GBA-associated PD: chances and obstacles for targeted treatment strategies.

[en] Given the clear role of GBA in the pathogenesis of Parkinson's disease (PD) and its impact on phenotypical characteristics, this review provides an overview of the current knowledge of GBA-associated PD with a special focus on clinical trajectories and the underlying pathological mechanisms. Importantly, differences and characteristics based on mutation severity are recognized, and current as well as potential future treatment options are discussed. These findings will inform future strategies for patient stratification and cohort enrichment as well as suitable outcome measures when designing clinical trials.

Disciplines :

Neurology

Author, co-author :

Höglinger, Günter

Schulte, Claudia

Jost, Wolfgang H.

Storch, Alexander

Woitalla, Dirk

Krüger, Rejko ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience

Falkenburger, Björn

Brockmann, Kathrin

External co-authors :

yes

Language :

English

Title :

GBA-associated PD: chances and obstacles for targeted treatment strategies.

Publication date :

31 May 2022

Journal title :

Journal of neural transmission (Vienna, Austria : 1996)

ISSN :

0300-9564

eISSN :

1435-1463

Volume :

129

Issue :

Pages :

1219-1233

Peer reviewed :

Peer reviewed

Focus Area :

Systems Biomedicine

Commentary :

Available on ORBilu :

since 16 January 2023

Statistics

Number of views

26 (5 by Unilu)

Number of downloads

10 (0 by Unilu)

More statistics

Scopus citations^®

Scopus citations^®
without self-citations

OpenCitations

WoS citations^™

Bibliography

Aarsland D, Perry R, Brown A, Larsen JP, Ballard C (2005) Neuropathology of dementia in Parkinson’s disease: a prospective, community-based study. Ann Neurol 58:773–776 DOI: 10.1002/ana.20635
Abeliovich A, Hefti F, Sevigny J (2021) Gene therapy for Parkinson’s disease associated with GBA1 mutations. J Parkinsons Dis 11:S183–S188 DOI: 10.3233/JPD-212739
Aflaki E, Borger DK, Moaven N, Stubblefield BK, Rogers SA, Patnaik S, Schoenen FJ, Westbroek W, Zheng W, Sullivan P, Fujiwara H, Sidhu R, Khaliq ZM, Lopez GJ, Goldstein DS, Ory DS, Marugan J, Sidransky E (2016) A new glucocerebrosidase chaperone reduces alpha-synuclein and glycolipid levels in iPSC-derived dopaminergic neurons from patients with Gaucher disease and Parkinsonism. J Neurosci 36:7441–7452 DOI: 10.1523/JNEUROSCI.0636-16.2016
Aflaki E, Stubblefield BK, McGlinchey RP, McMahon B, Ory DS, Sidransky E (2020) A characterization of Gaucher iPS-derived astrocytes: potential implications for Parkinson’s disease. Neurobiol Dis 134:104647 DOI: 10.1016/j.nbd.2019.104647
Alcalay RN, Levy OA, Waters CC, Fahn S, Ford B, Kuo SH, Mazzoni P, Pauciulo MW, Nichols WC, Gan-Or Z, Rouleau GA, Chung WK, Wolf P, Oliva P, Keutzer J, Marder K, Zhang X (2015) Glucocerebrosidase activity in Parkinson’s disease with and without GBA mutations. Brain 138:2648–2658 DOI: 10.1093/brain/awv179
Alcalay RN, Wolf P, Chiang MSR, Helesicova K, Zhang XK, Merchant K, Hutten SJ, Scherzer C, Caspell-Garcia C, Blauwendraat C, Foroud T, Nudelman K, Gan-Or Z, Simuni T, Chahine LM, Levy O, Zheng D, Li G, Sardi SP, Parkinson’s Progression Markers I (2020) Longitudinal Measurements of Glucocerebrosidase activity in Parkinson’s patients. Ann Clin Transl Neurol 7:1816–1830 DOI: 10.1002/acn3.51164
Ambrosi G, Ghezzi C, Zangaglia R, Levandis G, Pacchetti C, Blandini F (2015) Ambroxol-induced rescue of defective glucocerebrosidase is associated with increased LIMP-2 and saposin C levels in GBA1 mutant Parkinson’s disease cells. Neurobiol Dis 82:235–242 DOI: 10.1016/j.nbd.2015.06.008
Anheim M, Elbaz A, Lesage S, Durr A, Condroyer C, Viallet F, Pollak P, Bonaiti B, Bonaiti-Pellie C, Brice A, French Parkinson Disease Genetic G (2012) Penetrance of Parkinson disease in glucocerebrosidase gene mutation carriers. Neurology 78:417–420 DOI: 10.1212/WNL.0b013e318245f476
Avenali M, Toffoli M, Mullin S, McNeil A, Hughes DA, Mehta A, Blandini F, Schapira AHV (2019) Evolution of prodromal parkinsonian features in a cohort of GBA mutation-positive individuals: a 6-year longitudinal study. J Neurol Neurosurg Psychiatry 90:1091–1097 DOI: 10.1136/jnnp-2019-320394
Barrett MJ, Shanker VL, Severt WL, Raymond D, Gross SJ, Schreiber-Agus N, Kornreich R, Ozelius LJ, Bressman SB, Saunders-Pullman R (2014) Cognitive and antipsychotic medication use in monoallelic GBA-related Parkinson disease. JIMD Rep 16:31–38 DOI: 10.1007/8904_2014_315
Beavan M, McNeill A, Proukakis C, Hughes DA, Mehta A, Schapira AH (2015) Evolution of prodromal clinical markers of Parkinson disease in a GBA mutation-positive cohort. JAMA Neurol 72:201–208 DOI: 10.1001/jamaneurol.2014.2950
Berg D, Postuma RB, Adler CH, Bloem BR, Chan P, Dubois B, Gasser T, Goetz CG, Halliday G, Joseph L, Lang AE, Liepelt-Scarfone I, Litvan I, Marek K, Obeso J, Oertel W, Olanow CW, Poewe W, Stern M, Deuschl G (2015) MDS research criteria for prodromal Parkinson’s disease. Mov Disord 30:1600–1611 DOI: 10.1002/mds.26431
Beutler E (1992) Gaucher disease: new molecular approaches to diagnosis and treatment. Science 256:794–799 DOI: 10.1126/science.256.5058.794
Blauwendraat C, Heilbron K, Vallerga CL, Bandres-Ciga S, von Coelln R, Pihlstrom L, Simon-Sanchez J, Schulte C, Sharma M, Krohn L, Siitonen A, Iwaki H, Leonard H, Noyce AJ, Tan M, Gibbs JR, Hernandez DG, Scholz SW, Jankovic J, Shulman LM, Lesage S, Corvol JC, Brice A, van Hilten JJ, Marinus J, Andme Research T, Eerola-Rautio J, Tienari P, Majamaa K, Toft M, Grosset DG, Gasser T, Heutink P, Shulman JM, Wood N, Hardy J, Morris HR, Hinds DA, Gratten J, Visscher PM, Gan-Or Z, Nalls MA, Singleton AB, International Parkinson’s Disease Genomics C (2019) Parkinson’s disease age at onset genome-wide association study: Defining heritability, genetic loci, and alpha-synuclein mechanisms. Mov Disord 34:866–875 DOI: 10.1002/mds.27659
Blauwendraat C, Nalls MA, Singleton AB (2020a) The genetic architecture of Parkinson’s disease. Lancet Neurol 19:170–178 DOI: 10.1016/S1474-4422(19)30287-X
Blauwendraat C, Reed X, Krohn L, Heilbron K, Bandres-Ciga S, Tan M, Gibbs JR, Hernandez DG, Kumaran R, Langston R, Bonet-Ponce L, Alcalay RN, Hassin-Baer S, Greenbaum L, Iwaki H, Leonard HL, Grenn FP, Ruskey JA, Sabir M, Ahmed S, Makarious MB, Pihlstrom L, Toft M, van Hilten JJ, Marinus J, Schulte C, Brockmann K, Sharma M, Siitonen A, Majamaa K, Eerola-Rautio J, Tienari PJ, Andme Research T, Pantelyat A, Hillis AE, Dawson TM, Rosenthal LS, Albert MS, Resnick SM, Ferrucci L, Morris CM, Pletnikova O, Troncoso J, Grosset D, Lesage S, Corvol JC, Brice A, Noyce AJ, Masliah E, Wood N, Hardy J, Shulman LM, Jankovic J, Shulman JM, Heutink P, Gasser T, Cannon P, Scholz SW, Morris H, Cookson MR, Nalls MA, Gan-Or Z, Singleton AB (2020b) Genetic modifiers of risk and age at onset in GBA associated Parkinson’s disease and Lewy body dementia. Brain 143:234–248 DOI: 10.1093/brain/awz350
Bodennec J, Pelled D, Riebeling C, Trajkovic S, Futerman AH (2002) Phosphatidylcholine synthesis is elevated in neuronal models of Gaucher disease due to direct activation of CTP:phosphocholine cytidylyltransferase by glucosylceramide. FASEB J 16:1814–1816 DOI: 10.1096/fj.02-0149fje
Brockmann K, Srulijes K, Hauser AK, Schulte C, Csoti I, Gasser T, Berg D (2011) GBA-associated PD presents with nonmotor characteristics. Neurology 77:276–280 DOI: 10.1212/WNL.0b013e318225ab77
Brockmann K, Hilker R, Pilatus U, Baudrexel S, Srulijes K, Magerkurth J, Hauser AK, Schulte C, Csoti I, Merten CD, Gasser T, Berg D, Hattingen E (2012) GBA-associated PD. Neurodegeneration, altered membrane metabolism, and lack of energy failure. Neurology 79:213–220 DOI: 10.1212/WNL.0b013e31825dd369
Brockmann K, Schulte C, Deuschle C, Hauser AK, Heger T, Gasser T, Maetzler W, Berg D (2015a) Neurodegenerative CSF markers in genetic and sporadic PD: classification and prediction in a longitudinal study. Parkinsonism Relat Disord 21:1427–1434 DOI: 10.1016/j.parkreldis.2015.10.008
Brockmann K, Srulijes K, Pflederer S, Hauser AK, Schulte C, Maetzler W, Gasser T, Berg D (2015b) GBA-associated Parkinson’s disease: reduced survival and more rapid progression in a prospective longitudinal study. Mov Disord 30:407–411 DOI: 10.1002/mds.26071
Brockmann K, Lerche S, Dilger SS, Stirnkorb JG, Apel A, Hauser AK, Liepelt-Scarfone I, Berg D, Gasser T, Schulte C, Maetzler W (2017) SNPs in Abeta clearance proteins: Lower CSF Abeta1-42 levels and earlier onset of dementia in PD. Neurology 89:2335–2340 DOI: 10.1212/WNL.0000000000004705
Brockmann K, Quadalti C, Lerche S, Rossi M, Wurster I, Baiardi S, Roeben B, Mammana A, Zimmermann M, Hauser AK, Deuschle C, Schulte C, Waniek K, Lachmann I, Sjodin S, Brinkmalm A, Blennow K, Zetterberg H, Gasser T, Parchi P (2021) Association between CSF alpha-synuclein seeding activity and genetic status in Parkinson’s disease and dementia with Lewy bodies. Acta Neuropathol Commun 9:175 DOI: 10.1186/s40478-021-01276-6
Burbulla LF, Jeon S, Zheng J, Song P, Silverman RB, Krainc D (2019) A modulator of wild-type glucocerebrosidase improves pathogenic phenotypes in dopaminergic neuronal models of Parkinson’s disease. Sci Transl Med 11:eaau6870 DOI: 10.1126/scitranslmed.aau6870
Chen J, Li W, Zhang T, Wang YJ, Jiang XJ, Xu ZQ (2014) Glucocerebrosidase gene mutations associated with Parkinson’s disease: a meta-analysis in a Chinese population. PLoS ONE 9:e115747 DOI: 10.1371/journal.pone.0115747
Cilia R, Tunesi S, Marotta G, Cereda E, Siri C, Tesei S, Zecchinelli AL, Canesi M, Mariani CB, Meucci N, Sacilotto G, Zini M, Barichella M, Magnani C, Duga S, Asselta R, Solda G, Seresini A, Seia M, Pezzoli G, Goldwurm S (2016) Survival and dementia in GBA-associated Parkinson’s disease: the mutation matters. Ann Neurol 80:662–673 DOI: 10.1002/ana.24777
Compta Y, Parkkinen L, O’Sullivan SS, Vandrovcova J, Holton JL, Collins C, Lashley T, Kallis C, Williams DR, de Silva R, Lees AJ, Revesz T (2011) Lewy- and Alzheimer-type pathologies in Parkinson’s disease dementia: which is more important? Brain 134:1493–1505 DOI: 10.1093/brain/awr031
den Heijer JM, Cullen VC, Quadri M, Schmitz A, Hilt DC, Lansbury P, Berendse HW, van de Berg WDJ, de Bie RMA, Boertien JM, Boon AJW, Contarino MF, van Hilten JJ, Hoff JI, van Mierlo T, Munts AG, van der Plas AA, Ponsen MM, Baas F, Majoor-Krakauer D, Bonifati V, van Laar T, Groeneveld GJ (2020) A large-scale full GBA1 gene screening in Parkinson’s disease in the Netherlands. Mov Disord 35:1667–1674 DOI: 10.1002/mds.28112
Elleder M (2006) Glucosylceramide transfer from lysosomes—the missing link in molecular pathology of glucosylceramidase deficiency: a hypothesis based on existing data. J Inherit Metab Dis 29:707–715 DOI: 10.1007/s10545-006-0411-z
Fairfoul G, McGuire LI, Pal S, Ironside JW, Neumann J, Christie S, Joachim C, Esiri M, Evetts SG, Rolinski M, Baig F, Ruffmann C, Wade-Martins R, Hu MT, Parkkinen L, Green AJ (2016) Alpha-synuclein RT-QuIC in the CSF of patients with alpha-synucleinopathies. Ann Clin Transl Neurol 3:812–818 DOI: 10.1002/acn3.338
Ferraz MJ, Marques AR, Appelman MD, Verhoek M, Strijland A, Mirzaian M, Scheij S, Ouairy CM, Lahav D, Wisse P, Overkleeft HS, Boot RG, Aerts JM (2016) Lysosomal glycosphingolipid catabolism by acid ceramidase: formation of glycosphingoid bases during deficiency of glycosidases. FEBS Lett 590:716–725 DOI: 10.1002/1873-3468.12104
Gegg ME, Burke D, Heales SJ, Cooper JM, Hardy J, Wood NW, Schapira AH (2012) Glucocerebrosidase deficiency in substantia nigra of parkinson disease brains. Ann Neurol 72:455–463 DOI: 10.1002/ana.23614
Glajch KE, Moors TE, Chen Y, Bechade PA, Nam AY, Rajsombath MM, Mccaffery TD, Dettmer U, Weihofen A, Hirst WD, Selkoe DJ, Nuber S (2021) Wild-type GBA1 increases the alpha-synuclein tetramer-monomer ratio, reduces lipid-rich aggregates, and attenuates motor and cognitive deficits in mice. Proc Natl Acad Sci USA 118
Goker-Alpan O, Schiffmann R, Lamarca ME, Nussbaum RL, McInerney-Leo A, Sidransky E (2004) Parkinsonism among Gaucher disease carriers. J Med Genet 41:937–940 DOI: 10.1136/jmg.2004.024455
Gundner AL, Duran-Pacheco G, Zimmermann S, Ruf I, Moors T, Baumann K, Jagasia R, van de Berg WDJ, Kremer T (2019) Path mediation analysis reveals GBA impacts Lewy body disease status by increasing alpha-synuclein levels. Neurobiol Dis 121:205–213 DOI: 10.1016/j.nbd.2018.09.015
Hallett PJ, Huebecker M, Brekk OR, Moloney EB, Rocha EM, Priestman DA, Platt FM, Isacson O (2018) Glycosphingolipid levels and glucocerebrosidase activity are altered in normal aging of the mouse brain. Neurobiol Aging 67:189–200 DOI: 10.1016/j.neurobiolaging.2018.02.028
Halliday G, Hely M, Reid W, Morris J (2008) The progression of pathology in longitudinally followed patients with Parkinson’s disease. Acta Neuropathol 115:409–415 DOI: 10.1007/s00401-008-0344-8
Halperin A, Elstein D, Zimran A (2006) Increased incidence of Parkinson disease among relatives of patients with Gaucher disease. Blood Cells Mol Dis 36:426–428 DOI: 10.1016/j.bcmd.2006.02.004
Heckman MG, Soto-Ortolaza AI, Contreras MYS, Murray ME, Pedraza O, Diehl NN, Walton R, Labbe C, Lorenzo-Betancor O, Uitti RJ, van Gerpen J, Ertekin-Taner N, Smith GE, Kantarci K, Savica R, Jones DT, Graff-Radford J, Knopman DS, Lowe VJ, Jack CR, Petersen RC, Parisi JE, Rademakers R, Wszolek ZK, Graff-Radford NR, Ferman TJ, Dickson DW, Boeve BF, Ross OA (2016) LRRK2 variation and dementia with Lewy bodies. Parkinsonism Relat Disord 31:98–103 DOI: 10.1016/j.parkreldis.2016.07.015
Hein LK, Meikle PJ, Hopwood JJ, Fuller M (2007) Secondary sphingolipid accumulation in a macrophage model of Gaucher disease. Mol Genet Metab 92:336–345 DOI: 10.1016/j.ymgme.2007.08.001
Honeycutt L, Montplaisir JY, Gagnon JF, Ruskey J, Pelletier A, Gan-Or Z, Postuma RB (2019) Glucocerebrosidase mutations and phenoconversion of REM sleep behavior disorder to parkinsonism and dementia. Parkinsonism Relat Disord 65:230–233 DOI: 10.1016/j.parkreldis.2019.04.016
Huebecker M, Moloney EB, van der Spoel AC, Priestman DA, Isacson O, Hallett PJ, Platt FM (2019) Reduced sphingolipid hydrolase activities, substrate accumulation and ganglioside decline in Parkinson’s disease. Mol Neurodegener 14:40 DOI: 10.1186/s13024-019-0339-z
Iwaki H, Blauwendraat C, Leonard HL, Liu G, Maple-Grodem J, Corvol JC, Pihlstrom L, van Nimwegen M, Hutten SJ, Nguyen KH, Rick J, Eberly S, Faghri F, Auinger P, Scott KM, Wijeyekoon R, van Deerlin VM, Hernandez DG, Day-Williams AG, Brice A, Alves G, Noyce AJ, Tysnes OB, Evans JR, Breen DP, Estrada K, Wegel CE, Danjou F, Simon DK, Ravina B, Toft M, Heutink P, Bloem BR, Weintraub D, Barker RA, Williams-Gray CH, van de Warrenburg BP, van Hilten JJ, Scherzer CR, Singleton AB, Nalls MA (2019) Genetic risk of Parkinson disease and progression: an analysis of 13 longitudinal cohorts. Neurol Genet 5:e348 DOI: 10.1212/NXG.0000000000000348
Jankovic J, Tan EK (2020) Parkinson’s disease: etiopathogenesis and treatment. J Neurol Neurosurg Psychiatry 91:795–808 DOI: 10.1136/jnnp-2019-322338
Jo J, Yang L, Tran HD, Yu W, Sun AX, Chang YY, Jung BC, Lee SJ, Saw TY, Xiao B, Khoo ATT, Yaw LP, Xie JJ, Lokman H, Ong WY, Lim GGY, Lim KL, Tan EK, Ng HH, Je HS (2021) Lewy body-like inclusions in human midbrain organoids carrying glucocerebrosidase and alpha-synuclein mutations. Ann Neurol 90:490–505 DOI: 10.1002/ana.26166
Kalia LV, Lang AE, Hazrati LN, Fujioka S, Wszolek ZK, Dickson DW, Ross OA, van Deerlin VM, Trojanowski JQ, Hurtig HI, Alcalay RN, Marder KS, Clark LN, Gaig C, Tolosa E, Ruiz-Martinez J, Marti-Masso JF, Ferrer I, Munain AL, Goldman SM, Schule B, Langston JW, Aasly JO, Giordana MT, Bonifati V, Puschmann A, Canesi M, Pezzoli G, de Paula AM, Hasegawa K, Duyckaerts C, Brice A, Stoessl AJ, Marras C (2015) Clinical correlations with Lewy body pathology in LRRK2-related Parkinson disease. JAMA Neurol 72:100–105 DOI: 10.1001/jamaneurol.2014.2704
Kang JH, Mollenhauer B, Coffey CS, Toledo JB, Weintraub D, Galasko DR, Irwin DJ, van Deerlin V, Chen-Plotkin AS, Caspell-Garcia C, Waligorska T, Taylor P, Shah N, Pan S, Zero P, Frasier M, Marek K, Kieburtz K, Jennings D, Tanner CM, Simuni T, Singleton A, Toga AW, Chowdhury S, Trojanowski JQ, Shaw LM, Parkinson’s Progression Marker I (2016) CSF biomarkers associated with disease heterogeneity in early Parkinson’s disease: the Parkinson’s Progression Markers Initiative study. Acta Neuropathol 131:935–949 DOI: 10.1007/s00401-016-1552-2
Kang UJ, Boehme AK, Fairfoul G, Shahnawaz M, Ma TC, Hutten SJ, Green A, Soto C (2019) Comparative study of cerebrospinal fluid alpha-synuclein seeding aggregation assays for diagnosis of Parkinson’s disease. Mov Disord 34:536–544 DOI: 10.1002/mds.27646
Kim S, Yun SP, Lee S, Umanah GE, Bandaru VVR, Yin X, Rhee P, Karuppagounder SS, Kwon SH, Lee H, Mao X, Kim D, Pandey A, Lee G, Dawson VL, Dawson TM, Ko HS (2018) GBA1 deficiency negatively affects physiological alpha-synuclein tetramers and related multimers. Proc Natl Acad Sci USA 115:798–803 DOI: 10.1073/pnas.1700465115
Kopytova AE, Rychkov GN, Nikolaev MA, Baydakova GV, Cheblokov AA, Senkevich KA, Bogdanova DA, Bolshakova OI, Miliukhina IV, Bezrukikh VA, Salogub GN, Sarantseva SV, Usenko TC, Zakharova EY, Emelyanov AK, Pchelina SN (2021) Ambroxol increases glucocerebrosidase (GCase) activity and restores GCase translocation in primary patient-derived macrophages in Gaucher disease and Parkinsonism. Parkinsonism Relat Disord 84:112–121 DOI: 10.1016/j.parkreldis.2021.02.003
Kurzawa-Akanbi M, Tammireddy S, Fabrik I, Gliaudelyte L, Doherty MK, Heap R, Matecko-Burmann I, Burmann BM, Trost M, Lucocq JM, Gherman AV, Fairfoul G, Singh P, Burte F, Green A, McKeith IG, Hartlova A, Whitfield PD, Morris CM (2021) Altered ceramide metabolism is a feature in the extracellular vesicle-mediated spread of alpha-synuclein in Lewy body disorders. Acta Neuropathol 142:961–984 DOI: 10.1007/s00401-021-02367-3
Lerche S, Machetanz G, Wurster I, Roeben B, Zimmermann M, Pilotto A, Preische O, Stransky E, Deuschle C, Hauser AK, Schulte C, Lachmann I, Waniek K, Gasser T, Berg D, Maetzler W, Brockmann K (2019a) Dementia with lewy bodies: GBA1 mutations are associated with cerebrospinal fluid alpha-synuclein profile. Mov Disord 34:1069–1073 DOI: 10.1002/mds.27731
Lerche S, Wurster I, Roben B, Machetanz G, Zimmermann M, Bernhard F, Stransky E, Deuschle C, Schulte C, Hansson O, Zetterberg H, Gasser T, Berg D, Maetzler W, Brockmann K (2019b) Parkinson’s disease: evolution of cognitive impairment and CSF Abeta1-42 profiles in a prospective longitudinal study. J Neurol Neurosurg Psychiatry 90:165–170 DOI: 10.1136/jnnp-2018-318956
Lerche S, Wurster I, Roeben B, Zimmermann M, Riebenbauer B, Deuschle C, Hauser AK, Schulte C, Berg D, Maetzler W, Waniek K, Lachmann I, Liepelt-Scarfone I, Gasser T, Brockmann K (2020) Parkinson’s disease: glucocerebrosidase 1 mutation severity is associated with CSF alpha-synuclein profiles. Mov Disord 35:495–499 DOI: 10.1002/mds.27884
Lerche S, Schulte C, Wurster I, Machetanz G, Roeben B, Zimmermann M, Deuschle C, Hauser AK, Bohringer J, Krageloh-Mann I, Waniek K, Lachmann I, Petterson XT, Chiang R, Park H, Wang B, Liepelt-Scarfone I, Maetzler W, Galasko D, Scherzer CR, Gasser T, Mielke MM, Hutten SJ, Mollenhauer B, Sardi SP, Berg D, Brockmann K (2021a) The mutation matters: CSF profiles of GCase, sphingolipids, alpha-synuclein in PDGBA. Mov Disord 36:1216–1228 DOI: 10.1002/mds.28472
Lerche S, Sjodin S, Brinkmalm A, Blennow K, Wurster I, Roeben B, Zimmermann M, Hauser AK, Liepelt-Scarfone I, Waniek K, Lachmann I, Gasser T, Zetterberg H, Brockmann K (2021b) CSF protein level of neurotransmitter secretion, synaptic plasticity, and autophagy in PD and DLB. Mov Disord 36:2595–2604 DOI: 10.1002/mds.28704
Lesage S, Anheim M, Condroyer C, Pollak P, Durif F, Dupuits C, Viallet F, Lohmann E, Corvol JC, Honore A, Rivaud S, Vidailhet M, Durr A, Brice A, FRENCH PARKINSON’S DISEASE GENETICS STUDY G (2011) Large-scale screening of the Gaucher’s disease-related glucocerebrosidase gene in Europeans with Parkinson’s disease. Hum Mol Genet 20:202–210 DOI: 10.1093/hmg/ddq454
Maegawa GH, Tropak MB, Buttner JD, Rigat BA, Fuller M, Pandit D, Tang L, Kornhaber GJ, Hamuro Y, Clarke JT, Mahuran DJ (2009) Identification and characterization of ambroxol as an enzyme enhancement agent for Gaucher disease. J Biol Chem 284:23502–23516 DOI: 10.1074/jbc.M109.012393
Magalhaes J, Gegg ME, Migdalska-Richards A, Doherty MK, Whitfield PD, Schapira AH (2016) Autophagic lysosome reformation dysfunction in glucocerebrosidase deficient cells: relevance to Parkinson disease. Hum Mol Genet 25:3432–3445 DOI: 10.1093/hmg/ddw185
Magalhaes J, Gegg ME, Migdalska-Richards A, Schapira AH (2018) Effects of ambroxol on the autophagy-lysosome pathway and mitochondria in primary cortical neurons. Sci Rep 8:1385 DOI: 10.1038/s41598-018-19479-8
Mahungu AC, Anderson DG, Rossouw AC, van Coller R, Carr JA, Ross OA, Bardien S (2020) Screening of the glucocerebrosidase (GBA) gene in South Africans of African ancestry with Parkinson’s disease. Neurobiol Aging 88:156 e11-156 e14 DOI: 10.1016/j.neurobiolaging.2019.12.011
Malek N, Swallow D, Grosset KA, Anichtchik O, Spillantini M, Grosset DG (2014) Alpha-synuclein in peripheral tissues and body fluids as a biomarker for Parkinson’s disease - a systematic review. Acta Neurol Scand 130:59–72 DOI: 10.1111/ane.12247
Malek N, Weil RS, Bresner C, Lawton MA, Grosset KA, Tan M, Bajaj N, Barker RA, Burn DJ, Foltynie T, Hardy J, Wood NW, Ben-Shlomo Y, Williams NW, Grosset DG, Morris HR, Consortium PRC (2018) Features of GBA-associated Parkinson’s disease at presentation in the UK Tracking Parkinson’s study. J Neurol Neurosurg Psychiatry 89:702–709 DOI: 10.1136/jnnp-2017-317348
Mazzulli JR, Xu YH, Sun Y, Knight AL, McLean PJ, Caldwell GA, Sidransky E, Grabowski GA, Krainc D (2011) Gaucher disease glucocerebrosidase and alpha-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell 146:37–52 DOI: 10.1016/j.cell.2011.06.001
Mazzulli JR, Zunke F, Isacson O, Studer L, Krainc D (2016) alpha-Synuclein-induced lysosomal dysfunction occurs through disruptions in protein trafficking in human midbrain synucleinopathy models. Proc Natl Acad Sci USA 113:1931–1936 DOI: 10.1073/pnas.1520335113
McNeill A, Magalhaes J, Shen C, Chau KY, Hughes D, Mehta A, Foltynie T, Cooper JM, Abramov AY, Gegg M, Schapira AH (2014) Ambroxol improves lysosomal biochemistry in glucocerebrosidase mutation-linked Parkinson disease cells. Brain 137:1481–1495 DOI: 10.1093/brain/awu020
Mielke MM, Maetzler W, Haughey NJ, Bandaru VV, Savica R, Deuschle C, Gasser T, Hauser AK, Graber-Sultan S, Schleicher E, Berg D, Liepelt-Scarfone I (2013) Plasma ceramide and glucosylceramide metabolism is altered in sporadic Parkinson’s disease and associated with cognitive impairment: a pilot study. PLoS ONE 8:e73094 DOI: 10.1371/journal.pone.0073094
Migdalska-Richards A, Daly L, Bezard E, Schapira AH (2016) Ambroxol effects in glucocerebrosidase and alpha-synuclein transgenic mice. Ann Neurol 80:766–775 DOI: 10.1002/ana.24790
Mollenhauer B, Caspell-Garcia CJ, Coffey CS, Taylor P, Singleton A, Shaw LM, Trojanowski JQ, Frasier M, Simuni T, Iranzo A, Oertel W, Siderowf A, Weintraub D, Seibyl J, Toga AW, Tanner CM, Kieburtz K, Chahine LM, Marek K, Galasko D, Study P (2019) Longitudinal analyses of cerebrospinal fluid alpha-Synuclein in prodromal and early Parkinson’s disease. Mov Disord 34:1354–1364 DOI: 10.1002/mds.27806
Moors TE, Paciotti S, Ingrassia A, Quadri M, Breedveld G, Tasegian A, Chiasserini D, Eusebi P, Duran-Pacheco G, Kremer T, Calabresi P, Bonifati V, Parnetti L, Beccari T, van de Berg WDJ (2019) Characterization of brain lysosomal activities in GBA-related and sporadic Parkinson’s disease and dementia with Lewy bodies. Mol Neurobiol 56:1344–1355 DOI: 10.1007/s12035-018-1090-0
Mullin S, Beavan M, Bestwick J, McNeill A, Proukakis C, Cox T, Hughes D, Mehta A, Zetterberg H, Schapira AHV (2019) Evolution and clustering of prodromal parkinsonian features in GBA1 carriers. Mov Disord 34:1365–1373 DOI: 10.1002/mds.27775
Mullin S, Smith L, Lee K, D’Souza G, Woodgate P, Elflein J, Hallqvist J, Toffoli M, Streeter A, Hosking J, Heywood WE, Khengar R, Campbell P, Hehir J, Cable S, Mills K, Zetterberg H, Limousin P, Libri V, Foltynie T, Schapira AHV (2020) Ambroxol for the treatment of patients with Parkinson disease with and without glucocerebrosidase gene mutations: a nonrandomized, noncontrolled trial. JAMA Neurol 77:427–434 DOI: 10.1001/jamaneurol.2019.4611
Murphy KE, Gysbers AM, Abbott SK, Tayebi N, Kim WS, Sidransky E, Cooper A, Garner B, Halliday GM (2014) Reduced glucocerebrosidase is associated with increased alpha-synuclein in sporadic Parkinson’s disease. Brain 137:834–848 DOI: 10.1093/brain/awt367
Nalls MA, Duran R, Lopez G, Kurzawa-Akanbi M, McKeith IG, Chinnery PF, Morris CM, Theuns J, Crosiers D, Cras P, Engelborghs S, de Deyn PP, van Broeckhoven C, Mann DM, Snowden J, Pickering-Brown S, Halliwell N, Davidson Y, Gibbons L, Harris J, Sheerin UM, Bras J, Hardy J, Clark L, Marder K, Honig LS, Berg D, Maetzler W, Brockmann K, Gasser T, Novellino F, Quattrone A, Annesi G, de Marco EV, Rogaeva E, Masellis M, Black SE, Bilbao JM, Foroud T, Ghetti B, Nichols WC, Pankratz N, Halliday G, Lesage S, Klebe S, Durr A, Duyckaerts C, Brice A, Giasson BI, Trojanowski JQ, Hurtig HI, Tayebi N, Landazabal C, Knight MA, Keller M, Singleton AB, Wolfsberg TG, Sidransky E (2013) A multicenter study of glucocerebrosidase mutations in dementia with Lewy bodies. JAMA Neurol 70:727–735 DOI: 10.1001/jamaneurol.2013.1925
Neumann J, Bras J, Deas E, O’Sullivan SS, Parkkinen L, Lachmann RH, Li A, Holton J, Guerreiro R, Paudel R, Segarane B, Singleton A, Lees A, Hardy J, Houlden H, Revesz T, Wood NW (2009) Glucocerebrosidase mutations in clinical and pathologically proven Parkinson’s disease. Brain 132:1783–1794 DOI: 10.1093/brain/awp044
Paciotti S, Gatticchi L, Beccari T, Parnetti L (2019) Lysosomal enzyme activities as possible CSF biomarkers of synucleinopathies. Clin Chim Acta 495:13–24 DOI: 10.1016/j.cca.2019.03.1627
Pal G, Mangone G, Hill EJ, Ouyang B, Liu Y, Lythe V, Ehrlich D, Saunders-Pullman R, Shanker V, Bressman S, Alcalay RN, Garcia P, Marder KS, Aasly J, Mouradian MM, Link S, Rosenbaum M, Anderson S, Bernard B, Wilson R, Stebbins G, Nichols WC, Welter ML, Sani S, Afshari M, Verhagen L, de Bie RMA, Foltynie T, Hall D, Corvol JC, Goetz CG (2022) Parkinson disease and subthalamic nucleus deep brain stimulation: cognitive effects in GBA mutation carriers. Ann Neurol 91:424–435 DOI: 10.1002/ana.26302
Parnetti L, Paciotti S, Eusebi P, Dardis A, Zampieri S, Chiasserini D, Tasegian A, Tambasco N, Bembi B, Calabresi P, Beccari T (2017) Cerebrospinal fluid beta-glucocerebrosidase activity is reduced in Parkinson’s disease patients. Mov Disord 32:1423–1431 DOI: 10.1002/mds.27136
Petrucci S, Ginevrino M, Trezzi I, Monfrini E, Ricciardi L, Albanese A, Avenali M, Barone P, Bentivoglio AR, Bonifati V, Bove F, Bonanni L, Brusa L, Cereda C, Cossu G, Criscuolo C, Dati G, de Rosa A, Eleopra R, Fabbrini G, Fadda L, Garbellini M, Minafra B, Onofrj M, Pacchetti C, Palmieri I, Pellecchia MT, Petracca M, Picillo M, Pisani A, Vallelunga A, Zangaglia R, di Fonzo A, Morgante F, Valente EM (2020) GBA-related parkinson’s disease: dissection of genotype-phenotype correlates in a large Italian cohort. Mov Disord 35:2106–2111 DOI: 10.1002/mds.28195
Piccinini M, Scandroglio F, Prioni S, Buccinna B, Loberto N, Aureli M, Chigorno V, Lupino E, Demarco G, Lomartire A, Rinaudo MT, Sonnino S, Prinetti A (2010) Deregulated sphingolipid metabolism and membrane organization in neurodegenerative disorders. Mol Neurobiol 41:314–340 DOI: 10.1007/s12035-009-8096-6
Rocha EM, Smith GA, Park E, Cao H, Brown E, Hallett P, Isacson O (2015a) Progressive decline of glucocerebrosidase in aging and Parkinson’s disease. Ann Clin Transl Neurol 2:433–438 DOI: 10.1002/acn3.177
Rocha EM, Smith GA, Park E, Cao H, Brown E, Hayes MA, Beagan J, McLean JR, Izen SC, Perez-Torres E, Hallett PJ, Isacson O (2015b) Glucocerebrosidase gene therapy prevents alpha-synucleinopathy of midbrain dopamine neurons. Neurobiol Dis 82:495–503 DOI: 10.1016/j.nbd.2015.09.009
Rossi M, Candelise N, Baiardi S, Capellari S, Giannini G, Orru CD, Antelmi E, Mammana A, Hughson AG, Calandra-Buonaura G, Ladogana A, Plazzi G, Cortelli P, Caughey B, Parchi P (2020) Ultrasensitive RT-QuIC assay with high sensitivity and specificity for Lewy body-associated synucleinopathies. Acta Neuropathol 140:49–62 DOI: 10.1007/s00401-020-02160-8
Sardi SP, Clarke J, Kinnecom C, Tamsett TJ, Li L, Stanek LM, Passini MA, Grabowski GA, Schlossmacher MG, Sidman RL, Cheng SH, Shihabuddin LS (2011) CNS expression of glucocerebrosidase corrects alpha-synuclein pathology and memory in a mouse model of Gaucher-related synucleinopathy. Proc Natl Acad Sci USA 108:12101–12106 DOI: 10.1073/pnas.1108197108
Schneider SA, Alcalay RN (2017) Neuropathology of genetic synucleinopathies with parkinsonism: Review of the literature. Mov Disord 32:1504–1523 DOI: 10.1002/mds.27193
Schondorf DC, Aureli M, McAllister FE, Hindley CJ, Mayer F, Schmid B, Sardi SP, Valsecchi M, Hoffmann S, Schwarz LK, Hedrich U, Berg D, Shihabuddin LS, Hu J, Pruszak J, Gygi SP, Sonnino S, Gasser T, Deleidi M (2014) iPSC-derived neurons from GBA1-associated Parkinson’s disease patients show autophagic defects and impaired calcium homeostasis. Nat Commun 5:4028 DOI: 10.1038/ncomms5028
Shahnawaz M, Tokuda T, Waragai M, Mendez N, Ishii R, Trenkwalder C, Mollenhauer B, Soto C (2017) Development of a biochemical diagnosis of Parkinson disease by detection of alpha-synuclein misfolded aggregates in cerebrospinal fluid. JAMA Neurol 74:163–172 DOI: 10.1001/jamaneurol.2016.4547
Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, Barbosa ER, Bar-Shira A, Berg D, Bras J, Brice A, Chen CM, Clark LN, Condroyer C, de Marco EV, Durr A, Eblan MJ, Fahn S, Farrer MJ, Fung HC, Gan-Or Z, Gasser T, Gershoni-Baruch R, Giladi N, Griffith A, Gurevich T, Januario C, Kropp P, Lang AE, Lee-Chen GJ, Lesage S, Marder K, Mata IF, Mirelman A, Mitsui J, Mizuta I, Nicoletti G, Oliveira C, Ottman R, Orr-Urtreger A, Pereira LV, Quattrone A, Rogaeva E, Rolfs A, Rosenbaum H, Rozenberg R, Samii A, Samaddar T, Schulte C, Sharma M, Singleton A, Spitz M, Tan EK, Tayebi N, Toda T, Troiano AR, Tsuji S, Wittstock M, Wolfsberg TG, Wu YR, Zabetian CP, Zhao Y, Ziegler SG (2009) Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease. N Engl J Med 361:1651–1661 DOI: 10.1056/NEJMoa0901281
Stoker TB, Camacho M, Winder-Rhodes S, Liu G, Scherzer CR, Foltynie T, Evans J, Breen DP, Barker RA, Williams-Gray CH (2020) Impact of GBA1 variants on long-term clinical progression and mortality in incident Parkinson’s disease. J Neurol Neurosurg Psychiatry 91:695–702 DOI: 10.1136/jnnp-2020-322857
Straniero L, Asselta R, Bonvegna S, Rimoldi V, Melistaccio G, Solda G, Aureli M, Della Porta M, Lucca U, di Fonzo A, Zecchinelli A, Pezzoli G, Cilia R, Duga S (2020) The SPID-GBA study: sex distribution, penetrance, incidence, and dementia in GBA-PD. Neurol Genet 6:e523 DOI: 10.1212/NXG.0000000000000523
Surface M, Balwani M, Waters C, Haimovich A, Gan-Or Z, Marder KS, Hsieh T, Song L, Padmanabhan S, Hsieh F, Merchant KM, Alcalay RN (2022) Plasma glucosylsphingosine in gba1 mutation carriers with and without Parkinson’s disease. Mov Disord 37:416–421 DOI: 10.1002/mds.28846
Taguchi YV, Liu J, Ruan J, Pacheco J, Zhang X, Abbasi J, Keutzer J, Mistry PK, Chandra SS (2017) Glucosylsphingosine promotes alpha-synuclein pathology in mutant GBA-associated Parkinson’s disease. J Neurosci 37:9617–9631 DOI: 10.1523/JNEUROSCI.1525-17.2017
Thaler A, Gurevich T, Bar Shira A, Gana Weisz M, Ash E, Shiner T, Orr-Urtreger A, Giladi N, Mirelman A (2017) A “dose” effect of mutations in the GBA gene on Parkinson’s disease phenotype. Parkinsonism Relat Disord 36:47–51 DOI: 10.1016/j.parkreldis.2016.12.014
Thaler A, Bregman N, Gurevich T, Shiner T, Dror Y, Zmira O, Gan-Or Z, Bar-Shira A, Gana-Weisz M, Orr-Urtreger A, Giladi N, Mirelman A (2018) Parkinson’s disease phenotype is influenced by the severity of the mutations in the GBA gene. Parkinsonism Relat Disord 55:45–49 DOI: 10.1016/j.parkreldis.2018.05.009
van der Lee SJ, van Steenoven I, van de Beek M, Tesi N, Jansen IE, van Schoor NM, Reinders MJT, Huisman M, Scheltens P, Teunissen CE, Holstege H, van der Flier WM, Lemstra AW (2021) Genetics contributes to concomitant pathology and clinical presentation in dementia with Lewy bodies. J Alzheimers Dis 83:269–279 DOI: 10.3233/JAD-210365
Wang G, Bieberich E (2018) Sphingolipids in neurodegeneration (with focus on ceramide and S1P). Adv Biol Regul 70:51–64 DOI: 10.1016/j.jbior.2018.09.013
Yang SY, Taanman JW, Gegg M, Schapira AHV (2022) Ambroxol reverses tau and alpha-synuclein accumulation in a cholinergic N370S GBA1 mutation model. Hum Mol Genet
Zhang Y, Shu L, Sun Q, Zhou X, Pan H, Guo J, Tang B (2018) Integrated genetic analysis of racial differences of common GBA variants in Parkinson’s disease: a meta-analysis. Front Mol Neurosci 11:43 DOI: 10.3389/fnmol.2018.00043
Zimmermann M, Gaenslen A, Prahl K, Srulijes K, Hauser AK, Schulte C, Csoti I, Berg D, Brockmann K (2018) Patient’s perception: shorter and more severe prodromal phase in GBA-associated PD. Eur J Neurol 26:694–698 DOI: 10.1111/ene.13776
Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, Kachergus J, Hulihan M, Uitti RJ, Calne DB, Stoessl AJ, Pfeiffer RF, Patenge N, Carbajal IC, Vieregge P, Asmus F, Muller-Myhsok B, Dickson DW, Meitinger T, Strom TM, Wszolek ZK, Gasser T (2004) Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44:601–607 DOI: 10.1016/j.neuron.2004.11.005
Zunke F, Moise AC, Belur NR, Gelyana E, Stojkovska I, Dzaferbegovic H, Toker NJ, Jeon S, Fredriksen K, Mazzulli JR (2018) Reversible conformational conversion of alpha-synuclein into toxic assemblies by glucosylceramide. Neuron 97(92–107):e10