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Review
. 2022 Sep;129(9):1219-1233.
doi: 10.1007/s00702-022-02511-7. Epub 2022 May 31.

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

Günter Höglinger  1   2 , Claudia Schulte  3   4 , Wolfgang H Jost  5 , Alexander Storch  6   7 , Dirk Woitalla  8 , Rejko Krüger  9   10   11 , Björn Falkenburger  12 , Kathrin Brockmann  13   14
Affiliations
Review

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

Günter Höglinger et al. J Neural Transm (Vienna). 2022 Sep.

Abstract

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.

Keywords: GBA; Lysosomal; PD; α-Synuclein.

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Conflict of interest statement

Günther Höglinger was supported by Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy—ID 390857198) and within the Hannover Cluster RESIST (EXC 2155—ID 390874280), DFG grants (HO2402/6-2, HO2402/18-1 MSAomics), the German Federal Ministry of Education and Research (BMBF, 01KU1403A EpiPD; 01EK1605A HitTau; 01DH18025 TauTherapy), the German Center for Neurodegenerative Diseases e.V. (DZNE), Niedersächsisches Ministerium für Wissenschaft und Kunst (MWK, ZN3440.TP): REBIRTH—Forschungszentrum für translationale regenerative Medizin; VolkswagenStiftung (Niedersächsisches Vorab); Petermax-Müller Foundation (Etiology and Therapy of Synucleinopathies and Tauopathies); the German Parkinson Society (DPG; ProAPS), the German PSP Association (PSP Gesellschaft; ProPSP); participated in industry-sponsored research projects from Abbvie, Biogen, Biohaven, Novartis, Roche, Sanofi, UCB. Claudia Schulte has nothing to disclose. Wolfgang H. Jost is/was speaker and/or advisor Abbvie, Bial, Kyowa Kirin, Merz, UCB, Zambon. Alexander Storch has received funding from the Deutsche Forschungsgemeinschaft (DFG) and the Helmholtz-Association. He received honoraria for presentations/lectures/consultancies or advisory boards from AbbVie, Bayer Healthcare, Desitin, Bial, GKC, Grünenthal, UCB, Zambon, Ca, AbbVie, TEVA, Lundbeck, and UCB Pharma, outside the submitted work. He has served on the editorial boards of Stem Cells and Stem Cells International and received royalties from Kohlhammer Verlag and Elsevier Press. Dirk Woitalla has nothing to disclose. Rejko Krüger has nothing to disclose. Björn Falkenburger has nothing to disclose.

Figures

Fig. 1
Fig. 1
Pathogenic mechanisms underlying PDGBA. Loss of lysosomal GCase activity results in impaired autophagy affecting the degradation of both physiological (red dot) and misfolded α-synuclein (red dot complex) resulting in the aggregation of α-synuclein (red strains). GBA variants also cause the GCase protein to misfold in the ER (brown enzyme) with impaired trafficking to the lysosome which also affects α-synuclein degradation. Accumulation of GCase substrates (GlcCer and GlcSph, yellow) also causes α-synuclein misfolding and aggregation, as may changes in the lipid homeostasis (both sphingolipids and phospholipids) of cellular membranes (yellow) due to decreased lysosomal function. In PDGBA_wildtype, the trafficking of wild-type GCase (green enzyme) can be inhibited by increased levels of α-synuclein (red dot complex) and α-synuclein fibrils (red strains), and contribute GCase deficiency (brown enzyme) irrespective of a GBA mutation. This figure was adapted from “Brainstem with Callout” and “Structural Overview of an Animal Cell”, by BioRender.com (2022). Retrieved from https://app.biorender.com/biorender-templates
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