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Cited by 23Lysosomal Storage Disorders ResearchParkinson's Disease Mechanisms and TreatmentsAlzheimer's disease research and treatments

A novel glucosylceramide synthase inhibitor attenuates alpha synuclein pathology and lysosomal dysfunction in preclinical models of synucleinopathy

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Cosden, Mali, Jinn, Sarah, Yao, Lihang, Gretzula, Cheryl A., Kandebo, Monika, Toolan, Dawn, Hatcher, Nathan G., Ma, Lei +11 more·2021·Neurobiology of Disease
DOI 10.1016/j.nbd.2021.105507
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Abstract

Mutations in the lysosomal enzyme glucocerebrosidase (GCase, GBA1 gene) are the most common genetic risk factor for developing Parkinson's disease (PD). GCase metabolizes the glycosphingolipids glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph). Mutations in GBA1 reduce enzyme activity and the resulting accumulation of glycosphingolipids may contribute to the underlying pathology of PD, possibly via altering lysosomal function. While reduction of GCase activity exacerbates α-synuclein (α-syn) aggregation, it has not been determined that this effect is the result of altered glycosphingolipid levels and lysosome function or some other effect of altering GCase. The glycosphingolipid GlcCer is synthesized by a single enzyme, glucosylceramide synthase (GCS), and small molecule inhibitors (GCSi) reduce cellular glycosphingolipid levels. In the present studies, we utilize a preformed fibril (PFF) rodent primary neuron in vitro model of α-syn pathology to investigate the relationship between glycosphingolipid levels, α-syn pathology, and lysosomal function. In primary cultures, pharmacological inhibition of GCase and D409V GBA1 mutation enhanced accumulation of glycosphingolipids and insoluble phosphorylated α-syn. Administration of a novel small molecule GCSi, benzoxazole 1 (BZ1), significantly decreased glycosphingolipid concentrations in rodent primary neurons and reduced α-syn pathology. BZ1 rescued lysosomal deficits associated with the D409V GBA1 mutation and α-syn PFF administration, and attenuated α-syn induced neurodegeneration of dopamine neurons. In vivo studies revealed BZ1 had pharmacological activity and reduced glycosphingolipids in the mouse brain to a similar extent observed in neuronal cultures. These data support the hypothesis that reduction of glycosphingolipids through GCS inhibition may impact progression of synucleinopathy and BZ1 is useful tool to further examine this important biology.

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  • Myelin is a sphingolipid, and this class of lipids is broken down exclusively in endolysosomes by a series of enzymes, many of which are implicated in the sphingolipidoses.

    “First, myelin is a sphingolipid, and this class of lipids is broken down exclusively in endolysosomes by a series of enzymes, many of which are implicated in the sphingolipidoses, a sub-category of lysosomal storage disorders.35”

    From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [35]

    The Introduction (page unavailable) says that the lysosomal enzyme GCase metabolizes two glycosphingolipids and that GBA1 mutations cause Gaucher’s disease, a lysosomal storage disorder. It does not identify myelin as a sphingolipid or say that sphingolipids are broken down exclusively in endolysosomes by a series of enzymes implicated in the sphingolipidoses. (LLM, conf=0.84)

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Authors
Cosden, M., Jinn, S., Yao, L., Gretzula, C. A., Kandebo, M., Toolan, D., Hatcher, N. G., Ma, L., Lemaire, W., Adam, G. C., Burlein, C., Minnick, C., Flick, R., Watt, M. L., Mulhearn, J., Fraley, M., Drolet, R. E., Marcus, J. N., & Smith, S. M.
Affiliations
Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
Corresponding author
Smith, Sean M.
ORCID
Venue
Neurobiology of Disease
Publisher
Elsevier BV
Published
2021-11
Volume
159
Pages
105507
ISSN
0969-9961 (ISSN-L)
DOI
10.1016/j.nbd.2021.105507
OpenAlex
W3199941846
Cited by
23
References
3
Citations by year
2026: 3 · 2025: 3 · 2024: 3 · 2023: 6 · 2022: 8
FWCI
2.98
Type
journal article
Language
en
Open access
Licence
Locations
  • Neurobiology of Disease (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Merck
Topics
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
glucosylceramide synthase inhibitor, glucosylceramide, glucosylsphingosine, glucocerebrosidase, GBA mutations, alpha-synuclein aggregation, synucleinopathies, Parkinson's disease, lysosomal dysfunction, glycosphingolipids, dopaminergic neurons, neurodegeneration, small molecule inhibitors
MeSH terms
Synucleinopathies, Animals, Benzoxazoles, Glucosylceramidase, Glucosyltransferases, Glycosphingolipids, Lysosomes, Neurons, Parkinson Disease, Mice, Rats, alpha-Synuclein, Dopaminergic Neurons, Primary Cell Culture, In Vitro Techniques, Protein Aggregates

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