title: Peptidylprolyl isomerase A governs TARDBP function and assembly in heterogeneous nuclear ribonucleoprotein complexes.
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.
authors: 1 Dulbecco Telethon Institute, IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Via La Masa 19, 20156 Milano, Italy.
authors: Eliana
authors: E
authors: Lauranzano
authors: 1 Dulbecco Telethon Institute, IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Via La Masa 19, 20156 Milano, Italy.
authors: Silvia
authors: S
authors: Pozzi
authors: 2 Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Via La Masa 19, 20156 Milano, Italy.
authors: Laura
authors: L
authors: Pasetto
authors: 1 Dulbecco Telethon Institute, IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Via La Masa 19, 20156 Milano, Italy.
authors: Riccardo
authors: R
authors: Stucchi
authors: 1 Dulbecco Telethon Institute, IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Via La Masa 19, 20156 Milano, Italy.
authors: Tania
authors: T
authors: Massignan
authors: 2 Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Via La Masa 19, 20156 Milano, Italy.
authors: Katia
authors: K
authors: Paolella
authors: 2 Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Via La Masa 19, 20156 Milano, Italy.
authors: Melissa
authors: M
authors: Mombrini
authors: 3 Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Via La Masa 19, 20156 Milano, Italy.
authors: Giovanni
authors: G
authors: Nardo
authors: 4 NeuroMuscular Omnicentre (NEMO), Niguarda Cà Granda Hospital, Piazza Ospedale Maggiore, 3, 20162 Milano, Italy.
authors: Christian
authors: C
authors: Lunetta
authors: 5 Department of Neurorehabilitation Sciences, Casa Cura Policlinico, Via Dezza 48, 20144 Milano, Italy.
authors: Massimo
authors: M
authors: Corbo
authors: 6 IRCCS Fondazione Salvatore Maugeri, Via Camaldoli 64, 20138 Milano, Italy.
authors: Gabriele
authors: G
authors: Mora
authors: 3 Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Via La Masa 19, 20156 Milano, Italy.
authors: Caterina
authors: C
authors: Bendotti
authors: 1 Dulbecco Telethon Institute, IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Via La Masa 19, 20156 Milano, Italy valentina.bonetto@marionegri.it.
authors: Valentina
authors: V
authors: Bonetto
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000502:physiology*; D005260:Female; D057809:HEK293 Cells; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008822:Mice, Transgenic; D008875:Middle Aged; D019696:Peptidylprolyl Isomerase / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D034441:Heterogeneous-Nuclear Ribonucleoproteins; C000598624:TARDBP protein, human; D019696:Peptidylprolyl Isomerase
keywords: RNA metabolism; TDP-43; aggregation; cyclophilin A; heterogeneous nuclear ribonucleoprotein