Expression of mutant TDP-43 induces neuronal dysfunction in transgenic mice.
BACKGROUND
Abnormal distribution, modification and aggregation of transactivation response DNA-binding protein 43 (TDP-43) are the hallmarks of multiple neurodegenerative diseases, especially frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS). Researchers have identified 44 mutations in the TARDBP gene that encode TDP-43 as causative for cases of sporadic and familial ALS http://www.molgen.ua.ac.be/FTDMutations/. Certain mutant forms of TDP-43, such as M337V, are associated with increased low molecular weight (LMW) fragments compared to wild-type (WT) TDP-43 and cause neuronal apoptosis and developmental delay in chick embryos. Such findings support a direct link between altered TDP-43 function and neurodegeneration.


RESULTS
To explore the pathogenic properties of the M337V mutation, we generated and characterized two mouse lines expressing human TDP-43 (hTDP-43(M337V)) carrying this mutation. hTDP-43(M337V) was expressed primarily in the nuclei of neurons in the brain and spinal cord, and intranuclear and cytoplasmic phosphorylated TDP-43 aggregates were frequently detected. The levels of TDP-43 LMW products of ~25 kDa and ~35 kDa species were also increased in the transgenic mice. Moreover, overexpression of hTDP-43(M337V) dramatically down regulated the levels of mouse TDP-43 (mTDP-43) protein and RNA, indicating TDP-43 levels are tightly controlled in mammalian systems. TDP-43M337V mice displayed reactive gliosis, widespread ubiquitination, chromatolysis, gait abnormalities, and early lethality. Abnormal cytoplasmic mitochondrial aggregates and abnormal phosphorylated tau were also detected in the mice.


CONCLUSIONS
Our novel TDP-43M337V mouse model indicates that overexpression of hTDP-43(M337V) alone is toxic in vivo. Because overexpression of hTDP-43 in wild-type TDP-43 and TDP-43M337V mouse models produces similar phenotypes, the mechanisms causing pathogenesis in the mutant model remain unknown. However, our results suggest that overexpression of the hTDP-43(M337V) can cause neuronal dysfunction due to its effect on a number of cell organelles and proteins, such as mitochondria and TDP-43, that are critical for neuronal activity. The mutant model will serve as a valuable tool in the development of future studies designed to uncover pathways associated with TDP-43 neurotoxicity and the precise roles TDP-43 RNA targets play in neurodegeneration.
Department of Neuroscience, Mayo Clinic, Jacksonville, 32224, USA.
Ya-Fei
YF
Xu
Yong-Jie
YJ
Zhang
Wen-Lang
WL
Lin
Xiangkun
X
Cao
Caroline
C
Stetler
Dennis W
DW
Dickson
Jada
J
Lewis
Leonard
L
Petrucelli
D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D009069:Movement Disorders / Q000473:pathology / Q000503:physiopathology; D009154:Mutation; D009410:Nerve Degeneration / Q000473:pathology / Q000503:physiopathology*; D019636:Neurodegenerative Diseases / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000166:cytology / Q000473:pathology / Q000502:physiology*; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
D004268:DNA-Binding Proteins; D016875:tau Proteins