{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T02:09:46Z","timestamp":1782526186691,"version":"3.54.5"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"14","license":[{"start":{"date-parts":[[2022,2,18]],"date-time":"2022-02-18T00:00:00Z","timestamp":1645142400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"MRC","doi-asserted-by":"publisher","award":["MR\/T046007\/1"],"award-info":[{"award-number":["MR\/T046007\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Parkinson\u2019s UK","award":["G-1704"],"award-info":[{"award-number":["G-1704"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,7,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Cognitive impairment is a common non-motor complication of Parkinson\u2019s disease (PD). Glucocerebrosidase gene (GBA1) variants are found in 10\u201315% of PD cases and are numerically the most important risk factor for PD and dementia with Lewy bodies. Accumulation of \u03b1-synuclein and tau pathology is thought to underlie cognitive impairment in PD and likely involves cholinergic as well as dopaminergic neurons. Neural crest stem cells were isolated from both PD patients with the common heterozygous N370S GBA1 mutation and normal subjects without GBA1 mutations. The stem cells were used to generate a cholinergic neuronal cell model. The effects of the GBA1 variant on glucocerebrosidase (GCase) protein and activity, and cathepsin D, tau and \u03b1-synuclein protein levels in cholinergic neurons were examined. Ambroxol, a GCase chaperone, was used to investigate whether GCase enhancement was able to reverse the effects of the GBA1 variant on cholinergic neurons. Significant reductions in GCase protein and activity, as well as in cathepsin D levels, were found in GBA1 mutant (N370S\/WT) cholinergic neurons. Both tau and \u03b1-synuclein levels were significantly increased in GBA1 mutant (N370S\/WT) cholinergic neurons. Ambroxol significantly enhanced GCase activity and decreased both tau and \u03b1-synuclein levels in cholinergic neurons. GBA1 mutations interfere with the metabolism of \u03b1-synuclein and tau proteins and induce higher levels of \u03b1-synuclein and tau proteins in cholinergic neurons. The GCase pathway provides a potential therapeutic target for neurodegenerative disorders related to pathological \u03b1-synuclein or tau accumulation.<\/jats:p>","DOI":"10.1093\/hmg\/ddac038","type":"journal-article","created":{"date-parts":[[2022,2,15]],"date-time":"2022-02-15T13:35:06Z","timestamp":1644932106000},"page":"2396-2405","source":"Crossref","is-referenced-by-count":25,"title":["Ambroxol reverses tau and \u03b1-synuclein accumulation in a cholinergic N370S <i>GBA1<\/i> mutation model"],"prefix":"10.1093","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8517-9238","authenticated-orcid":false,"given":"Shi Yu","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London , Royal Free Campus, London NW3 2PF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan-Willem","family":"Taanman","sequence":"additional","affiliation":[{"name":"Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London , Royal Free Campus, London NW3 2PF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8093-0723","authenticated-orcid":false,"given":"Matthew","family":"Gegg","sequence":"additional","affiliation":[{"name":"Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London , Royal Free Campus, London NW3 2PF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony H V","family":"Schapira","sequence":"additional","affiliation":[{"name":"Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London , Royal Free Campus, London NW3 2PF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,2,18]]},"reference":[{"key":"2022072316285506100_ref1","doi-asserted-by":"crossref","first-page":"III\/1","DOI":"10.1007\/s00415-002-1301-4","article-title":"Staging of the intracerebral inclusion body pathology associated with idiopathic Parkinson's disease (preclinical and clinical stages)","volume":"249","author":"Braak","year":"2002","journal-title":"J. Neurol."},{"key":"2022072316285506100_ref2","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1001\/jamaneurol.2014.2757","article-title":"Frequency of cholinergic and caudate nucleus dopaminergic deficits across the predemented cognitive spectrum of Parkinson disease and evidence of interaction effects","volume":"72","author":"Bohnen","year":"2015","journal-title":"JAMA Neurol."},{"key":"2022072316285506100_ref3","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1038\/nrn.2017.91","article-title":"Non-motor features of Parkinson disease","volume":"18","author":"Schapira","year":"2017","journal-title":"Nat. Rev. Neurosci."},{"key":"2022072316285506100_ref4","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.1056\/NEJMoa0901281","article-title":"Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease","volume":"361","author":"Sidransky","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"2022072316285506100_ref5","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1001\/archneurol.2009.54","article-title":"Association of glucocerebrosidase mutations with dementia with Lewy bodies","volume":"66","author":"Clark","year":"2009","journal-title":"Arch. Neurol."},{"key":"2022072316285506100_ref6","doi-asserted-by":"crossref","first-page":"1434","DOI":"10.1212\/WNL.0b013e318253d54b","article-title":"Cognitive performance of GBA mutation carriers with early-onset PD: the CORE-PD study","volume":"78","author":"Alcalay","year":"2012","journal-title":"Neurology"},{"key":"2022072316285506100_ref7","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/ana.23614","article-title":"Glucocerebrosidase deficiency in substantia nigra of Parkinson disease brains","volume":"72","author":"Gegg","year":"2012","journal-title":"Ann. Neurol."},{"key":"2022072316285506100_ref8","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1016\/j.stemcr.2017.01.011","article-title":"A human neural crest stem cell-derived dopaminergic neuronal model recapitulates biochemical abnormalities in GBA1 mutation carriers","volume":"8","author":"Yang","year":"2017","journal-title":"Stem Cell Reports."},{"key":"2022072316285506100_ref9","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1016\/j.stem.2013.01.009","article-title":"Modeling Alzheimer's disease with iPSCs reveals stress phenotypes associated with intracellular A\u03b2 and differential drug responsiveness","volume":"12","author":"Kondo","year":"2013","journal-title":"Cell Stem Cell"},{"key":"2022072316285506100_ref10","doi-asserted-by":"crossref","first-page":"3523","DOI":"10.1093\/hmg\/ddu064","article-title":"The familial Alzheimer's disease APPV717I mutation alters APP processing and tau expression in iPSC-derived neurons","volume":"23","author":"Muratore","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"2022072316285506100_ref11","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1038\/nature10821","article-title":"Probing sporadic and familial Alzheimer's disease using induced pluripotent stem cells","volume":"482","author":"Israel","year":"2012","journal-title":"Nature"},{"key":"2022072316285506100_ref12","doi-asserted-by":"crossref","first-page":"23502","DOI":"10.1074\/jbc.M109.012393","article-title":"Identification and characterization of ambroxol as an enzyme enhancement agent for Gaucher disease","volume":"284","author":"Maegawa","year":"2009","journal-title":"J. Biol. Chem."},{"key":"2022072316285506100_ref13","doi-asserted-by":"crossref","first-page":"31380","DOI":"10.1038\/srep31380","article-title":"Parkinson disease-linked GBA mutation effects reversed by molecular chaperones in human cell and fly models","volume":"6","author":"Sanchez-Martinez","year":"2016","journal-title":"Sci. Rep."},{"key":"2022072316285506100_ref14","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.parkreldis.2021.02.003","article-title":"Ambroxol increases glucocerebrosidase (GCase) activity and restores GCase translocation in primary patient-derived macrophages in Gaucher disease and parkinsonism","volume":"84","author":"Kopytova","year":"2021","journal-title":"Parkinsonism Relat. Disord."},{"key":"2022072316285506100_ref15","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1242\/dev.108.4.605","article-title":"Pathways of trunk neural crest cell migration in the mouse embryo as revealed by vital dye labelling","volume":"108","author":"Serbedzija","year":"1990","journal-title":"Development"},{"key":"2022072316285506100_ref16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/15419061.2018.1444034","article-title":"Kr\u00fcppel-like factor 4 mediates cellular migration and invasion by altering RhoA activity","volume":"24","author":"Brauer","year":"2018","journal-title":"Cell Commun. Adhes."},{"key":"2022072316285506100_ref17","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1002\/stem.626","article-title":"The controlled generation of functional basal forebrain cholinergic neurons from human embryonic stem cells","volume":"29","author":"Bissonnette","year":"2011","journal-title":"Stem Cells"},{"key":"2022072316285506100_ref18","doi-asserted-by":"crossref","first-page":"1476","DOI":"10.1111\/j.1582-4934.2009.00916.x","article-title":"Neurotrophic factors promote cholinergic differentiation in human embryonic stem cell-derived neurons","volume":"14","author":"Nilbratt","year":"2010","journal-title":"J. Cell. Mol. Med."},{"key":"2022072316285506100_ref19","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.jneumeth.2016.03.017","article-title":"Directed differentiation of basal forebrain cholinergic neurons from human pluripotent stem cells","volume":"266","author":"Hu","year":"2016","journal-title":"J. Neurosci. Methods"},{"key":"2022072316285506100_ref20","doi-asserted-by":"crossref","first-page":"2450","DOI":"10.1096\/fj.00-0206rev","article-title":"Molecular analysis of vesicular amine transporter function and targeting to secretory organelles","volume":"14","author":"Erickson","year":"2000","journal-title":"FASEB J."},{"key":"2022072316285506100_ref21","doi-asserted-by":"crossref","first-page":"101","DOI":"10.2174\/1570159X13666150716165726","article-title":"Alzheimer's disease: targeting the cholinergic system","volume":"14","author":"Ferreira-Vieira","year":"2016","journal-title":"Curr. Neuropharmacol."},{"key":"2022072316285506100_ref22","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1016\/j.stemcr.2015.09.010","article-title":"ESC-derived basal forebrain cholinergic neurons ameliorate the cognitive symptoms associated with Alzheimer's disease in mouse models","volume":"5","author":"Yue","year":"2015","journal-title":"Stem Cell Reports."},{"key":"2022072316285506100_ref23","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.neuron.2014.01.023","article-title":"Striatal cholinergic interneurons drive GABA release from dopamine terminals","volume":"82","author":"Nelson","year":"2014","journal-title":"Neuron"},{"key":"2022072316285506100_ref24","doi-asserted-by":"crossref","first-page":"5442","DOI":"10.1523\/JNEUROSCI.22-13-05442.2002","article-title":"A third vesicular glutamate transporter expressed by cholinergic and serotoninergic neurons","volume":"22","author":"Gras","year":"2002","journal-title":"J. Neurosci."},{"key":"2022072316285506100_ref25","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1016\/j.neuroscience.2003.10.039","article-title":"Localization of VGLUT3, the vesicular glutamate transporter type 3, in the rat brain","volume":"123","author":"Herzog","year":"2004","journal-title":"Neuroscience"},{"key":"2022072316285506100_ref26","doi-asserted-by":"crossref","first-page":"2739","DOI":"10.1083\/jcb.103.6.2739","article-title":"Tau protein function in living cells","volume":"103","author":"Drubin","year":"1986","journal-title":"J. Cell Biol."},{"key":"2022072316285506100_ref27","first-page":"1234","article-title":"Neuropathology of dementia in patients with Parkinson\u2019s disease: a systematic review of autopsy studies","volume":"90","author":"Smith","year":"2019","journal-title":"J. Neurosurg Psychiatry"},{"key":"2022072316285506100_ref28","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1002\/ana.21192","article-title":"Tau and alpha-synuclein in susceptibility to, and dementia in, Parkinson's disease","volume":"62","author":"Goris","year":"2007","journal-title":"Ann. Neurol."},{"key":"2022072316285506100_ref29","doi-asserted-by":"crossref","DOI":"10.1016\/j.nbd.2019.104620","article-title":"Glucocerebrosidase activity, cathepsin D and monomeric \u03b1-synuclein interactions in a stem cell derived neuronal model of a PD associated GBA1 mutation","volume":"134","author":"Yang","year":"2020","journal-title":"Neurobiol. Dis."},{"key":"2022072316285506100_ref30","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.1093\/brain\/awu020","article-title":"Ambroxol improves lysosomal biochemistry in glucocerebrosidase mutation-linked Parkinson disease cells","volume":"137","author":"McNeill","year":"2014","journal-title":"Brain"},{"key":"2022072316285506100_ref31","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1002\/mds.24045","article-title":"Glucocerebrosidase mutations confer a greater risk of dementia during Parkinson's disease course","volume":"27","author":"Set\u00f3-Salvia","year":"2012","journal-title":"Mov. Disord."},{"key":"2022072316285506100_ref32","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1093\/brain\/aws318","article-title":"Glucocerebrosidase mutations influence the natural history of Parkinson's disease in a community-based incident cohort","volume":"136","author":"Winder-Rhodes","year":"2013","journal-title":"Brain"},{"key":"2022072316285506100_ref33","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1001\/jamaneurol.2013.1274","article-title":"Clinical and biochemical differences in patients having Parkinson disease with vs without GBA mutations","volume":"70","author":"Chahine","year":"2013","journal-title":"JAMA Neurol."},{"key":"2022072316285506100_ref34","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.molcel.2010.08.004","article-title":"Identification of regulators of chaperone-mediated autophagy","volume":"39","author":"Bandyopadhyay","year":"2010","journal-title":"Mol. Cell"},{"key":"2022072316285506100_ref35","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1016\/j.bbadis.2013.04.013","article-title":"Impairment of proteostasis network in down syndrome prior to the development of Alzheimer\u2019s disease neuropathology: redox proteomics analysis of the human brain","volume":"1832","author":"Di Domenico","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"2022072316285506100_ref36","doi-asserted-by":"crossref","first-page":"9678","DOI":"10.1021\/bi800699v","article-title":"Cathepsin D is the main lysosomal enzyme involved in the degradation of alpha-synuclein and generation of its carboxy-terminally truncated species","volume":"47","author":"Sevlever","year":"2008","journal-title":"Biochemistry"},{"key":"2022072316285506100_ref37","doi-asserted-by":"crossref","first-page":"2026","DOI":"10.1046\/j.1471-4159.1997.69052026.x","article-title":"Degradation of tau by lysosomal enzyme cathepsin D: implication for Alzheimer neurofibrillary degeneration","volume":"69","author":"Kenessey","year":"1997","journal-title":"J. Neurochem."},{"key":"2022072316285506100_ref38","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.1007\/s12035-018-1090-0","article-title":"Characterization of brain lysosomal activities in GBA-related and sporadic Parkinson's disease and dementia with Lewy bodies","volume":"56","author":"Moors","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"2022072316285506100_ref39","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1093\/brain\/awz350","article-title":"Genetic modifiers of risk and age at onset in GBA associated Parkinson's disease and Lewy body dementia","volume":"143","author":"Blauwendraat","year":"2020","journal-title":"Brain"},{"key":"2022072316285506100_ref40","doi-asserted-by":"crossref","DOI":"10.1016\/j.bpc.2020.106534","article-title":"The interplay between glucocerebrosidase, \u03b1-synuclein and lipids in human models of Parkinson's disease","volume":"273","author":"Munoz","year":"2021","journal-title":"Biophys. Chem."},{"key":"2022072316285506100_ref41","doi-asserted-by":"crossref","DOI":"10.3389\/fnmol.2020.586731","article-title":"Degradation and transmission of tau by autophagic-endolysosomal networks and potential therapeutic targets for tauopathy","volume":"13","author":"Jiang","year":"2020","journal-title":"Front. Mol. Neurosci."},{"key":"2022072316285506100_ref42","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1016\/j.cmet.2013.04.014","article-title":"Mitochondria and quality control defects in a mouse model of Gaucher disease--links to Parkinson's disease","volume":"17","author":"Osellame","year":"2013","journal-title":"Cell Metab."},{"key":"2022072316285506100_ref43","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1002\/ana.24777","article-title":"Survival and dementia in GBA-associated Parkinson's disease: the mutation matters","volume":"80","author":"Cilia","year":"2016","journal-title":"Ann. Neurol."},{"key":"2022072316285506100_ref44","doi-asserted-by":"crossref","first-page":"3537","DOI":"10.1073\/pnas.1220464110","article-title":"Augmenting CNS glucocerebrosidase activity as a therapeutic strategy for parkinsonism and other Gaucher-related synucleinopathies","volume":"110","author":"Sardi","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2022072316285506100_ref45","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1002\/ana.24790","article-title":"Ambroxol effects in glucocerebrosidase and alpha-synuclein transgenic mice","volume":"80","author":"Migdalska-Richards","year":"2016","journal-title":"Ann. Neurol."},{"key":"2022072316285506100_ref46","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1038\/s41598-018-19479-8","article-title":"Effects of ambroxol on the autophagy-lysosome pathway and mitochondria in primary cortical neurons","volume":"8","author":"Magalhaes","year":"2018","journal-title":"Sci. Rep."},{"key":"2022072316285506100_ref47","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1001\/jamaneurol.2019.4611","article-title":"Ambroxol for the treatment of patients with Parkinson disease with and without glucocerebrosidase gene mutations: a nonrandomized, noncontrolled trial","volume":"77","author":"Mullin","year":"2020","journal-title":"JAMA Neurol."}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/hmg\/advance-article-pdf\/doi\/10.1093\/hmg\/ddac038\/42950676\/ddac038.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/31\/14\/2396\/45050273\/ddac038.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/31\/14\/2396\/45050273\/ddac038.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,23]],"date-time":"2022-07-23T16:29:32Z","timestamp":1658593772000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/31\/14\/2396\/6530531"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,18]]},"references-count":47,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2022,2,18]]},"published-print":{"date-parts":[[2022,7,21]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddac038","relation":{},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"value":"0964-6906","type":"print"},{"value":"1460-2083","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,7,15]]},"published":{"date-parts":[[2022,2,18]]}}}