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2015 ; 43
(18
): 8990-9005
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gab.com Text
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TDP-43 affects splicing profiles and isoform production of genes involved in the
apoptotic and mitotic cellular pathways
#MMPMID26261209
De Conti L
; Akinyi MV
; Mendoza-Maldonado R
; Romano M
; Baralle M
; Buratti E
Nucleic Acids Res
2015[Oct]; 43
(18
): 8990-9005
PMID26261209
show ga
In recent times, high-throughput screening analyses have broadly defined the RNA
cellular targets of TDP-43, a nuclear factor involved in neurodegeneration. A
common outcome of all these studies is that changing the expression levels of
this protein can alter the expression of several hundred RNAs within cells. What
still remains to be clarified is which changes represent direct cellular targets
of TDP-43 or just secondary variations due to the general role played by this
protein in RNA metabolism. Using an HTS-based splicing junction analysis we
identified at least six bona fide splicing events that are consistent with being
controlled by TDP-43. Validation of the data, both in neuronal and non-neuronal
cell lines demonstrated that TDP-43 substantially alters the levels of isoform
expression in four genes potentially important for neuropathology: MADD/IG20,
STAG2, FNIP1 and BRD8. For MADD/IG20 and STAG2, these changes could also be
confirmed at the protein level. These alterations were also observed in a
cellular model that successfully mimics TDP-43 loss of function effects following
its aggregation. Most importantly, our study demonstrates that cell cycle
alterations induced by TDP-43 knockdown can be recovered by restoring the STAG2,
an important component of the cohesin complex, normal splicing profile.