise that cytoplasmic TDP-43(Q331K) aggregates facilitate the recruitment of WT protein in compound animals, which dramatically accelerates neurodegeneration and disease progression. The exploration of disease mechanisms in slow and rapid disease models of TDP-43 proteinopathy will help elucidate novel drug targets and provide a more informative platform for preclinical trials. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40478-015-0212-4) contains supplementary material, which is available to authorized users.
format Online
Article
Text
id pubmed-4479086
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-44790862015-06-25 Wild type human TDP-43 potentiates ALS-linked mutant TDP-43 driven progressive motor and cortical neuron degeneration with pathological features of ALS Mitchell, Jacqueline C Constable, Remy So, Eva Vance, Caroline Scotter, Emma Glover, Leanne Hortobagyi, Tibor Arnold, Eveline S. Ling, Shuo-Chien McAlonis, Melissa Da Cruz, Sandrine Polymenidou, Magda Tessarolo, Lino Cleveland, Don W Shaw, Christopher E Acta Neuropathol Commun Research INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disorder, and cytoplasmic inclusions containing transactive response (TAR) DNA binding protein (TDP-43) are present in ~90 % of cases. Here we report detailed pathology in human TDP-43 transgenic mice that recapitulate key features of TDP-43-linked ALS. RESULTS: Expression of human wild-type TDP-43 (TDP-43(WT)) caused no clinical or pathological phenotype, while expression of Q331K mutant (TDP-43(Q331K)) resulted in a non-lethal age-dependent motor phenotype, accompanied by cytoplasmic TDP-43 aggregation, mild neuronal loss, with astroglial and microglial activation in the motor cortex and spinal cord at 24 months. However, co-expression of WT and Q331K mutant (TDP-43(WTxQ331K)) resulted in an extremely aggressive motor phenotype with tremor from 3 weeks and progressive hind-limb paralysis necessitating euthanasia by 8–10 weeks of age. Neuronal loss and reactive gliosis was observed in the spinal cord and layer V region of the cortex, with TDP-43, ubiquitin and p62 cytoplasmic inclusions and an increase in insoluble TDP-43. Nuclear clearance of TDP-43 was not observed in TDP-43(Q331K) mice but was seen in 65 % of aggregate containing spinal cord motor neurons in TDP-43(WTxQ331K) mice. CONCLUSIONS: We hypothesise that cytoplasmic TDP-43(Q331K) aggregates facilitate the recruitment of WT protein in compound animals, which dramatically accelerates neurodegeneration and disease progression. The exploration of disease mechanisms in slow and rapid disease models of TDP-43 proteinopathy will help elucidate novel drug targets and provide a more informative platform for preclinical trials. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40478-015-0212-4) contains supplementary material, which is available to authorized users. BioMed Central 2015-06-25 /pmc/articles/PMC4479086/ /pubmed/26108367 http://dx.doi.org/10.1186/s40478-015-0212-4 Text en © Mitchell et al. 2015 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Mitchell, Jacqueline C
Constable, Remy
So, Eva
Vance, Caroline
Scotter, Emma
Glover, Leanne
Hortobagyi, Tibor
Arnold, Eveline S.
Ling, Shuo-Chien
McAlonis, Melissa
Da Cruz, Sandrine
Polymenidou, Magda
Tessarolo, Lino
Cleveland, Don W
Shaw, Christopher E
Wild type human TDP-43 potentiates ALS-linked mutant TDP-43 driven progressive motor and cortical neuron degeneration with pathological features of ALS
title Wild type human TDP-43 potentiates ALS-linked mutant TDP-43 driven progressive motor and cortical neuron degeneration with pathological features of ALS
title_full Wild type human TDP-43 potentiates ALS-linked mutant TDP-43 driven progressive motor and cortical neuron degeneration with pathological features of ALS
title_fullStr Wild type human TDP-43 potentiates ALS-linked mutant TDP-43 driven progressive motor and cortical neuron degeneration with pathological features of ALS
title_full_unstemmed Wild type human TDP-43 potentiates ALS-linked mutant TDP-43 driven progressive motor and cortical neuron degeneration with pathological features of ALS
title_short Wild type human TDP-43 potentiates ALS-linked mutant TDP-43 driven progressive motor and cortical neuron degeneration with pathological features of ALS
title_sort wild type human tdp-43 potentiates als-linked mutant tdp-43 driven progressive motor and cortical neuron degeneration with pathological features of als
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4479086/
https://www.ncbi.nlm.nih.gov/pubmed/26108367
http://dx.doi.org/10.1186/s40478-015-0212-4
work_keys_str_mv AT mitchelljacquelinec wildtypehumantdp43potentiatesalslinkedmutanttdp43drivenprogressivemotorandcorticalneurondegenerationwithpathologicalfeaturesofals
AT constableremy wildtypehumantdp43potentiatesalslinkedmutanttdp43drivenprogressivemotorandcorticalneurondegenerationwithpathologicalfeaturesofals
AT soeva wildtypehumantdp43potentiatesalslinkedmutanttdp43drivenprogressivemotorandcorticalneurondegenerationwithpathologicalfeaturesofals
AT vancecaroline wildtypehumantdp43potentiatesalslinkedmutanttdp43drivenprogressivemotorandcorticalneurondegenerationwithpathologicalfeaturesofals
AT scotteremma wildtypehumantdp43potentiatesalslinkedmutanttdp43drivenprogressivemotorandcorticalneurondegenerationwithpathologicalfeaturesofals
AT gloverleanne wildtypehumantdp43potentiatesalslinkedmutanttdp43drivenprogressivemotorandcorticalneurondegenerationwithpathologicalfeaturesofals
AT hortobagyitibor wildtypehumantdp43potentiatesalslinkedmutanttdp43drivenprogressivemotorandcorticalneurondegenerationwithpathologicalfeaturesofals
AT arnoldevelines wildtypehumantdp43potentiatesalslinkedmutanttdp43drivenprogressivemotorandcorticalneurondegenerationwithpathologicalfeaturesofals
AT lingshuochien wildtypehumantdp43potentiatesalslinkedmutanttdp43drivenprogressivemotorandcorticalneurondegenerationwithpathologicalfeaturesofals
AT mcalonismelissa wildtypehumantdp43potentiatesalslinkedmutanttdp43drivenprogressivemotorandcorticalneurondegenerationwithpathologicalfeaturesofals
AT dacruzsandrine wildtypehumantdp43potentiatesalslinkedmutanttdp43drivenprogressivemotorandcorticalneurondegenerationwithpathologicalfeaturesofals
AT polymenidoumagda wildtypehumantdp43potentiatesalslinkedmutanttdp43drivenprogressivemotorandcorticalneurondegenerationwithpathologicalfeaturesofals
AT tessarololino wildtypehumantdp43potentiatesalslinkedmutanttdp43drivenprogressivemotorandcorticalneurondegenerationwithpathologicalfeaturesofals
AT clevelanddonw wildtypehumantdp43potentiatesalslinkedmutanttdp43drivenprogressivemotorandcorticalneurondegenerationwithpathologicalfeaturesofals
AT shawchristophere wildtypehumantdp43potentiatesalslinkedmutanttdp43drivenprogressivemotorandcorticalneurondegenerationwithpathologicalfeaturesofals