Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=26334913
&cmd=llinks): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 215
Cytoplasmic mislocalization of RNA splicing factors and aberrant neuronal gene
splicing in TDP-43 transgenic pig brain
#MMPMID26334913
Wang G
; Yang H
; Yan S
; Wang CE
; Liu X
; Zhao B
; Ouyang Z
; Yin P
; Liu Z
; Zhao Y
; Liu T
; Fan N
; Guo L
; Li S
; Li XJ
; Lai L
Mol Neurodegener
2015[Sep]; 10
(?): 42
PMID26334913
show ga
BACKGROUND: TAR DNA-binding protein 43 (TDP-43) is a nuclear protein, but it is
redistributed in the neuronal cytoplasm in both amyotrophic lateral sclerosis
(ALS) and frontotemporal lobar degeneration (FTLD). Because small transgenic
animal models often lack cytoplasmic TDP-43, how the cytoplasmic accumulation of
TDP-43 contributes to these diseases remains unclear. The current study is aimed
at studying the mechanism of cytoplasmic pathology of TDP-43. RESULTS: We
established transgenic pigs expressing mutant TDP-43 (M337V). This pig model
shows severe phenotypes and early death. We found that transgenic TDP-43 is also
distributed in the cytoplasm of neuronal cells in the spinal cord and brain.
Transgenic TDP-43 interacts with PSF, an RNA splicing factor that associates with
NeuN to regulate neuronal RNA splicing. The interaction of TDP-43, PSF and NeuN
causes PSF and NeuN mislocalize into the neuronal cytoplasm in transgenic pigs.
Consistently, abnormal PSF-related neuronal RNA splicing is seen in TDP-43
transgenic pigs. The cytoplasmic localization of PSF and NeuN as well as abnormal
PSF-related neuronal RNA splicing was also found in ALS patient brains.
CONCLUSION: Our findings from a large mammalian model suggest that cytoplasmic
mutant TDP-43 could reduce the nuclear function of RNA splicing factors,
contributing to neuropathology.
free
free
free
