TY  - JOUR
A1  - Briese, Michael
A1  - Saal-Bauernschubert, Lena
A1  - Lüningschrör, Patrick
A1  - Moradi, Mehri
A1  - Dombert, Benjamin
A1  - Surrey, Verena
A1  - Appenzeller, Silke
A1  - Deng, Chunchu
A1  - Jablonka, Sibylle
A1  - Sendtner, Michael
T1  - Loss of Tdp-43 disrupts the axonal transcriptome of motoneurons accompanied by impaired axonal translation and mitochondria function
JF  - Acta Neuropathologica Communications
N2  - Protein inclusions containing the RNA-binding protein TDP-43 are a pathological hallmark of amyotrophic lateral sclerosis and other neurodegenerative disorders. The loss of TDP-43 function that is associated with these inclusions affects post-transcriptional processing of RNAs in multiple ways including pre-mRNA splicing, nucleocytoplasmic transport, modulation of mRNA stability and translation. In contrast, less is known about the role of TDP-43 in axonal RNA metabolism in motoneurons. Here we show that depletion of Tdp-43 in primary motoneurons affects axon growth. This defect is accompanied by subcellular transcriptome alterations in the axonal and somatodendritic compartment. The axonal localization of transcripts encoding components of the cytoskeleton, the translational machinery and transcripts involved in mitochondrial energy metabolism were particularly affected by loss of Tdp-43. Accordingly, we observed reduced protein synthesis and disturbed mitochondrial functions in axons of Tdp-43-depleted motoneurons. Treatment with nicotinamide rescued the axon growth defect associated with loss of Tdp-43. These results show that Tdp-43 depletion in motoneurons affects several pathways integral to axon health indicating that loss of TDP-43 function could thus make a major contribution to axonal pathomechanisms in ALS.
KW  - amyotrophic lateral sclerosis
KW  - Tdp-43
KW  - axonal transcriptome
KW  - nicotinamide
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230322
VL  - 8
ER  -