Profilin 1 controls a microglial cytoskeleton checkpoint to prevent senescence and premature synaptic decline
Year: 2025
Type: article
Abstract: Profilin 1 (Pfn1) expression decreases significantly in aged human microglia, suggesting that loss of cytoskeletal integrity may trigger microglial senescence and increased synaptic vulnerability. To test this hypothesis, we used an inducible, microglia-specific Pfn1 knockout in adult mice, a strategy designed to isolate the direct effects of acute Pfn1 loss at the cellular and circuit levels, avoiding confounding factors from development or chronic aging. Using a multi-omics approach combined with intravital two-photon imaging, we found that Pfn1 ablation disrupts actin–microtubule coupling, leading to a collapse of microglial morphodynamics and a complete failure to respond to focal brain injury. This cytoskeletal disruption triggers a cell-autonomous, senescence-associated secretory phenotype (SASP), driven by the ERK/NF-κB signaling axis. SASP factors secreted by Pfn1-deficient microglia reprogram the synaptic environment, resulting in significant deficits in mitochondrial energy production and a selective reduction in the frequency of GABAergic inhibitory postsynaptic currents in the prefrontal cortex. These circuit-level disturbances lead to behaviors characterized by altered anxiety and risk assessment. Our findings identify Pfn1 as a critical checkpoint against microglial senescence and show that its loss is sufficient to drive circuit-specific synaptic decline, highlighting the Pfn1-cytoskeleton axis as a potential therapeutic target to enhance brain resilience.
Source: Journal of Neuroinflammation
Authors: Camila Cabral Portugal, Tiago Oliveira Almeida, Joana Tedim-Moreira, Cátia Silva, Teresa Canedo, João Galvão, Ana Magalhães, Teresa Summavielle, Xianshu Bai, Frank Kirchhoff, Boris Rubinstein, Irina Moreira, Jéssica Costa, Joana Guedes, Inês Mendes Pinto, João Peça, Renato Socodato, João Bettencourt Relvas
Institutions: i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Instituto de Biologia Molecular e Celular, Instituto de Ciências Biomédicas Albel Salazar, Universidade do Porto, University of Minho, Saarland University, Stowers Institute for Medical Research, Centro de Neurociências e Biologia Celular, Centro de Inovação em Biomedicina e Biotecnologia, University of Coimbra, International Iberian Nanotechnology Laboratory
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,090
Awards: Terapêuticas Inovadoras no âmbito da toxicodependência: a neuroinflamação como alvo, G1516346500, G1555396074, G1709334129, G1763632427, G1830165626, G2061926898, G2195151728, INL Fellowship programme in nanotechnologies for biomedical, environment and food applications., G2427613718, G2733542715, G274581676, G2964751290, G3379593517, G3432522462, G3840324753, G473357141, Role of cdc42 in microglia function, G5224927334, G5703433246, G6193589897, Profilina1 na interface entre microglia, envelhecimento e neurodegeneração, G7584003722, Astrosomes: Artificial Astrocytes as a Novel Therapeutic to Amyotrophic Lateral Sclerosis (ALS), PHAGOBOOST: RhoA-boosted Microglia Phagocytosis of ß-amyloid, G7965899483, G7979947301, G862925997, G946021960
OpenAlex ID: W4416070412