ArticleBrain : a journal of neurology2021
Defective cyclophilin A induces TDP-43 proteinopathy: implications for amyotrophic lateral sclerosis and frontotemporal dementia.
Article in Brain : a journal of neurology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 30 citations in OpenAlex.
- Effect of RNS60 in amyotrophic lateral sclerosis: a phase II multicentre, randomized, double-blind, placebo-controlled trial.European journal of neurology · 2023Trial
- Human Brain Contusions Contain Pathogenic Transmissible Species that Induce Progressive Cognitive Decline and Tau Pathology in Mice.Annals of neurology · 2026Article
- Beyond motor neurons: peripheral TDP-43 pathology in skeletal muscle and intramuscular nerves in amyotrophic lateral sclerosis.Brain communications · 2026Review
- Cerebrospinal fluid proteomic signatures in cognitively normal individuals identify distinct clusters linked to neurodegeneration.Nature aging · 2025Article
- A Disease-Associated Mutation Impedes PPIA through Allosteric Dynamics Modulation.Biochemistry · 2025Article
- Challenges of modelling TDP-43 pathology in mice.Mammalian genome : official journal of the International Mammalian Genome Society · 2025Review
- Inflammatory proteins as acute biomarkers of post-traumatic epilepsy.Frontiers in neurology · 2025Article
- A novel role for the peptidyl-prolyl cis-trans isomerase Cyclophilin A in DNA-repair following replication fork stalling via the MRE11-RAD50-NBS1 complex.EMBO reports · 2024Article
- Multiomic ALS signatures highlight subclusters and sex differences suggesting the MAPK pathway as therapeutic target.Nature communications · 2024Article
- Drug Screening and Validation Targeting TDP-43 Proteinopathy for Amyotrophic Lateral Sclerosis.Aging and disease · 2024Review
- Conserved region of human TDP-43 is structurally similar to membrane binding protein FARP1 and protein chaperons BAG6 and CYP33.microPublication biology · 2024Article
- Cyclophilin inhibition as a strategy for the treatment of human disease.Frontiers in pharmacology · 2024Review
- Transactive response DNA-binding protein 43 is enriched at the centrosome in human cells.Brain : a journal of neurology · 2023Article
- Identifying novel genes for amyotrophic lateral sclerosis by integrating human brain proteomes with genome-wide association data.Journal of neurology · 2023Article
- Synaptic Dysfunction and Plasticity in Amyotrophic Lateral Sclerosis.International journal of molecular sciences · 2023Review
- Review
- The positive impact on translational research of Fondazione italiana di ricerca per la Sclerosi Laterale Amiotrofica (AriSLA), a non-profit foundation focused on amyotrophic lateral sclerosis. Convergence of ex-ante evaluation and ex-post outcomes when goals are set upfront.Frontiers in research metrics and analytics · 2023Article
- Chaperoning activity of the cyclophilin family prevents tau aggregation.Protein science : a publication of the Protein Society · 2022Article
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Authors and funding
21 authors at 5 institutions in 3 countries.
Funding
Abstract
Aggregation and cytoplasmic mislocalization of TDP-43 are pathological hallmarks of amyotrophic lateral sclerosis and frontotemporal dementia spectrum. However, the molecular mechanism by which TDP-43 aggregates form and cause neurodegeneration remains poorly understood. Cyclophilin A, also known as peptidyl-prolyl cis-trans isomerase A (PPIA), is a foldase and molecular chaperone. We previously found that PPIA interacts with TDP-43 and governs some of its functions, and its deficiency accelerates disease in a mouse model of amyotrophic lateral sclerosis. Here we characterized PPIA knock-out mice throughout their lifespan and found that they develop a neurodegenerative disease with key behavioural features of frontotemporal dementia, marked TDP-43 pathology and late-onset motor dysfunction. In the mouse brain, deficient PPIA induces mislocalization and aggregation of the GTP-binding nuclear protein Ran, a PPIA interactor and a master regulator of nucleocytoplasmic transport, also for TDP-43. Moreover, in absence of PPIA, TDP-43 autoregulation is perturbed and TDP-43 and proteins involved in synaptic function are downregulated, leading to impairment of synaptic plasticity. Finally, we found that PPIA was downregulated in several patients with amyotrophic lateral sclerosis and amyotrophic lateral sclerosis-frontotemporal dementia, and identified a PPIA loss-of-function mutation in a patient with sporadic amyotrophic lateral sclerosis . The mutant PPIA has low stability, altered structure and impaired interaction with TDP-43. These findings strongly implicate that defective PPIA function causes TDP-43 mislocalization and dysfunction and should be considered in future therapeutic approaches.
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