TY  - JOUR
AU  - Khosravi, Bahram
AU  - Hartmann, Hannelore
AU  - May, Stephanie
AU  - Möhl, Christoph
AU  - Ederle, Helena
AU  - Michaelsen, Meike
AU  - Schludi, Martin H
AU  - Dormann, Dorothee
AU  - Edbauer, Dieter
TI  - Cytoplasmic poly-GA aggregates impair nuclear import of TDP-43 in C9orf72 ALS/FTLD.
JO  - Human molecular genetics
VL  - 26
IS  - 4
SN  - 0964-6906
CY  - Oxford
PB  - Oxford Univ. Press
M1  - DZNE-2020-05449
SP  - ddw432
PY  - 2017
AB  - A repeat expansion in the non-coding region of C9orf72 gene is the most common mutation causing frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Sense and antisense transcripts are translated into aggregating dipeptide repeat (DPR) proteins in all reading frames (poly-GA,-GP,-GR,-PA and -PR) through an unconventional mechanism. How these changes contribute to cytoplasmic mislocalization and aggregation of TDP-43 and thereby ultimately leading to neuron loss remains unclear. The repeat RNA itself and poly-GR/PR have been linked to impaired nucleocytoplasmic transport. Here, we show that compact cytoplasmic poly-GA aggregates impair nuclear import of a reporter containing the TDP-43 nuclear localization (NLS) signal. However, a reporter containing a non-classical PY-NLS was not affected. Moreover, poly-GA expression prevents TNFα induced nuclear translocation of p65 suggesting that poly-GA predominantly impairs the importin-α/β-dependent pathway. In neurons, prolonged poly-GA expression induces partial mislocalization of TDP-43 into cytoplasmic granules. Rerouting poly-GA to the nucleus prevented TDP-43 mislocalization, suggesting a cytoplasmic mechanism. In rescue experiments, expression of importin-α (KPNA3, KPNA4) or nucleoporins (NUP54, NUP62) restores the nuclear localization of the TDP reporter. Taken together, inhibition of nuclear import of TDP-43 by cytoplasmic poly-GA inclusions causally links the two main aggregating proteins in C9orf72 ALS/FTLD pathogenesis.
KW  - Amyotrophic Lateral Sclerosis: genetics
KW  - Amyotrophic Lateral Sclerosis: metabolism
KW  - Amyotrophic Lateral Sclerosis: pathology
KW  - Animals
KW  - C9orf72 Protein
KW  - DNA Repeat Expansion
KW  - DNA-Binding Proteins: genetics
KW  - DNA-Binding Proteins: metabolism
KW  - Frontotemporal Lobar Degeneration: genetics
KW  - Frontotemporal Lobar Degeneration: metabolism
KW  - Frontotemporal Lobar Degeneration: pathology
KW  - Humans
KW  - Inclusion Bodies: genetics
KW  - Inclusion Bodies: metabolism
KW  - Membrane Glycoproteins: genetics
KW  - Membrane Glycoproteins: metabolism
KW  - Neurons: metabolism
KW  - Nuclear Localization Signals: genetics
KW  - Nuclear Localization Signals: metabolism
KW  - Nuclear Pore Complex Proteins: genetics
KW  - Nuclear Pore Complex Proteins: metabolism
KW  - Proteins: genetics
KW  - Proteins: metabolism
KW  - Rats
KW  - Tumor Necrosis Factor-alpha: genetics
KW  - Tumor Necrosis Factor-alpha: metabolism
KW  - alpha Karyopherins: genetics
KW  - alpha Karyopherins: metabolism
KW  - C9orf72 Protein (NLM Chemicals)
KW  - C9orf72 protein, human (NLM Chemicals)
KW  - DNA-Binding Proteins (NLM Chemicals)
KW  - KPNA3 protein, human (NLM Chemicals)
KW  - KPNA4 protein, human (NLM Chemicals)
KW  - Membrane Glycoproteins (NLM Chemicals)
KW  - Nuclear Localization Signals (NLM Chemicals)
KW  - Nuclear Pore Complex Proteins (NLM Chemicals)
KW  - Proteins (NLM Chemicals)
KW  - TDP-43 protein, human (NLM Chemicals)
KW  - Tumor Necrosis Factor-alpha (NLM Chemicals)
KW  - alpha Karyopherins (NLM Chemicals)
KW  - nuclear pore protein p62 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:28040728
C2  - pmc:PMC5409121
DO  - DOI:10.1093/hmg/ddw432
UR  - https://pub.dzne.de/record/139127
ER  -