--- _id: '14543' abstract: - lang: eng text: The acyl-CoA-binding domain-containing protein 6 (ACBD6) is ubiquitously expressed, plays a role in the acylation of lipids and proteins, and regulates the N-myristoylation of proteins via N-myristoyltransferase enzymes (NMTs). However, its precise function in cells is still unclear, as is the consequence of ACBD6 defects on human pathophysiology. Utilizing exome sequencing and extensive international data sharing efforts, we identified 45 affected individuals from 28 unrelated families (consanguinity 93%) with bi-allelic pathogenic, predominantly loss-of-function (18/20) variants in ACBD6. We generated zebrafish and Xenopus tropicalis acbd6 knockouts by CRISPR/Cas9 and characterized the role of ACBD6 on protein N-myristoylation with YnMyr chemical proteomics in the model organisms and human cells, with the latter also being subjected further to ACBD6 peroxisomal localization studies. The affected individuals (23 males and 22 females), with ages ranging from 1 to 50 years old, typically present with a complex and progressive disease involving moderate-to-severe global developmental delay/intellectual disability (100%) with significant expressive language impairment (98%), movement disorders (97%), facial dysmorphism (95%), and mild cerebellar ataxia (85%) associated with gait impairment (94%), limb spasticity/hypertonia (76%), oculomotor (71%) and behavioural abnormalities (65%), overweight (59%), microcephaly (39%) and epilepsy (33%). The most conspicuous and common movement disorder was dystonia (94%), frequently leading to early-onset progressive postural deformities (97%), limb dystonia (55%), and cervical dystonia (31%). A jerky tremor in the upper limbs (63%), a mild head tremor (59%), parkinsonism/hypokinesia developing with advancing age (32%), and simple motor and vocal tics were among other frequent movement disorders. Midline brain malformations including corpus callosum abnormalities (70%), hypoplasia/agenesis of the anterior commissure (66%), short midbrain and small inferior cerebellar vermis (38% each), as well as hypertrophy of the clava (24%) were common neuroimaging findings. acbd6-deficient zebrafish and Xenopus models effectively recapitulated many clinical phenotypes reported in patients including movement disorders, progressive neuromotor impairment, seizures, microcephaly, craniofacial dysmorphism, and midbrain defects accompanied by developmental delay with increased mortality over time. Unlike ACBD5, ACBD6 did not show a peroxisomal localisation and ACBD6-deficiency was not associated with altered peroxisomal parameters in patient fibroblasts. Significant differences in YnMyr-labelling were observed for 68 co- and 18 post-translationally N-myristoylated proteins in patient-derived fibroblasts. N-Myristoylation was similarly affected in acbd6-deficient zebrafish and Xenopus tropicalis models, including Fus, Marcks, and Chchd-related proteins implicated in neurological diseases. The present study provides evidence that bi-allelic pathogenic variants in ACBD6 lead to a distinct neurodevelopmental syndrome accompanied by complex and progressive cognitive and movement disorders. article_number: awad380 article_processing_charge: No article_type: original author: - first_name: Rauan full_name: Kaiyrzhanov, Rauan last_name: Kaiyrzhanov - first_name: Aboulfazl full_name: Rad, Aboulfazl last_name: Rad - first_name: Sheng-Jia full_name: Lin, Sheng-Jia last_name: Lin - first_name: Aida full_name: Bertoli-Avella, Aida last_name: Bertoli-Avella - first_name: Wouter W full_name: Kallemeijn, Wouter W last_name: Kallemeijn - first_name: Annie full_name: Godwin, Annie last_name: Godwin - first_name: Maha S full_name: Zaki, Maha S last_name: Zaki - first_name: Kevin full_name: Huang, Kevin id: 3b3d2888-1ff6-11ee-9fa6-8f209ca91fe3 last_name: Huang orcid: 0000-0002-2512-7812 - first_name: Tracy full_name: Lau, Tracy last_name: Lau - first_name: Cassidy full_name: Petree, Cassidy last_name: Petree - first_name: Stephanie full_name: Efthymiou, Stephanie last_name: Efthymiou - first_name: Ehsan full_name: Ghayoor Karimiani, Ehsan last_name: Ghayoor Karimiani - first_name: Maja full_name: Hempel, Maja last_name: Hempel - first_name: Elizabeth A full_name: Normand, Elizabeth A last_name: Normand - first_name: Sabine full_name: Rudnik-Schöneborn, Sabine last_name: Rudnik-Schöneborn - first_name: Ulrich A full_name: Schatz, Ulrich A last_name: Schatz - first_name: Marc P full_name: Baggelaar, Marc P last_name: Baggelaar - first_name: Muhammad full_name: Ilyas, Muhammad last_name: Ilyas - first_name: Tipu full_name: Sultan, Tipu last_name: Sultan - first_name: Javeria Raza full_name: Alvi, Javeria Raza last_name: Alvi - first_name: Manizha full_name: Ganieva, Manizha last_name: Ganieva - first_name: Ben full_name: Fowler, Ben last_name: Fowler - first_name: Ruxandra full_name: Aanicai, Ruxandra last_name: Aanicai - first_name: Gulsen full_name: Akay Tayfun, Gulsen last_name: Akay Tayfun - first_name: Abdulaziz full_name: Al Saman, Abdulaziz last_name: Al Saman - first_name: Abdulrahman full_name: Alswaid, Abdulrahman last_name: Alswaid - first_name: Nafise full_name: Amiri, Nafise last_name: Amiri - first_name: Nilufar full_name: Asilova, Nilufar last_name: Asilova - first_name: Vorasuk full_name: Shotelersuk, Vorasuk last_name: Shotelersuk - first_name: Patra full_name: Yeetong, Patra last_name: Yeetong - first_name: Matloob full_name: Azam, Matloob last_name: Azam - first_name: Meisam full_name: Babaei, Meisam last_name: Babaei - first_name: Gholamreza full_name: Bahrami Monajemi, Gholamreza last_name: Bahrami Monajemi - first_name: Pouria full_name: Mohammadi, Pouria last_name: Mohammadi - first_name: Saeed full_name: Samie, Saeed last_name: Samie - first_name: Selina Husna full_name: Banu, Selina Husna last_name: Banu - first_name: Jorge Pinto full_name: Basto, Jorge Pinto last_name: Basto - first_name: Fanny full_name: Kortüm, Fanny last_name: Kortüm - first_name: Mislen full_name: Bauer, Mislen last_name: Bauer - first_name: Peter full_name: Bauer, Peter last_name: Bauer - first_name: Christian full_name: Beetz, Christian last_name: Beetz - first_name: Masoud full_name: Garshasbi, Masoud last_name: Garshasbi - first_name: Awatif full_name: Hameed Issa, Awatif last_name: Hameed Issa - first_name: Wafaa full_name: Eyaid, Wafaa last_name: Eyaid - first_name: Hind full_name: Ahmed, Hind last_name: Ahmed - first_name: Narges full_name: Hashemi, Narges last_name: Hashemi - first_name: Kazem full_name: Hassanpour, Kazem last_name: Hassanpour - first_name: Isabella full_name: Herman, Isabella last_name: Herman - first_name: Sherozjon full_name: Ibrohimov, Sherozjon last_name: Ibrohimov - first_name: Ban A full_name: Abdul-Majeed, Ban A last_name: Abdul-Majeed - first_name: Maria full_name: Imdad, Maria last_name: Imdad - first_name: Maksudjon full_name: Isrofilov, Maksudjon last_name: Isrofilov - first_name: Qassem full_name: Kaiyal, Qassem last_name: Kaiyal - first_name: Suliman full_name: Khan, Suliman last_name: Khan - first_name: Brian full_name: Kirmse, Brian last_name: Kirmse - first_name: Janet full_name: Koster, Janet last_name: Koster - first_name: Charles Marques full_name: Lourenço, Charles Marques last_name: Lourenço - first_name: Tadahiro full_name: Mitani, Tadahiro last_name: Mitani - first_name: Oana full_name: Moldovan, Oana last_name: Moldovan - first_name: David full_name: Murphy, David last_name: Murphy - first_name: Maryam full_name: Najafi, Maryam last_name: Najafi - first_name: Davut full_name: Pehlivan, Davut last_name: Pehlivan - first_name: Maria Eugenia full_name: Rocha, Maria Eugenia last_name: Rocha - first_name: Vincenzo full_name: Salpietro, Vincenzo last_name: Salpietro - first_name: Miriam full_name: Schmidts, Miriam last_name: Schmidts - first_name: Adel full_name: Shalata, Adel last_name: Shalata - first_name: Mohammad full_name: Mahroum, Mohammad last_name: Mahroum - first_name: Jawabreh Kassem full_name: Talbeya, Jawabreh Kassem last_name: Talbeya - first_name: Robert W full_name: Taylor, Robert W last_name: Taylor - first_name: Dayana full_name: Vazquez, Dayana last_name: Vazquez - first_name: Annalisa full_name: Vetro, Annalisa last_name: Vetro - first_name: Hans R full_name: Waterham, Hans R last_name: Waterham - first_name: Mashaya full_name: Zaman, Mashaya last_name: Zaman - first_name: Tina A full_name: Schrader, Tina A last_name: Schrader - first_name: Wendy K full_name: Chung, Wendy K last_name: Chung - first_name: Renzo full_name: Guerrini, Renzo last_name: Guerrini - first_name: James R full_name: Lupski, James R last_name: Lupski - first_name: Joseph full_name: Gleeson, Joseph last_name: Gleeson - first_name: Mohnish full_name: Suri, Mohnish last_name: Suri - first_name: Yalda full_name: Jamshidi, Yalda last_name: Jamshidi - first_name: Kailash P full_name: Bhatia, Kailash P last_name: Bhatia - first_name: Barbara full_name: Vona, Barbara last_name: Vona - first_name: Michael full_name: Schrader, Michael last_name: Schrader - first_name: Mariasavina full_name: Severino, Mariasavina last_name: Severino - first_name: Matthew full_name: Guille, Matthew last_name: Guille - first_name: Edward W full_name: Tate, Edward W last_name: Tate - first_name: Gaurav K full_name: Varshney, Gaurav K last_name: Varshney - first_name: Henry full_name: Houlden, Henry last_name: Houlden - first_name: Reza full_name: Maroofian, Reza last_name: Maroofian citation: ama: Kaiyrzhanov R, Rad A, Lin S-J, et al. Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders. Brain. 2023. doi:10.1093/brain/awad380 apa: Kaiyrzhanov, R., Rad, A., Lin, S.-J., Bertoli-Avella, A., Kallemeijn, W. W., Godwin, A., … Maroofian, R. (2023). Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders. Brain. Oxford University Press. https://doi.org/10.1093/brain/awad380 chicago: Kaiyrzhanov, Rauan, Aboulfazl Rad, Sheng-Jia Lin, Aida Bertoli-Avella, Wouter W Kallemeijn, Annie Godwin, Maha S Zaki, et al. “Bi-Allelic ACBD6 Variants Lead to a Neurodevelopmental Syndrome with Progressive and Complex Movement Disorders.” Brain. Oxford University Press, 2023. https://doi.org/10.1093/brain/awad380. ieee: R. Kaiyrzhanov et al., “Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders,” Brain. Oxford University Press, 2023. ista: Kaiyrzhanov R, Rad A, Lin S-J, Bertoli-Avella A, Kallemeijn WW, Godwin A, Zaki MS, Huang K, Lau T, Petree C, Efthymiou S, Ghayoor Karimiani E, Hempel M, Normand EA, Rudnik-Schöneborn S, Schatz UA, Baggelaar MP, Ilyas M, Sultan T, Alvi JR, Ganieva M, Fowler B, Aanicai R, Akay Tayfun G, Al Saman A, Alswaid A, Amiri N, Asilova N, Shotelersuk V, Yeetong P, Azam M, Babaei M, Bahrami Monajemi G, Mohammadi P, Samie S, Banu SH, Basto JP, Kortüm F, Bauer M, Bauer P, Beetz C, Garshasbi M, Hameed Issa A, Eyaid W, Ahmed H, Hashemi N, Hassanpour K, Herman I, Ibrohimov S, Abdul-Majeed BA, Imdad M, Isrofilov M, Kaiyal Q, Khan S, Kirmse B, Koster J, Lourenço CM, Mitani T, Moldovan O, Murphy D, Najafi M, Pehlivan D, Rocha ME, Salpietro V, Schmidts M, Shalata A, Mahroum M, Talbeya JK, Taylor RW, Vazquez D, Vetro A, Waterham HR, Zaman M, Schrader TA, Chung WK, Guerrini R, Lupski JR, Gleeson J, Suri M, Jamshidi Y, Bhatia KP, Vona B, Schrader M, Severino M, Guille M, Tate EW, Varshney GK, Houlden H, Maroofian R. 2023. Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders. Brain., awad380. mla: Kaiyrzhanov, Rauan, et al. “Bi-Allelic ACBD6 Variants Lead to a Neurodevelopmental Syndrome with Progressive and Complex Movement Disorders.” Brain, awad380, Oxford University Press, 2023, doi:10.1093/brain/awad380. short: R. Kaiyrzhanov, A. Rad, S.-J. Lin, A. Bertoli-Avella, W.W. Kallemeijn, A. Godwin, M.S. Zaki, K. Huang, T. Lau, C. Petree, S. Efthymiou, E. Ghayoor Karimiani, M. Hempel, E.A. Normand, S. Rudnik-Schöneborn, U.A. Schatz, M.P. Baggelaar, M. Ilyas, T. Sultan, J.R. Alvi, M. Ganieva, B. Fowler, R. Aanicai, G. Akay Tayfun, A. Al Saman, A. Alswaid, N. Amiri, N. Asilova, V. Shotelersuk, P. Yeetong, M. Azam, M. Babaei, G. Bahrami Monajemi, P. Mohammadi, S. Samie, S.H. Banu, J.P. Basto, F. Kortüm, M. Bauer, P. Bauer, C. Beetz, M. Garshasbi, A. Hameed Issa, W. Eyaid, H. Ahmed, N. Hashemi, K. Hassanpour, I. Herman, S. Ibrohimov, B.A. Abdul-Majeed, M. Imdad, M. Isrofilov, Q. Kaiyal, S. Khan, B. Kirmse, J. Koster, C.M. Lourenço, T. Mitani, O. Moldovan, D. Murphy, M. Najafi, D. Pehlivan, M.E. Rocha, V. Salpietro, M. Schmidts, A. Shalata, M. Mahroum, J.K. Talbeya, R.W. Taylor, D. Vazquez, A. Vetro, H.R. Waterham, M. Zaman, T.A. Schrader, W.K. Chung, R. Guerrini, J.R. Lupski, J. Gleeson, M. Suri, Y. Jamshidi, K.P. Bhatia, B. Vona, M. Schrader, M. Severino, M. Guille, E.W. Tate, G.K. Varshney, H. Houlden, R. Maroofian, Brain (2023). date_created: 2023-11-16T12:36:51Z date_published: 2023-11-10T00:00:00Z date_updated: 2023-11-20T10:17:32Z day: '10' department: - _id: GradSch doi: 10.1093/brain/awad380 extern: '1' keyword: - Neurology (clinical) language: - iso: eng main_file_link: - open_access: '1' url: https://doi.org/10.1093/brain/awad380 month: '11' oa: 1 oa_version: Submitted Version publication: Brain publication_identifier: eissn: - 1460-2156 issn: - 0006-8950 publication_status: epub_ahead publisher: Oxford University Press quality_controlled: '1' scopus_import: '1' status: public title: Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders type: journal_article user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87 year: '2023' ... --- _id: '12174' abstract: - lang: eng text: "Vacuolar-type H+-ATPase (V-ATPase) is a multimeric complex present in a variety of cellular membranes that acts as an ATP-dependent proton pump and plays a key role in pH homeostasis and intracellular signalling pathways. In humans, 22 autosomal genes encode for a redundant set of subunits allowing the composition of diverse V-ATPase complexes with specific properties and expression. Sixteen subunits have been linked to human disease.\r\nHere we describe 26 patients harbouring 20 distinct pathogenic de novo missense ATP6V1A variants, mainly clustering within the ATP synthase α/β family-nucleotide-binding domain. At a mean age of 7 years (extremes: 6 weeks, youngest deceased patient to 22 years, oldest patient) clinical pictures included early lethal encephalopathies with rapidly progressive massive brain atrophy, severe developmental epileptic encephalopathies and static intellectual disability with epilepsy. The first clinical manifestation was early hypotonia, in 70%; 81% developed epilepsy, manifested as developmental epileptic encephalopathies in 58% of the cohort and with infantile spasms in 62%; 63% of developmental epileptic encephalopathies failed to achieve any developmental, communicative or motor skills. Less severe outcomes were observed in 23% of patients who, at a mean age of 10 years and 6 months, exhibited moderate intellectual disability, with independent walking and variable epilepsy. None of the patients developed communicative language. Microcephaly (38%) and amelogenesis imperfecta/enamel dysplasia (42%) were additional clinical features. Brain MRI demonstrated hypomyelination and generalized atrophy in 68%. Atrophy was progressive in all eight individuals undergoing repeated MRIs.\r\n \ Fibroblasts of two patients with developmental epileptic encephalopathies showed decreased LAMP1 expression, Lysotracker staining and increased organelle pH, consistent with lysosomal impairment and loss of V-ATPase function. Fibroblasts of two patients with milder disease, exhibited a different phenotype with increased Lysotracker staining, decreased organelle pH and no significant modification in LAMP1 expression. Quantification of substrates for lysosomal enzymes in cellular extracts from four patients revealed discrete accumulation. Transmission electron microscopy of fibroblasts of four patients with variable severity and of induced pluripotent stem cell-derived neurons from two patients with developmental epileptic encephalopathies showed electron-dense inclusions, lipid droplets, osmiophilic material and lamellated membrane structures resembling phospholipids. Quantitative assessment in induced pluripotent stem cell-derived neurons identified significantly smaller lysosomes.\r\nATP6V1A-related encephalopathy represents a new paradigm among lysosomal disorders. It results from a dysfunctional endo-lysosomal membrane protein causing altered pH homeostasis. Its pathophysiology implies intracellular accumulation of substrates whose composition remains unclear, and a combination of developmental brain abnormalities and neurodegenerative changes established during prenatal and early postanal development, whose severity is variably determined by specific pathogenic variants." acknowledged_ssus: - _id: EM-Fac - _id: LifeSc acknowledgement: "We thank all patients and family members for their participation in this study. We thank Melanie Pieraks and Eva Reinthaler (Neurolentech, Austria) for generating the human iPSC lines and\r\nfor performing quality checks. We thank Vanessa Zheden and Daniel Gütl for their excellent technical support in the specimen preparation for transmission electron microscopy and Flavia Leite for preparing the lentiviruses. The support from Electron Microscopy Facility and Molecular Biology Services at IST Austria is greatly acknowledged. We would like to thank Doctors Jane Hurst and Richard Scott for their help in retrieving the detailed clinical information of Patient 17. The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network. See Supplementary Material for Undiagnosed Disease Network consortium details. Genetic information on Patient 23 was made available through access to the data and findings generated by the 100 000 Genomes\r\nProject; www.genomicsengland.co.uk (to K.L.). \r\nThis work was supported by the EU 7th Framework Programme (FP7) under the project DESIRE grant N602531 (to R.G.); the Regione Toscana under the Call for Health 2018 (grant\r\nDECODE-EE) (to R.G.); the ‘Brain Project’ by Fondazione Cassa di Risparmio di Firenze (to R.G.); IRCCS Ospedale Policlinico San Martino 5×1000 and Ricerca Corrente (to A.F. and F.B.). The European Reference Network (ERN) for rare and complex epilepsies (EpiCARE) provided financial support for meetings organization. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute (grant number WT098051). The views expressed in this publication\r\nare those of the author(s) and not necessarily those of Wellcome or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12 granted by the Republic of Ireland REC). This study makes use of DECIPHER (https://www.deciphergenomics.org), which is funded by Wellcome. K.K.-S. was supported by the ISTplus fellowship. " article_processing_charge: No article_type: original author: - first_name: Renzo full_name: Guerrini, Renzo last_name: Guerrini - first_name: Davide full_name: Mei, Davide last_name: Mei - first_name: Margit Katalin full_name: Szigeti, Margit Katalin id: 44F4BDC0-F248-11E8-B48F-1D18A9856A87 last_name: Szigeti orcid: 0000-0001-9500-8758 - first_name: Sara full_name: Pepe, Sara last_name: Pepe - first_name: Mary Kay full_name: Koenig, Mary Kay last_name: Koenig - first_name: Gretchen full_name: Von Allmen, Gretchen last_name: Von Allmen - first_name: Megan T full_name: Cho, Megan T last_name: Cho - first_name: Kimberly full_name: McDonald, Kimberly last_name: McDonald - first_name: Janice full_name: Baker, Janice last_name: Baker - first_name: Vikas full_name: Bhambhani, Vikas last_name: Bhambhani - first_name: Zöe full_name: Powis, Zöe last_name: Powis - first_name: Lance full_name: Rodan, Lance last_name: Rodan - first_name: Rima full_name: Nabbout, Rima last_name: Nabbout - first_name: Giulia full_name: Barcia, Giulia last_name: Barcia - first_name: Jill A full_name: Rosenfeld, Jill A last_name: Rosenfeld - first_name: Carlos A full_name: Bacino, Carlos A last_name: Bacino - first_name: Cyril full_name: Mignot, Cyril last_name: Mignot - first_name: Lillian H full_name: Power, Lillian H last_name: Power - first_name: Catharine J full_name: Harris, Catharine J last_name: Harris - first_name: Dragan full_name: Marjanovic, Dragan last_name: Marjanovic - first_name: Rikke S full_name: Møller, Rikke S last_name: Møller - first_name: Trine B full_name: Hammer, Trine B last_name: Hammer - first_name: Riikka full_name: Keski Filppula, Riikka last_name: Keski Filppula - first_name: Päivi full_name: Vieira, Päivi last_name: Vieira - first_name: Clara full_name: Hildebrandt, Clara last_name: Hildebrandt - first_name: Stephanie full_name: Sacharow, Stephanie last_name: Sacharow - first_name: Luca full_name: Maragliano, Luca last_name: Maragliano - first_name: Fabio full_name: Benfenati, Fabio last_name: Benfenati - first_name: Katherine full_name: Lachlan, Katherine last_name: Lachlan - first_name: Andreas full_name: Benneche, Andreas last_name: Benneche - first_name: Florence full_name: Petit, Florence last_name: Petit - first_name: Jean Madeleine full_name: de Sainte Agathe, Jean Madeleine last_name: de Sainte Agathe - first_name: Barbara full_name: Hallinan, Barbara last_name: Hallinan - first_name: Yue full_name: Si, Yue last_name: Si - first_name: Ingrid M full_name: Wentzensen, Ingrid M last_name: Wentzensen - first_name: Fanggeng full_name: Zou, Fanggeng last_name: Zou - first_name: Vinodh full_name: Narayanan, Vinodh last_name: Narayanan - first_name: Naomichi full_name: Matsumoto, Naomichi last_name: Matsumoto - first_name: Alessandra full_name: Boncristiano, Alessandra last_name: Boncristiano - first_name: Giancarlo full_name: la Marca, Giancarlo last_name: la Marca - first_name: Mitsuhiro full_name: Kato, Mitsuhiro last_name: Kato - first_name: Kristin full_name: Anderson, Kristin last_name: Anderson - first_name: Carmen full_name: Barba, Carmen last_name: Barba - first_name: Luisa full_name: Sturiale, Luisa last_name: Sturiale - first_name: Domenico full_name: Garozzo, Domenico last_name: Garozzo - first_name: Roberto full_name: Bei, Roberto last_name: Bei - first_name: Laura full_name: Masuelli, Laura last_name: Masuelli - first_name: Valerio full_name: Conti, Valerio last_name: Conti - first_name: Gaia full_name: Novarino, Gaia id: 3E57A680-F248-11E8-B48F-1D18A9856A87 last_name: Novarino orcid: 0000-0002-7673-7178 - first_name: Anna full_name: Fassio, Anna last_name: Fassio citation: ama: 'Guerrini R, Mei D, Szigeti MK, et al. Phenotypic and genetic spectrum of ATP6V1A encephalopathy: A disorder of lysosomal homeostasis. Brain. 2022;145(8):2687-2703. doi:10.1093/brain/awac145' apa: 'Guerrini, R., Mei, D., Szigeti, M. K., Pepe, S., Koenig, M. K., Von Allmen, G., … Fassio, A. (2022). Phenotypic and genetic spectrum of ATP6V1A encephalopathy: A disorder of lysosomal homeostasis. Brain. Oxford University Press. https://doi.org/10.1093/brain/awac145' chicago: 'Guerrini, Renzo, Davide Mei, Margit Katalin Szigeti, Sara Pepe, Mary Kay Koenig, Gretchen Von Allmen, Megan T Cho, et al. “Phenotypic and Genetic Spectrum of ATP6V1A Encephalopathy: A Disorder of Lysosomal Homeostasis.” Brain. Oxford University Press, 2022. https://doi.org/10.1093/brain/awac145.' ieee: 'R. Guerrini et al., “Phenotypic and genetic spectrum of ATP6V1A encephalopathy: A disorder of lysosomal homeostasis,” Brain, vol. 145, no. 8. Oxford University Press, pp. 2687–2703, 2022.' ista: 'Guerrini R, Mei D, Szigeti MK, Pepe S, Koenig MK, Von Allmen G, Cho MT, McDonald K, Baker J, Bhambhani V, Powis Z, Rodan L, Nabbout R, Barcia G, Rosenfeld JA, Bacino CA, Mignot C, Power LH, Harris CJ, Marjanovic D, Møller RS, Hammer TB, Keski Filppula R, Vieira P, Hildebrandt C, Sacharow S, Maragliano L, Benfenati F, Lachlan K, Benneche A, Petit F, de Sainte Agathe JM, Hallinan B, Si Y, Wentzensen IM, Zou F, Narayanan V, Matsumoto N, Boncristiano A, la Marca G, Kato M, Anderson K, Barba C, Sturiale L, Garozzo D, Bei R, Masuelli L, Conti V, Novarino G, Fassio A. 2022. Phenotypic and genetic spectrum of ATP6V1A encephalopathy: A disorder of lysosomal homeostasis. Brain. 145(8), 2687–2703.' mla: 'Guerrini, Renzo, et al. “Phenotypic and Genetic Spectrum of ATP6V1A Encephalopathy: A Disorder of Lysosomal Homeostasis.” Brain, vol. 145, no. 8, Oxford University Press, 2022, pp. 2687–703, doi:10.1093/brain/awac145.' short: R. Guerrini, D. Mei, M.K. Szigeti, S. Pepe, M.K. Koenig, G. Von Allmen, M.T. Cho, K. McDonald, J. Baker, V. Bhambhani, Z. Powis, L. Rodan, R. Nabbout, G. Barcia, J.A. Rosenfeld, C.A. Bacino, C. Mignot, L.H. Power, C.J. Harris, D. Marjanovic, R.S. Møller, T.B. Hammer, R. Keski Filppula, P. Vieira, C. Hildebrandt, S. Sacharow, L. Maragliano, F. Benfenati, K. Lachlan, A. Benneche, F. Petit, J.M. de Sainte Agathe, B. Hallinan, Y. Si, I.M. Wentzensen, F. Zou, V. Narayanan, N. Matsumoto, A. Boncristiano, G. la Marca, M. Kato, K. Anderson, C. Barba, L. Sturiale, D. Garozzo, R. Bei, L. Masuelli, V. Conti, G. Novarino, A. Fassio, Brain 145 (2022) 2687–2703. date_created: 2023-01-12T12:11:45Z date_published: 2022-08-01T00:00:00Z date_updated: 2023-08-04T09:13:08Z day: '01' department: - _id: GaNo doi: 10.1093/brain/awac145 ec_funded: 1 external_id: isi: - '000807770000001' intvolume: ' 145' isi: 1 issue: '8' keyword: - Neurology (clinical) language: - iso: eng main_file_link: - open_access: '1' url: https://doi.org/10.1093/brain/awac145 month: '08' oa: 1 oa_version: Published Version page: 2687-2703 project: - _id: 260C2330-B435-11E9-9278-68D0E5697425 call_identifier: H2020 grant_number: '754411' name: ISTplus - Postdoctoral Fellowships publication: Brain publication_identifier: eissn: - 1460-2156 issn: - 0006-8950 publication_status: published publisher: Oxford University Press quality_controlled: '1' scopus_import: '1' status: public title: 'Phenotypic and genetic spectrum of ATP6V1A encephalopathy: A disorder of lysosomal homeostasis' type: journal_article user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8 volume: 145 year: '2022' ... --- _id: '12212' abstract: - lang: eng text: Alzheimer’s disease (AD) is characterized by a reorganization of brain activity determining network hyperexcitability and loss of synaptic plasticity. Precisely, a dysfunction in metabotropic GABAB receptor signalling through G protein-gated inwardly rectifying K+ (GIRK or Kir3) channels on the hippocampus has been postulated. Thus, we determined the impact of amyloid-β (Aβ) pathology in GIRK channel density, subcellular distribution, and its association with GABAB receptors in hippocampal CA1 pyramidal neurons from the APP/PS1 mouse model using quantitative SDS-digested freeze-fracture replica labelling (SDS-FRL) and proximity ligation in situ assay (P-LISA). In wild type mice, single SDS-FRL detection revealed a similar dendritic gradient for GIRK1 and GIRK2 in CA1 pyramidal cells, with higher densities in spines, and GIRK3 showed a lower and uniform distribution. Double SDS-FRL showed a co-clustering of GIRK2 and GIRK1 in post- and presynaptic compartments, but not for GIRK2 and GIRK3. Likewise, double GABAB1 and GIRK2 SDS-FRL detection displayed a high degree of co-clustering in nanodomains (40–50 nm) mostly in spines and axon terminals. In APP/PS1 mice, the density of GIRK2 and GIRK1, but not for GIRK3, was significantly reduced along the neuronal surface of CA1 pyramidal cells and in axon terminals contacting them. Importantly, GABAB1 and GIRK2 co-clustering was not present in APP/PS1 mice. Similarly, P-LISA experiments revealed a significant reduction in GABAB1 and GIRK2 interaction on the hippocampus of this animal model. Overall, our results provide compelling evidence showing a significant reduction on the cell surface density of pre- and postsynaptic GIRK1 and GIRK2, but not GIRK3, and a decline in GABAB receptors and GIRK2 channels co-clustering in hippocampal pyramidal neurons from APP/PS1 mice, thus suggesting that a disruption in the GABAB receptor–GIRK channel membrane assembly causes dysregulation in the GABAB signalling via GIRK channels in this AD animal model. acknowledgement: "We thank Ms. Diane Latawiec for the English revision of the manuscript. Funding sources were the Spanish Ministerio de Economía y Competitividad, Junta de Comunidades de Castilla-La Mancha (Spain), and Life Science Innovation Center at University of Fukui. We thank Centres de Recerca de Catalunya (CERCA) Programme/Generalitat de Catalunya for IDIBELL institutional support. We thank Hitoshi Takagi and Takako Maegawa at the University of Fukui for their technical assistance on SDS-FRL experiments.\r\nThis work was supported by grants from the Spanish Ministerio de Economía y Competitividad (BFU2015-63769-R, RTI2018-095812-B-I00, and PID2021-125875OB-I00) and Junta de Comunidades de Castilla-La Mancha (SBPLY/17/180501/000229 and SBPLY/21/180501/000064) to RL, Life Science Innovation Center at University of Fukui and JSPS KAKENHI (Grant Numbers 16H04662, 19H03323, and 20H05058) to YF, and Margarita Salas fellowship from Ministerio de Universidades and Universidad de Castilla-La Mancha to AMB." article_number: '136' article_processing_charge: No article_type: original author: - first_name: Alejandro full_name: Martín-Belmonte, Alejandro last_name: Martín-Belmonte - first_name: Carolina full_name: Aguado, Carolina last_name: Aguado - first_name: Rocío full_name: Alfaro-Ruiz, Rocío last_name: Alfaro-Ruiz - first_name: Ana Esther full_name: Moreno-Martínez, Ana Esther last_name: Moreno-Martínez - first_name: Luis full_name: de la Ossa, Luis last_name: de la Ossa - first_name: Ester full_name: Aso, Ester last_name: Aso - first_name: Laura full_name: Gómez-Acero, Laura last_name: Gómez-Acero - first_name: Ryuichi full_name: Shigemoto, Ryuichi id: 499F3ABC-F248-11E8-B48F-1D18A9856A87 last_name: Shigemoto orcid: 0000-0001-8761-9444 - first_name: Yugo full_name: Fukazawa, Yugo last_name: Fukazawa - first_name: Francisco full_name: Ciruela, Francisco last_name: Ciruela - first_name: Rafael full_name: Luján, Rafael last_name: Luján citation: ama: Martín-Belmonte A, Aguado C, Alfaro-Ruiz R, et al. Nanoscale alterations in GABAB receptors and GIRK channel organization on the hippocampus of APP/PS1 mice. Alzheimer’s Research & Therapy. 2022;14. doi:10.1186/s13195-022-01078-5 apa: Martín-Belmonte, A., Aguado, C., Alfaro-Ruiz, R., Moreno-Martínez, A. E., de la Ossa, L., Aso, E., … Luján, R. (2022). Nanoscale alterations in GABAB receptors and GIRK channel organization on the hippocampus of APP/PS1 mice. Alzheimer’s Research & Therapy. Springer Nature. https://doi.org/10.1186/s13195-022-01078-5 chicago: Martín-Belmonte, Alejandro, Carolina Aguado, Rocío Alfaro-Ruiz, Ana Esther Moreno-Martínez, Luis de la Ossa, Ester Aso, Laura Gómez-Acero, et al. “Nanoscale Alterations in GABAB Receptors and GIRK Channel Organization on the Hippocampus of APP/PS1 Mice.” Alzheimer’s Research & Therapy. Springer Nature, 2022. https://doi.org/10.1186/s13195-022-01078-5. ieee: A. Martín-Belmonte et al., “Nanoscale alterations in GABAB receptors and GIRK channel organization on the hippocampus of APP/PS1 mice,” Alzheimer’s Research & Therapy, vol. 14. Springer Nature, 2022. ista: Martín-Belmonte A, Aguado C, Alfaro-Ruiz R, Moreno-Martínez AE, de la Ossa L, Aso E, Gómez-Acero L, Shigemoto R, Fukazawa Y, Ciruela F, Luján R. 2022. Nanoscale alterations in GABAB receptors and GIRK channel organization on the hippocampus of APP/PS1 mice. Alzheimer’s Research & Therapy. 14, 136. mla: Martín-Belmonte, Alejandro, et al. “Nanoscale Alterations in GABAB Receptors and GIRK Channel Organization on the Hippocampus of APP/PS1 Mice.” Alzheimer’s Research & Therapy, vol. 14, 136, Springer Nature, 2022, doi:10.1186/s13195-022-01078-5. short: A. Martín-Belmonte, C. Aguado, R. Alfaro-Ruiz, A.E. Moreno-Martínez, L. de la Ossa, E. Aso, L. Gómez-Acero, R. Shigemoto, Y. Fukazawa, F. Ciruela, R. Luján, Alzheimer’s Research & Therapy 14 (2022). date_created: 2023-01-16T09:45:51Z date_published: 2022-09-21T00:00:00Z date_updated: 2023-08-04T09:23:10Z day: '21' ddc: - '570' department: - _id: RySh doi: 10.1186/s13195-022-01078-5 external_id: isi: - '000857985500001' file: - access_level: open_access checksum: 88e49715ad6a1abf0fdb27efd65368dc content_type: application/pdf creator: dernst date_created: 2023-01-27T07:53:18Z date_updated: 2023-01-27T07:53:18Z file_id: '12413' file_name: 2022_AlzheimersResearch_MartinBelmont.pdf file_size: 11013325 relation: main_file success: 1 file_date_updated: 2023-01-27T07:53:18Z has_accepted_license: '1' intvolume: ' 14' isi: 1 keyword: - Cognitive Neuroscience - Neurology (clinical) - Neurology language: - iso: eng month: '09' oa: 1 oa_version: Published Version publication: Alzheimer's Research & Therapy publication_identifier: issn: - 1758-9193 publication_status: published publisher: Springer Nature quality_controlled: '1' scopus_import: '1' status: public title: Nanoscale alterations in GABAB receptors and GIRK channel organization on the hippocampus of APP/PS1 mice tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: journal_article user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8 volume: 14 year: '2022' ...