Abstract
TDP-43 proteinopathies have been observed in a wide range of neurodegenerative diseases. Mutations in the gene encoding TDP-43 (i.e., TDP) have been identified in amyotrophic lateral sclerosis (ALS) and in frontotemporal lobe degeneration associated with motor neuron disease. To study the consequences of TDP mutation in an intact system, we created transgenic rats expressing normal human TDP or a mutant form of human TDP with a M337V substitution. Overexpression of mutant, but not normal, TDP caused widespread neurodegeneration that predominantly affected the motor system. TDP mutation reproduced ALS phenotypes in transgenic rats, as seen by progressive degeneration of motor neurons and denervation atrophy of skeletal muscles. This robust rat model also recapitulated features of TDP-43 proteinopathies including the formation of TDP-43 inclusions, cytoplasmic localization of phosphorylated TDP-43, and fragmentation of TDP-43 protein. TDP transgenic rats will be useful for deciphering the mechanisms underlying TDP-43–related neurodegenerative diseases.
Highlights
TAR DNA-binding protein (TDP-43) is a highly conserved ribonucleoprotein that is encoded by the TDP gene and can bind to RNA, DNA, and proteins [1,2,3]
TDP-43 proteinopathies have been identified in a wide range of neurodegenerative diseases including sporadic amyotrophic lateral sclerosis (ALS), frontotemporal lobe degeneration (FTLD), Alzheimer’s disease, and dementia with Lewy bodies [5,6,7,8,9], TDP-43 inclusions have not been detected in familial ALS caused by mutation of the SOD1 and FUS genes [10,11,12,13]
These findings suggest that the disease phenotypes observed in the miniTDP43M337V transgenic founder rats result from toxicity of the TDP gene mutation
Summary
TAR DNA-binding protein (TDP-43) is a highly conserved ribonucleoprotein that is encoded by the TDP gene and can bind to RNA, DNA, and proteins [1,2,3]. TDP-43 proteinopathies have been identified in a wide range of neurodegenerative diseases including sporadic ALS, FTLD, Alzheimer’s disease, and dementia with Lewy bodies [5,6,7,8,9], TDP-43 inclusions have not been detected in familial ALS caused by mutation of the SOD1 and FUS genes [10,11,12,13]. These findings imply that TDP-43 proteinopathy is common to neurodegenerative diseases and that divergent pathological processes may underlie sporadic and familial cases of ALS
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