Journal
BRAIN
Volume 138, Issue -, Pages 974-991Publisher
OXFORD UNIV PRESS
DOI: 10.1093/brain/awv005
Keywords
cyclophilin A; aggregation; TDP-43; heterogeneous nuclear ribonucleoprotein; RNA metabolism
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Funding
- Telethon Italy [TCR08002]
- Fondazione Aldo e Cele Dacco
- Italian Ministry of Health [CUP E41J12000220001]
- European Community's Health Seventh Framework Programme (FP7) [259867]
- Fondazione Vialli e Mauro per la ricerca e lo sport
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Peptidylprolyl isomerase A (PPIA) is linked to several diseases, but its role in pathogenesis is unclear. Lauranzano et al. show that PPIA regulates TDP-43 function and that impaired PPIA/TDP-43 interaction causes TDP-43 pathology. Targeting this interaction may have therapeutic potential in disorders including amyotrophic lateral sclerosis and frontotemporal lobar degeneration.Peptidylprolyl isomerase A (PPIA), also known as cyclophilin A, is a multifunctional protein with peptidyl-prolyl cis-trans isomerase activity. PPIA is also a translational biomarker for amyotrophic lateral sclerosis, and is enriched in aggregates isolated from amyotrophic lateral sclerosis and frontotemporal lobar degeneration patients. Its normal function in the central nervous system is unknown. Here we show that PPIA is a functional interacting partner of TARDBP (also known as TDP-43). PPIA regulates expression of known TARDBP RNA targets and is necessary for the assembly of TARDBP in heterogeneous nuclear ribonucleoprotein complexes. Our data suggest that perturbation of PPIA/TARDBP interaction causes 'TDP-43' pathology. Consistent with this model, we show that the PPIA/TARDBP interaction is impaired in several pathological conditions. Moreover, PPIA depletion induces TARDBP aggregation, downregulates HDAC6, ATG7 and VCP, and accelerates disease progression in the SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Targeting the PPIA/TARDBP interaction may represent a novel therapeutic avenue for conditions involving TARDBP/TDP-43 pathology, such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration.
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