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

Jacqueline C. Mitchell; Remy Constable; Eva So; Caroline Vance; Emma Scotter; Leanne Glover; Tibor Hortobagyi; Eveline S. Arnold; Shuo Chien Ling; Melissa McAlonis; Sandrine Da Cruz; Magda Polymenidou; Lino Tessarolo; Don W. Cleveland; Christopher E. Shaw

doi:10.1186/s40478-015-0212-4

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

Jacqueline C. Mitchell, Remy Constable, Eva So, Caroline Vance, Emma Scotter, Leanne Glover, Tibor Hortobagyi, Eveline S. Arnold, Shuo Chien Ling, Melissa McAlonis, Sandrine Da Cruz, Magda Polymenidou, Lino Tessarolo, Don W. Cleveland, Christopher E. Shaw

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Abstract

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.

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.

Original language	English
Pages (from-to)	36
Number of pages	1
Journal	Acta Neuropathologica Communications
Volume	3
DOIs	https://doi.org/10.1186/s40478-015-0212-4
Publication status	Published - 25 Jun 2015

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Mitchell, J. C., Constable, R., So, E., Vance, C., Scotter, E., Glover, L., Hortobagyi, T., Arnold, E. S., Ling, S. C., McAlonis, M., Da Cruz, S., Polymenidou, M., Tessarolo, L., Cleveland, D. W., & Shaw, C. E. (2015). Wild type human TDP-43 potentiates ALS-linked mutant TDP-43 driven progressive motor and cortical neuron degeneration with pathological features of ALS. Acta Neuropathologica Communications, 3, 36. https://doi.org/10.1186/s40478-015-0212-4

@article{e10e677483ce4f09823e293fddc6d8fd,

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

abstract = "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.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.",

author = "Mitchell, {Jacqueline C.} and Remy Constable and Eva So and Caroline Vance and Emma Scotter and Leanne Glover and Tibor Hortobagyi and Arnold, {Eveline S.} and Ling, {Shuo Chien} and Melissa McAlonis and {Da Cruz}, Sandrine and Magda Polymenidou and Lino Tessarolo and Cleveland, {Don W.} and Shaw, {Christopher E.}",

year = "2015",

month = jun,

day = "25",

doi = "10.1186/s40478-015-0212-4",

language = "English",

volume = "3",

pages = "36",

journal = "Acta Neuropathologica Communications",

issn = "2051-5960",

publisher = "BioMed Central",

}

Mitchell, JC, Constable, R, So, E , Vance, C , Scotter, E , Glover, L , Hortobagyi, T, Arnold, ES, Ling, SC, McAlonis, M, Da Cruz, S, Polymenidou, M, Tessarolo, L, Cleveland, DW & Shaw, CE 2015, 'Wild type human TDP-43 potentiates ALS-linked mutant TDP-43 driven progressive motor and cortical neuron degeneration with pathological features of ALS', Acta Neuropathologica Communications, vol. 3, pp. 36. https://doi.org/10.1186/s40478-015-0212-4

TY - JOUR

T1 - Wild type human TDP-43 potentiates ALS-linked mutant TDP-43 driven progressive motor and cortical neuron degeneration with pathological features of ALS

AU - Mitchell, Jacqueline C.

AU - Constable, Remy

AU - So, Eva

AU - Vance, Caroline

AU - Scotter, Emma

AU - Glover, Leanne

AU - Hortobagyi, Tibor

AU - Arnold, Eveline S.

AU - Ling, Shuo Chien

AU - McAlonis, Melissa

AU - Da Cruz, Sandrine

AU - Polymenidou, Magda

AU - Tessarolo, Lino

AU - Cleveland, Don W.

AU - Shaw, Christopher E.

PY - 2015/6/25

Y1 - 2015/6/25

N2 - 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.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.

AB - 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.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.

UR - http://www.scopus.com/inward/record.url?scp=85016021987&partnerID=8YFLogxK

U2 - 10.1186/s40478-015-0212-4

DO - 10.1186/s40478-015-0212-4

M3 - Article

C2 - 26108367

AN - SCOPUS:85016021987

SN - 2051-5960

VL - 3

SP - 36

JO - Acta Neuropathologica Communications

JF - Acta Neuropathologica Communications

ER -

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

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