Elevated expression of TDP-43 in the forebrain of mice is sufficient to cause neurological and pathological phenotypes mimicking FTLD-U.
TDP-43 is a multifunctional DNA/RNA-binding factor that has been implicated in the regulation of neuronal plasticity. TDP-43 has also been identified as the major constituent of the neuronal cytoplasmic inclusions (NCIs) that are characteristic of a range of neurodegenerative diseases, including the frontotemporal lobar degeneration with ubiquitin(+) inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS). We have generated a FTLD-U mouse model (CaMKII-TDP-43 Tg) in which TDP-43 is transgenically overexpressed in the forebrain resulting in phenotypic characteristics mimicking those of FTLD-U. In particular, the transgenic (Tg) mice exhibit impaired learning/memory, progressive motor dysfunction, and hippocampal atrophy. The cognitive and motor impairments are accompanied by reduced levels of the neuronal regulators phospho-extracellular signal-regulated kinase and phosphorylated cAMP response element-binding protein and increased levels of gliosis in the brains of the Tg mice. Moreover, cells with TDP-43(+), ubiquitin(+) NCIs and TDP-43-deleted nuclei appear in the Tg mouse brains in an age-dependent manner. Our data provide direct evidence that increased levels of TDP-43 protein in the forebrain is sufficient to lead to the formation of TDP-43(+), ubiquitin(+) NCIs and neurodegeneration. This FTLD-U mouse model should be valuable for the mechanistic analysis of the role of TDP-43 in the pathogenesis of FTLD-U and for the design of effective therapeutic approaches of the disease.
Tsai
Kuen-Jer
KJ
Institute of Clinical Medicine, National Cheng Kung University, Tainan 704, Taiwan.
Yang
Chun-Hung
CH
Fang
Yen-Hsin
YH
Cho
Kuan-Hung
KH
Chien
Wei-Lin
WL
Wang
Wei-Ting
WT
Wu
Tzu-Wei
TW
Lin
Ching-Po
CP
Fu
Wen-Mei
WM
Shen
Che-Kun James
CK
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001284:Atrophy / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics; D053148:Caspase 3 / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D003072:Cognition Disorders / Q000175:diagnosis / Q000209:etiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D055724:Electrophysiological Phenomena / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D057174:Frontotemporal Lobar Degeneration / Q000150:complications / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D015870:Gene Expression / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D017774:Long-Term Potentiation / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011596:Psychomotor Disorders / Q000175:diagnosis / Q000209:etiology; D012021:Reflex, Abnormal; D015996:Survival Rate; D025801:Ubiquitin / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D009419:Nerve Tissue Proteins; D025801:Ubiquitin; C528900:glial fibrillary astrocytic protein, mouse; D005680:gamma-Aminobutyric Acid; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D048049:Extracellular Signal-Regulated MAP Kinases; D053148:Caspase 3; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1