The GBA1 D409V mutation exacerbates synuclein pathology to differing extents in two alpha-synuclein models
Heterozygous mutations in the GBA1 gene – encoding lysosomal glucocerebrosidase (GCase) – are the most common genetic risk factors for Parkinson's disease (PD). Experimental evidence suggests a correlation between decreased GCase activity and accumulation of alpha-synuclein (aSyn). To enable a...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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The Company of Biologists
2022-06-01
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| Series: | Disease Models & Mechanisms |
| Subjects: | |
| Online Access: | http://dmm.biologists.org/content/15/6/dmm049192 |
| _version_ | 1811218203062304768 |
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| author | Nicole K. Polinski Terina N. Martinez Sylvie Ramboz Michael Sasner Mark Herberth Robert Switzer Syed O. Ahmad Lee J. Pelligrino Sean W. Clark Jacob N. Marcus Sean M. Smith Kuldip D. Dave Mark A. Frasier |
| author_facet | Nicole K. Polinski Terina N. Martinez Sylvie Ramboz Michael Sasner Mark Herberth Robert Switzer Syed O. Ahmad Lee J. Pelligrino Sean W. Clark Jacob N. Marcus Sean M. Smith Kuldip D. Dave Mark A. Frasier |
| author_sort | Nicole K. Polinski |
| collection | DOAJ |
| description | Heterozygous mutations in the GBA1 gene – encoding lysosomal glucocerebrosidase (GCase) – are the most common genetic risk factors for Parkinson's disease (PD). Experimental evidence suggests a correlation between decreased GCase activity and accumulation of alpha-synuclein (aSyn). To enable a better understanding of the relationship between aSyn and GCase activity, we developed and characterized two mouse models that investigate aSyn pathology in the context of reduced GCase activity. The first model used constitutive overexpression of wild-type human aSyn in the context of the homozygous GCase activity-reducing D409V mutant form of GBA1. Although increased aSyn pathology and grip strength reductions were observed in this model, the nigrostriatal system remained largely intact. The second model involved injection of aSyn preformed fibrils (PFFs) into the striatum of the homozygous GBA1 D409V knock-in mouse model. The GBA1 D409V mutation did not exacerbate the pathology induced by aSyn PFF injection. This study sheds light on the relationship between aSyn and GCase in mouse models, highlighting the impact of model design on the ability to model a relationship between these proteins in PD-related pathology. |
| first_indexed | 2024-04-12T07:05:49Z |
| format | Article |
| id | doaj.art-2ff4a4f7438a460f8a91ec3fc7c58bc4 |
| institution | Directory Open Access Journal |
| issn | 1754-8403 1754-8411 |
| language | English |
| last_indexed | 2024-04-12T07:05:49Z |
| publishDate | 2022-06-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-2ff4a4f7438a460f8a91ec3fc7c58bc42022-12-22T03:42:47ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112022-06-0115610.1242/dmm.049192049192The GBA1 D409V mutation exacerbates synuclein pathology to differing extents in two alpha-synuclein modelsNicole K. Polinski0Terina N. Martinez1Sylvie Ramboz2Michael Sasner3Mark Herberth4Robert Switzer5Syed O. Ahmad6Lee J. Pelligrino7Sean W. Clark8Jacob N. Marcus9Sean M. Smith10Kuldip D. Dave11Mark A. Frasier12 The Michael J. Fox Foundation for Parkinson's Research, Grand Central Station PO Box 4777, New York, NY 10163, USA The Michael J. Fox Foundation for Parkinson's Research, Grand Central Station PO Box 4777, New York, NY 10163, USA PsychoGenics, Inc, 215 College Road, Paramus, NJ 07652, USA The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA Charles River Laboratories, 1407 George Road, Ashland, OH 44805, USA NeuroScience Associates, 10915 Lake Ridge Drive, Knoxville, TN 37934, USA Saint Louis University, 3437 Caroline Street, St. Louis, MO 63104, USA Amicus Therapeutics, 1 Cedarbrook Dr, Cranbury, NJ 08512, USA Amicus Therapeutics, 1 Cedarbrook Dr, Cranbury, NJ 08512, USA Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA The Michael J. Fox Foundation for Parkinson's Research, Grand Central Station PO Box 4777, New York, NY 10163, USA The Michael J. Fox Foundation for Parkinson's Research, Grand Central Station PO Box 4777, New York, NY 10163, USA Heterozygous mutations in the GBA1 gene – encoding lysosomal glucocerebrosidase (GCase) – are the most common genetic risk factors for Parkinson's disease (PD). Experimental evidence suggests a correlation between decreased GCase activity and accumulation of alpha-synuclein (aSyn). To enable a better understanding of the relationship between aSyn and GCase activity, we developed and characterized two mouse models that investigate aSyn pathology in the context of reduced GCase activity. The first model used constitutive overexpression of wild-type human aSyn in the context of the homozygous GCase activity-reducing D409V mutant form of GBA1. Although increased aSyn pathology and grip strength reductions were observed in this model, the nigrostriatal system remained largely intact. The second model involved injection of aSyn preformed fibrils (PFFs) into the striatum of the homozygous GBA1 D409V knock-in mouse model. The GBA1 D409V mutation did not exacerbate the pathology induced by aSyn PFF injection. This study sheds light on the relationship between aSyn and GCase in mouse models, highlighting the impact of model design on the ability to model a relationship between these proteins in PD-related pathology.http://dmm.biologists.org/content/15/6/dmm049192gcasealpha-synucleinparkinson's disease |
| spellingShingle | Nicole K. Polinski Terina N. Martinez Sylvie Ramboz Michael Sasner Mark Herberth Robert Switzer Syed O. Ahmad Lee J. Pelligrino Sean W. Clark Jacob N. Marcus Sean M. Smith Kuldip D. Dave Mark A. Frasier The GBA1 D409V mutation exacerbates synuclein pathology to differing extents in two alpha-synuclein models Disease Models & Mechanisms gcase alpha-synuclein parkinson's disease |
| title | The GBA1 D409V mutation exacerbates synuclein pathology to differing extents in two alpha-synuclein models |
| title_full | The GBA1 D409V mutation exacerbates synuclein pathology to differing extents in two alpha-synuclein models |
| title_fullStr | The GBA1 D409V mutation exacerbates synuclein pathology to differing extents in two alpha-synuclein models |
| title_full_unstemmed | The GBA1 D409V mutation exacerbates synuclein pathology to differing extents in two alpha-synuclein models |
| title_short | The GBA1 D409V mutation exacerbates synuclein pathology to differing extents in two alpha-synuclein models |
| title_sort | gba1 d409v mutation exacerbates synuclein pathology to differing extents in two alpha synuclein models |
| topic | gcase alpha-synuclein parkinson's disease |
| url | http://dmm.biologists.org/content/15/6/dmm049192 |
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