A novel glucosylceramide synthase inhibitor attenuates alpha synuclein pathology and lysosomal dysfunction in preclinical models of synucleinopathy
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2021-11-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996121002564 |
| _version_ | 1819041720271110144 |
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| author | Mali Cosden Sarah Jinn Lihang Yao Cheryl A. Gretzula Monika Kandebo Dawn Toolan Nathan G. Hatcher Lei Ma Wei Lemaire Gregory C. Adam Christine Burlein Christina Minnick Rose Flick Marla L. Watt James Mulhearn Mark Fraley Robert E. Drolet Jacob N. Marcus Sean M. Smith |
| author_facet | Mali Cosden Sarah Jinn Lihang Yao Cheryl A. Gretzula Monika Kandebo Dawn Toolan Nathan G. Hatcher Lei Ma Wei Lemaire Gregory C. Adam Christine Burlein Christina Minnick Rose Flick Marla L. Watt James Mulhearn Mark Fraley Robert E. Drolet Jacob N. Marcus Sean M. Smith |
| author_sort | Mali Cosden |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T09:29:29Z |
| format | Article |
| id | doaj.art-5bb119e476704557a1fe920f9ef43979 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-21T09:29:29Z |
| publishDate | 2021-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-5bb119e476704557a1fe920f9ef439792022-12-21T19:08:47ZengElsevierNeurobiology of Disease1095-953X2021-11-01159105507A novel glucosylceramide synthase inhibitor attenuates alpha synuclein pathology and lysosomal dysfunction in preclinical models of synucleinopathyMali Cosden0Sarah Jinn1Lihang Yao2Cheryl A. Gretzula3Monika Kandebo4Dawn Toolan5Nathan G. Hatcher6Lei Ma7Wei Lemaire8Gregory C. Adam9Christine Burlein10Christina Minnick11Rose Flick12Marla L. Watt13James Mulhearn14Mark Fraley15Robert E. Drolet16Jacob N. Marcus17Sean M. Smith18Neuroscience Discovery, Merck & Co., Inc., West Point, PA 19486, United StatesNeuroscience Discovery, Merck & Co., Inc., West Point, PA 19486, United StatesNeuroscience Discovery, Merck & Co., Inc., West Point, PA 19486, United StatesNeuroscience Discovery, Merck & Co., Inc., West Point, PA 19486, United StatesNeuroscience Discovery, Merck & Co., Inc., West Point, PA 19486, United StatesNeuroscience Discovery, Merck & Co., Inc., West Point, PA 19486, United StatesNeuroscience Discovery, Merck & Co., Inc., West Point, PA 19486, United StatesNeuroscience Discovery, Merck & Co., Inc., West Point, PA 19486, United StatesQuantitative Biosciences, Merck & Co., Inc., West Point, PA 19486, United StatesQuantitative Biosciences, Merck & Co., Inc., West Point, PA 19486, United StatesQuantitative Biosciences, Merck & Co., Inc., West Point, PA 19486, United StatesQuantitative Biosciences, Merck & Co., Inc., West Point, PA 19486, United StatesQuantitative Biosciences, Merck & Co., Inc., West Point, PA 19486, United StatesQuantitative Biosciences, Merck & Co., Inc., West Point, PA 19486, United StatesDiscovery Chemistry, Merck & Co., Inc., West Point, PA 19486, United StatesDiscovery Chemistry, Merck & Co., Inc., West Point, PA 19486, United StatesNeuroscience Discovery, Merck & Co., Inc., West Point, PA 19486, United StatesNeuroscience Discovery, Merck & Co., Inc., West Point, PA 19486, United StatesNeuroscience Discovery, Merck & Co., Inc., West Point, PA 19486, United States; Corresponding author at: Neuroscience Discovery, 770 Sumneytown Pike, West Point, PA 19486, United States.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.http://www.sciencedirect.com/science/article/pii/S0969996121002564GlucocerebrosidaseGlucosylceramide synthase inhibitorGlycosphingolipidsParkinson's diseaseLysosomal biologyPreformed fibril model |
| spellingShingle | Mali Cosden Sarah Jinn Lihang Yao Cheryl A. Gretzula Monika Kandebo Dawn Toolan Nathan G. Hatcher Lei Ma Wei Lemaire Gregory C. Adam Christine Burlein Christina Minnick Rose Flick Marla L. Watt James Mulhearn Mark Fraley Robert E. Drolet Jacob N. Marcus Sean M. Smith A novel glucosylceramide synthase inhibitor attenuates alpha synuclein pathology and lysosomal dysfunction in preclinical models of synucleinopathy Neurobiology of Disease Glucocerebrosidase Glucosylceramide synthase inhibitor Glycosphingolipids Parkinson's disease Lysosomal biology Preformed fibril model |
| title | A novel glucosylceramide synthase inhibitor attenuates alpha synuclein pathology and lysosomal dysfunction in preclinical models of synucleinopathy |
| title_full | A novel glucosylceramide synthase inhibitor attenuates alpha synuclein pathology and lysosomal dysfunction in preclinical models of synucleinopathy |
| title_fullStr | A novel glucosylceramide synthase inhibitor attenuates alpha synuclein pathology and lysosomal dysfunction in preclinical models of synucleinopathy |
| title_full_unstemmed | A novel glucosylceramide synthase inhibitor attenuates alpha synuclein pathology and lysosomal dysfunction in preclinical models of synucleinopathy |
| title_short | A novel glucosylceramide synthase inhibitor attenuates alpha synuclein pathology and lysosomal dysfunction in preclinical models of synucleinopathy |
| title_sort | novel glucosylceramide synthase inhibitor attenuates alpha synuclein pathology and lysosomal dysfunction in preclinical models of synucleinopathy |
| topic | Glucocerebrosidase Glucosylceramide synthase inhibitor Glycosphingolipids Parkinson's disease Lysosomal biology Preformed fibril model |
| url | http://www.sciencedirect.com/science/article/pii/S0969996121002564 |
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