Defective cyclophilin A induces TDP-43 proteinopathy: implications for amyotrophic lateral sclerosis and frontotemporal dementia

Abstract

Frontotemporal dementia (FTD) is a common cause of early-onset dementia, characterized by frontotemporal lobar degeneration and considerable clinical, genetic and neuropathological heterogeneity. Several mouse models of FTD have been generated targeting genes with known pathogenic roles. However, each of these models recapitulates only certain aspects of the human disease. Cyclophilin A (PPIA) is a multifunctional protein abundantly expressed in the brain, with double-edged functions. Intracellularly, it is mainly protective as a foldase and molecular chaperone with scaffolding properties. Extracellularly, it behaves as a proinflammatory cytokine able to activate an aberrant inflammatory response. In a previous work, we found that PPIA governs TDP-43 functions and its deficiency exacerbates disease in a mouse model of ALS.Selective inhibition of extracellular PPIA rescued motor neurons and increased survival. To decipher PPIA's functions in the central nervous system, we planned a deep neuropathological and behavioral characterization of PPIA knock-out (PPIA-/-) mice throughout their lifespan. They develop a neurodegenerative disease that recapitulates key features of the behavioral variant of FTD associated with TDP-43 pathology. PPIA-/-mice present progressive hippocampal and cortex atrophy, with neuronal death and clear-cut TDP-43 pathology that include fragmentation, hyperphosphorylation, and cytoplasmic mislocalization/nuclear clearing. Mice exhibit increased disinhibition, defects in social behavior, but no memory and motor impairment. On a molecular level, our findings indicate that PPIA is involved in multiple genes and pathways that have a dominant protective effect in the brain, and is fundamental for TDP-43 function. Considering that an impaired interaction of TDP-43 with PPIA has been observed in ALS/FTD patients, the PPIA-/-mouse is a useful experimental model to investigate the mechanism at the basis of TDP-43 pathology and develop novel therapeutic approaches for ALS/FTD and possibly other TDP-43 proteinopathies.

Proline/arginine dipeptide repeat polymers derail protein folding in amyotrophic lateral sclerosis

“…PPIA was independently identified as an interactor of PR repeat polymers in two other interactome studies 6,7 . Knock-out of PPIA causes aggregation of TDP-43 in mice and neurodegeneration 22 .…”

“…In addition, low levels of the prolyl isomerase PPIA in peripheral blood mononuclear cells are associated with early disease onset in ALS patients 20,21 . A link between neurodegeneration, protein misfolding, and prolyl isomerase activity is further supported by knock-out studies in mice 22 : when the gene of the prolyl isomerase PPIA is deleted, mice develop a neurodegenerative disease that recapitulates features of FTD, including the aggregation of TDP-43 into cytoplasmic deposits 22 .…”