2. Academic Validation
  3. Peptidylprolyl isomerase A governs TARDBP function and assembly in heterogeneous nuclear ribonucleoprotein complexes

Peptidylprolyl isomerase A governs TARDBP function and assembly in heterogeneous nuclear ribonucleoprotein complexes

  • Brain. 2015 Apr;138(Pt 4):974-91. doi: 10.1093/brain/awv005.
Eliana Lauranzano 1,  Silvia Pozzi 1,  Laura Pasetto 2,  Riccardo Stucchi 1,  Tania Massignan 1,  Katia Paolella 2,  Melissa Mombrini 2,  Giovanni Nardo 3,  Christian Lunetta 4,  Massimo Corbo 5,  Gabriele Mora 6,  Caterina Bendotti 3,  Valentina Bonetto 7
Affiliations

Affiliations

  • 1 1 Dulbecco Telethon Institute, IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Via La Masa 19, 20156 Milano, Italy.
  • 2 2 Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Via La Masa 19, 20156 Milano, Italy.
  • 3 3 Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Via La Masa 19, 20156 Milano, Italy.
  • 4 4 NeuroMuscular Omnicentre (NEMO), Niguarda Cà Granda Hospital, Piazza Ospedale Maggiore, 3, 20162 Milano, Italy.
  • 5 5 Department of Neurorehabilitation Sciences, Casa Cura Policlinico, Via Dezza 48, 20144 Milano, Italy.
  • 6 6 IRCCS Fondazione Salvatore Maugeri, Via Camaldoli 64, 20138 Milano, Italy.
  • 7 1 Dulbecco Telethon Institute, IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Via La Masa 19, 20156 Milano, Italy valentina.bonetto@marionegri.it.
PMID: 25678563 DOI: 10.1093/brain/awv005
Abstract

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.

Keywords

RNA metabolism; TDP-43; aggregation; cyclophilin A; heterogeneous nuclear ribonucleoprotein.

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