Spinal poly-GA inclusions in a C9orf72 mouse model trigger motor deficits and inflammation without neuron loss

Martin H. Schludi; Lore Becker; Lillian Garrett; Tania F. Gendron; Qihui Zhou; Franziska Schreiber; Bastian Popper; Leda Dimou; Tim M. Strom; Juliane Winkelmann; Anne von Thaden; Kristin Rentzsch; Stephanie May; Meike Michaelsen; Benjamin M. Schwenk; Jing Tan; Benedikt Schoser; Marianne Dieterich; Leonard Petrucelli; Sabine M. Hölter; Wolfgang Wurst; Helmut Fuchs; Valerie Gailus-Durner; Martin Hrabe de Angelis; Thomas Klopstock; Thomas Arzberger; Dieter Edbauer

doi:10.1007/s00401-017-1711-0

Spinal poly-GA inclusions in a C9orf72 mouse model trigger motor deficits and inflammation without neuron loss

Martin H. Schludi, Lore Becker, Lillian Garrett, Tania F. Gendron, Qihui Zhou, Franziska Schreiber, Bastian Popper, Leda Dimou, Tim M. Strom, Juliane Winkelmann, Anne von Thaden, Kristin Rentzsch, Stephanie May, Meike Michaelsen, Benjamin M. Schwenk, Jing Tan, Benedikt Schoser, Marianne Dieterich, Leonard Petrucelli, Sabine M. HölterWolfgang Wurst, Helmut Fuchs, Valerie Gailus-Durner, Martin Hrabe de Angelis, Thomas Klopstock, Thomas Arzberger, Dieter Edbauer

Chair of Developmental Genetics

Research output: Contribution to journal › Article › peer-review

92 Scopus citations

Abstract

Translation of the expanded (ggggcc)_n repeat in C9orf72 patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) causes abundant poly-GA inclusions. To elucidate their role in pathogenesis, we generated transgenic mice expressing codon-modified (GA)₁₄₉ conjugated with cyan fluorescent protein (CFP). Transgenic mice progressively developed poly-GA inclusions predominantly in motoneurons and interneurons of the spinal cord and brain stem and in deep cerebellar nuclei. Poly-GA co-aggregated with p62, Rad23b and the newly identified Mlf2, in both mouse and patient samples. Consistent with the expression pattern, 4-month-old transgenic mice showed abnormal gait and progressive balance impairment, but showed normal hippocampus-dependent learning and memory. Apart from microglia activation we detected phosphorylated TDP-43 but no neuronal loss. Thus, poly-GA triggers behavioral deficits through inflammation and protein sequestration that likely contribute to the prodromal symptoms and disease progression of C9orf72 patients.

Original language	English
Pages (from-to)	241-254
Number of pages	14
Journal	Acta Neuropathologica
Volume	134
Issue number	2
DOIs	https://doi.org/10.1007/s00401-017-1711-0
State	Published - 1 Aug 2017

Keywords

ALS
C9orf72
FTD
FTLD
MND
Mouse model
Neurodegeneration
Neurological disorder

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10.1007/s00401-017-1711-0

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Schludi, M. H., Becker, L., Garrett, L., Gendron, T. F., Zhou, Q., Schreiber, F., Popper, B., Dimou, L., Strom, T. M., Winkelmann, J., von Thaden, A., Rentzsch, K., May, S., Michaelsen, M., Schwenk, B. M., Tan, J., Schoser, B., Dieterich, M., Petrucelli, L., ... Edbauer, D. (2017). Spinal poly-GA inclusions in a C9orf72 mouse model trigger motor deficits and inflammation without neuron loss. Acta Neuropathologica, 134(2), 241-254. https://doi.org/10.1007/s00401-017-1711-0

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title = "Spinal poly-GA inclusions in a C9orf72 mouse model trigger motor deficits and inflammation without neuron loss",

abstract = "Translation of the expanded (ggggcc)n repeat in C9orf72 patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) causes abundant poly-GA inclusions. To elucidate their role in pathogenesis, we generated transgenic mice expressing codon-modified (GA)149 conjugated with cyan fluorescent protein (CFP). Transgenic mice progressively developed poly-GA inclusions predominantly in motoneurons and interneurons of the spinal cord and brain stem and in deep cerebellar nuclei. Poly-GA co-aggregated with p62, Rad23b and the newly identified Mlf2, in both mouse and patient samples. Consistent with the expression pattern, 4-month-old transgenic mice showed abnormal gait and progressive balance impairment, but showed normal hippocampus-dependent learning and memory. Apart from microglia activation we detected phosphorylated TDP-43 but no neuronal loss. Thus, poly-GA triggers behavioral deficits through inflammation and protein sequestration that likely contribute to the prodromal symptoms and disease progression of C9orf72 patients.",

keywords = "ALS, C9orf72, FTD, FTLD, MND, Mouse model, Neurodegeneration, Neurological disorder",

author = "Schludi, {Martin H.} and Lore Becker and Lillian Garrett and Gendron, {Tania F.} and Qihui Zhou and Franziska Schreiber and Bastian Popper and Leda Dimou and Strom, {Tim M.} and Juliane Winkelmann and {von Thaden}, Anne and Kristin Rentzsch and Stephanie May and Meike Michaelsen and Schwenk, {Benjamin M.} and Jing Tan and Benedikt Schoser and Marianne Dieterich and Leonard Petrucelli and H{\"o}lter, {Sabine M.} and Wolfgang Wurst and Helmut Fuchs and Valerie Gailus-Durner and {de Angelis}, {Martin Hrabe} and Thomas Klopstock and Thomas Arzberger and Dieter Edbauer",

note = "Publisher Copyright: {\textcopyright} 2017, The Author(s).",

year = "2017",

month = aug,

day = "1",

doi = "10.1007/s00401-017-1711-0",

language = "English",

volume = "134",

pages = "241--254",

journal = "Acta Neuropathologica",

issn = "0001-6322",

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Schludi, MH, Becker, L, Garrett, L, Gendron, TF, Zhou, Q, Schreiber, F, Popper, B, Dimou, L, Strom, TM, Winkelmann, J, von Thaden, A, Rentzsch, K, May, S, Michaelsen, M, Schwenk, BM, Tan, J, Schoser, B, Dieterich, M, Petrucelli, L, Hölter, SM, Wurst, W, Fuchs, H, Gailus-Durner, V, de Angelis, MH, Klopstock, T, Arzberger, T & Edbauer, D 2017, 'Spinal poly-GA inclusions in a C9orf72 mouse model trigger motor deficits and inflammation without neuron loss', Acta Neuropathologica, vol. 134, no. 2, pp. 241-254. https://doi.org/10.1007/s00401-017-1711-0

TY - JOUR

T1 - Spinal poly-GA inclusions in a C9orf72 mouse model trigger motor deficits and inflammation without neuron loss

AU - Schludi, Martin H.

AU - Becker, Lore

AU - Garrett, Lillian

AU - Gendron, Tania F.

AU - Zhou, Qihui

AU - Schreiber, Franziska

AU - Popper, Bastian

AU - Dimou, Leda

AU - Strom, Tim M.

AU - Winkelmann, Juliane

AU - von Thaden, Anne

AU - Rentzsch, Kristin

AU - May, Stephanie

AU - Michaelsen, Meike

AU - Schwenk, Benjamin M.

AU - Tan, Jing

AU - Schoser, Benedikt

AU - Dieterich, Marianne

AU - Petrucelli, Leonard

AU - Hölter, Sabine M.

AU - Wurst, Wolfgang

AU - Fuchs, Helmut

AU - Gailus-Durner, Valerie

AU - de Angelis, Martin Hrabe

AU - Klopstock, Thomas

AU - Arzberger, Thomas

AU - Edbauer, Dieter

PY - 2017/8/1

Y1 - 2017/8/1

N2 - Translation of the expanded (ggggcc)n repeat in C9orf72 patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) causes abundant poly-GA inclusions. To elucidate their role in pathogenesis, we generated transgenic mice expressing codon-modified (GA)149 conjugated with cyan fluorescent protein (CFP). Transgenic mice progressively developed poly-GA inclusions predominantly in motoneurons and interneurons of the spinal cord and brain stem and in deep cerebellar nuclei. Poly-GA co-aggregated with p62, Rad23b and the newly identified Mlf2, in both mouse and patient samples. Consistent with the expression pattern, 4-month-old transgenic mice showed abnormal gait and progressive balance impairment, but showed normal hippocampus-dependent learning and memory. Apart from microglia activation we detected phosphorylated TDP-43 but no neuronal loss. Thus, poly-GA triggers behavioral deficits through inflammation and protein sequestration that likely contribute to the prodromal symptoms and disease progression of C9orf72 patients.

AB - Translation of the expanded (ggggcc)n repeat in C9orf72 patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) causes abundant poly-GA inclusions. To elucidate their role in pathogenesis, we generated transgenic mice expressing codon-modified (GA)149 conjugated with cyan fluorescent protein (CFP). Transgenic mice progressively developed poly-GA inclusions predominantly in motoneurons and interneurons of the spinal cord and brain stem and in deep cerebellar nuclei. Poly-GA co-aggregated with p62, Rad23b and the newly identified Mlf2, in both mouse and patient samples. Consistent with the expression pattern, 4-month-old transgenic mice showed abnormal gait and progressive balance impairment, but showed normal hippocampus-dependent learning and memory. Apart from microglia activation we detected phosphorylated TDP-43 but no neuronal loss. Thus, poly-GA triggers behavioral deficits through inflammation and protein sequestration that likely contribute to the prodromal symptoms and disease progression of C9orf72 patients.

KW - ALS

KW - C9orf72

KW - FTD

KW - FTLD

KW - MND

KW - Mouse model

KW - Neurodegeneration

KW - Neurological disorder

UR - http://www.scopus.com/inward/record.url?scp=85017454628&partnerID=8YFLogxK

U2 - 10.1007/s00401-017-1711-0

DO - 10.1007/s00401-017-1711-0

M3 - Article

C2 - 28409281

AN - SCOPUS:85017454628

SN - 0001-6322

VL - 134

SP - 241

EP - 254

JO - Acta Neuropathologica

JF - Acta Neuropathologica

IS - 2

ER -

Spinal poly-GA inclusions in a C9orf72 mouse model trigger motor deficits and inflammation without neuron loss

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