PMID- 38418708 OWN - NLM STAT- MEDLINE DCOM- 20240301 LR - 20240302 IS - 1432-0533 (Electronic) IS - 0001-6322 (Print) IS - 0001-6322 (Linking) VI - 147 IP - 1 DP - 2024 Feb 28 TI - Astroglial calcium signaling and homeostasis in tuberous sclerosis complex. PG - 48 LID - 10.1007/s00401-024-02711-3 [doi] LID - 48 AB - Tuberous Sclerosis Complex (TSC) is a multisystem genetic disorder characterized by the development of benign tumors in various organs, including the brain, and is often accompanied by epilepsy, neurodevelopmental comorbidities including intellectual disability and autism. A key hallmark of TSC is the hyperactivation of the mechanistic target of rapamycin (mTOR) signaling pathway, which induces alterations in cortical development and metabolic processes in astrocytes, among other cellular functions. These changes could modulate seizure susceptibility, contributing to the progression of epilepsy and its associated comorbidities. Epilepsy is characterized by dysregulation of calcium (Ca(2+)) channels and intracellular Ca(2+) dynamics. These factors contribute to hyperexcitability, disrupted synaptogenesis, and altered synchronization of neuronal networks, all of which contribute to seizure activity. This study investigates the intricate interplay between altered Ca(2+) dynamics, mTOR pathway dysregulation, and cellular metabolism in astrocytes. The transcriptional profile of TSC patients revealed significant alterations in pathways associated with cellular respiration, ER and mitochondria, and Ca(2+) regulation. TSC astrocytes exhibited lack of responsiveness to various stimuli, compromised oxygen consumption rate and reserve respiratory capacity underscoring their reduced capacity to react to environmental changes or cellular stress. Furthermore, our study revealed significant reduction of store operated calcium entry (SOCE) along with strong decrease of basal mitochondrial Ca(2+) concentration and Ca(2+) influx in TSC astrocytes. In addition, we observed alteration in mitochondrial membrane potential, characterized by increased depolarization in TSC astrocytes. Lastly, we provide initial evidence of structural abnormalities in mitochondria within TSC patient-derived astrocytes, suggesting a potential link between disrupted Ca(2+) signaling and mitochondrial dysfunction. Our findings underscore the complexity of the relationship between Ca(2+) signaling, mitochondria dynamics, apoptosis, and mTOR hyperactivation. Further exploration is required to shed light on the pathophysiology of TSC and on TSC associated neuropsychiatric disorders offering further potential avenues for therapeutic development. CI - (c) 2024. The Author(s). FAU - Romagnolo, Alessia AU - Romagnolo A AUID- ORCID: 0000-0001-5357-0961 AD - Department of (Neuro) Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Amsterdam, The Netherlands. a.romagnolo@amsterdamumc.nl. FAU - Dematteis, Giulia AU - Dematteis G AD - Department of Pharmaceutical Sciences, Universita del Piemonte Orientale "Amedeo Avogadro", Novara, Italy. FAU - Scheper, Mirte AU - Scheper M AD - Department of (Neuro) Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Amsterdam, The Netherlands. FAU - Luinenburg, Mark J AU - Luinenburg MJ AD - Department of (Neuro) Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Amsterdam, The Netherlands. FAU - Muhlebner, Angelika AU - Muhlebner A AD - Department of (Neuro) Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Amsterdam, The Netherlands. AD - Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. FAU - Van Hecke, Wim AU - Van Hecke W AD - Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. FAU - Manfredi, Marcello AU - Manfredi M AD - Center on Autoimmune and Allergic Diseases (CAAD), UPO, Novara, Italy. AD - Department of Translational Medicine, UPO, Novara, Italy. FAU - De Giorgis, Veronica AU - De Giorgis V AD - Center on Autoimmune and Allergic Diseases (CAAD), UPO, Novara, Italy. AD - Department of Translational Medicine, UPO, Novara, Italy. FAU - Reano, Simone AU - Reano S AD - Center on Autoimmune and Allergic Diseases (CAAD), UPO, Novara, Italy. FAU - Filigheddu, Nicoletta AU - Filigheddu N AD - Department of Translational Medicine, UPO, Novara, Italy. FAU - Bortolotto, Valeria AU - Bortolotto V AD - Department of Pharmaceutical Sciences, Universita del Piemonte Orientale "Amedeo Avogadro", Novara, Italy. FAU - Tapella, Laura AU - Tapella L AD - Department of Pharmaceutical Sciences, Universita del Piemonte Orientale "Amedeo Avogadro", Novara, Italy. FAU - Anink, Jasper J AU - Anink JJ AD - Department of (Neuro) Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Amsterdam, The Netherlands. FAU - Francois, Liesbeth AU - Francois L AD - Neurosciences Therapeutic Area, UCB Pharma, Braine-L'Alleud, Belgium. FAU - Dedeurwaerdere, Stefanie AU - Dedeurwaerdere S AD - Neurosciences Therapeutic Area, UCB Pharma, Braine-L'Alleud, Belgium. FAU - Mills, James D AU - Mills JD AD - Department of (Neuro) Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Amsterdam, The Netherlands. AD - Department of Clinical and Experimental Epilepsy, UCL, London, UK. AD - Chalfont Centre for Epilepsy, Chalfont St Peter, UK. FAU - Genazzani, Armando A AU - Genazzani AA AD - Department of Pharmaceutical Sciences, Universita del Piemonte Orientale "Amedeo Avogadro", Novara, Italy. FAU - Lim, Dmitry AU - Lim D AD - Department of Pharmaceutical Sciences, Universita del Piemonte Orientale "Amedeo Avogadro", Novara, Italy. FAU - Aronica, Eleonora AU - Aronica E AD - Department of (Neuro) Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Amsterdam, The Netherlands. AD - Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, The Netherlands. LA - eng GR - 952455/H2020 European Research Council/ GR - 20-02/Stichting Epilepsie Instellingen Nederland/ PT - Journal Article DEP - 20240228 PL - Germany TA - Acta Neuropathol JT - Acta neuropathologica JID - 0412041 RN - SY7Q814VUP (Calcium) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Humans MH - Astrocytes/pathology MH - Calcium Signaling MH - *Tuberous Sclerosis/pathology MH - Calcium/metabolism MH - TOR Serine-Threonine Kinases/metabolism MH - *Epilepsy/genetics MH - Homeostasis MH - Seizures PMC - PMC10901927 OTO - NOTNLM OT - Astrocytes OT - Calcium signaling OT - Epilepsy OT - Mitochondria OT - Tuberous sclerosis complex OT - mTOR COIS- E.A. and J.D.M. received an unrestricted grant from UCB Pharma. L.F. and S.D. are employees of UCB Pharma, and S.D. receive stock or stock options from their employment. EDAT- 2024/02/29 00:43 MHDA- 2024/03/01 06:44 PMCR- 2024/02/28 CRDT- 2024/02/28 23:29 PHST- 2023/12/06 00:00 [received] PHST- 2024/02/20 00:00 [accepted] PHST- 2024/02/12 00:00 [revised] PHST- 2024/03/01 06:44 [medline] PHST- 2024/02/29 00:43 [pubmed] PHST- 2024/02/28 23:29 [entrez] PHST- 2024/02/28 00:00 [pmc-release] AID - 10.1007/s00401-024-02711-3 [pii] AID - 2711 [pii] AID - 10.1007/s00401-024-02711-3 [doi] PST - epublish SO - Acta Neuropathol. 2024 Feb 28;147(1):48. doi: 10.1007/s00401-024-02711-3.