TY - JOUR
T1 - Selective Spatiotemporal Vulnerability of Central Nervous System Neurons to Pathologic TAR DNA-Binding Protein 43 in Aged Transgenic Mice
AU - van Hummel, Annika
AU - Chan, Gabriella
AU - van der Hoven, Julia
AU - Morsch, Marco
AU - Ippati, Stefania
AU - Suh, Lisa
AU - Bi, Mian
AU - Asih, Prita R.
AU - Lee, Wei S.
AU - Butler, Troy A.
AU - Przybyla, Magdalena
AU - Halliday, Glenda M.
AU - Piguet, Olivier
AU - Kiernan, Matthew C.
AU - Chung, Roger S.
AU - Ittner, Lars M.
AU - Ke, Yazi D.
PY - 2018/6
Y1 - 2018/6
N2 - Amyotrophic lateral sclerosis (ALS) is a rapidly progressing and fatal disease characterized by muscular atrophy because of loss of upper and lower motor neurons. Histopathologically, most patients with ALS have abnormal cytoplasmic accumulation and aggregation of the nuclear RNA-regulating protein TAR DNA-binding protein 43 (TDP-43). Pathogenic mutations in the TARDBP gene that encode TDP-43 have been identified in familial ALS. We have previously reported transgenic mice with neuronal expression of human TDP-43 carrying the pathogenic A315T mutation (iTDP-43A315T mice), presenting with early-onset motor deficits in adolescent animals. Here, we analyzed aged iTDP-43A315T mice, focusing on the spatiotemporal profile and progression of neurodegeneration in upper and lower motor neurons. Magnetic resonance imaging and histologic analysis revealed a differential loss of upper motor neurons in a hierarchical order as iTDP-43A315T mice aged. Furthermore, we report progressive gait problems, profound motor deficits, and muscle atrophy in aged iTDP-43A315T mice. Despite these deficits and TDP-43 pathologic disorders in lower motor neurons, stereological analysis did not show cell loss in spinal cords. Taken together, neuronal populations in aging iTDP-43A315T mice show differential susceptibility to the expression of human TDP-43A315T.
AB - Amyotrophic lateral sclerosis (ALS) is a rapidly progressing and fatal disease characterized by muscular atrophy because of loss of upper and lower motor neurons. Histopathologically, most patients with ALS have abnormal cytoplasmic accumulation and aggregation of the nuclear RNA-regulating protein TAR DNA-binding protein 43 (TDP-43). Pathogenic mutations in the TARDBP gene that encode TDP-43 have been identified in familial ALS. We have previously reported transgenic mice with neuronal expression of human TDP-43 carrying the pathogenic A315T mutation (iTDP-43A315T mice), presenting with early-onset motor deficits in adolescent animals. Here, we analyzed aged iTDP-43A315T mice, focusing on the spatiotemporal profile and progression of neurodegeneration in upper and lower motor neurons. Magnetic resonance imaging and histologic analysis revealed a differential loss of upper motor neurons in a hierarchical order as iTDP-43A315T mice aged. Furthermore, we report progressive gait problems, profound motor deficits, and muscle atrophy in aged iTDP-43A315T mice. Despite these deficits and TDP-43 pathologic disorders in lower motor neurons, stereological analysis did not show cell loss in spinal cords. Taken together, neuronal populations in aging iTDP-43A315T mice show differential susceptibility to the expression of human TDP-43A315T.
KW - Amyotrophic lateral sclerosis (ALS)
KW - muscular atrophy
KW - abnormal cytoplasmic accumulation
KW - TAR DNA-binding protein 43 (TDP-43)
KW - pathogenic A315T mutation
KW - iTDP-43A315T mice
UR - http://purl.org/au-research/grants/NHMRC/1037746
UR - http://purl.org/au-research/grants/NHMRC/1081916
UR - http://purl.org/au-research/grants/NHMRC/1132524
UR - http://purl.org/au-research/grants/NHMRC/1143848
UR - http://purl.org/au-research/grants/NHMRC/1095215
UR - http://purl.org/au-research/grants/NHMRC/1143978
UR - http://purl.org/au-research/grants/ARC/DP150104321
UR - http://purl.org/au-research/grants/ARC/DP170100781
UR - http://purl.org/au-research/grants/ARC/DP170100843
UR - http://purl.org/au-research/grants/NHMRC/1123564
UR - http://purl.org/au-research/grants/NHMRC/1103258
UR - http://purl.org/au-research/grants/NHMRC/1136241
UR - http://www.scopus.com/inward/record.url?scp=85047081665&partnerID=8YFLogxK
U2 - 10.1016/j.ajpath.2018.03.002
DO - 10.1016/j.ajpath.2018.03.002
M3 - Article
VL - 188
SP - 1447
EP - 1456
JO - American Journal of Pathology
JF - American Journal of Pathology
SN - 0002-9440
IS - 6
ER -