Investigating the Endo-Lysosomal System in Major Neurocognitive Disorders Due to Alzheimer’s Disease, Frontotemporal Lobar Degeneration and Lewy Body Disease: Evidence for SORL1 as a Cross-Disease Gene
Dysfunctions in the endo-lysosomal system have been hypothesized to underlie neurodegeneration in major neurocognitive disorders due to Alzheimer’s disease (AD), Frontotemporal Lobar Degeneration (FTLD), and Lewy body disease (DLB). The aim of this study is to investigate whether these diseases shar...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/24/13633 |
| _version_ | 1797503754590748672 |
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| author | Luisa Benussi Antonio Longobardi Cemile Kocoglu Matteo Carrara Sonia Bellini Clarissa Ferrari Roland Nicsanu Claudia Saraceno Cristian Bonvicini Silvia Fostinelli Roberta Zanardini Marcella Catania Matthieu Moisse Philip Van Damme Giuseppe Di Fede Giuliano Binetti Christine Van Broeckhoven Julie van der Zee Roberta Ghidoni |
| author_facet | Luisa Benussi Antonio Longobardi Cemile Kocoglu Matteo Carrara Sonia Bellini Clarissa Ferrari Roland Nicsanu Claudia Saraceno Cristian Bonvicini Silvia Fostinelli Roberta Zanardini Marcella Catania Matthieu Moisse Philip Van Damme Giuseppe Di Fede Giuliano Binetti Christine Van Broeckhoven Julie van der Zee Roberta Ghidoni |
| author_sort | Luisa Benussi |
| collection | DOAJ |
| description | Dysfunctions in the endo-lysosomal system have been hypothesized to underlie neurodegeneration in major neurocognitive disorders due to Alzheimer’s disease (AD), Frontotemporal Lobar Degeneration (FTLD), and Lewy body disease (DLB). The aim of this study is to investigate whether these diseases share genetic variability in the endo-lysosomal pathway. In AD, DLB, and FTLD patients and in controls (948 subjects), we performed a targeted sequencing of the top 50 genes belonging to the endo-lysosomal pathway. Genetic analyses revealed (i) four previously reported disease-associated variants in the SORL1 (p.N1246K, p.N371T, p.D2065V) and DNAJC6 genes (p.M133L) in AD, FTLD, and DLB, extending the previous knowledge attesting SORL1 and DNAJC6 as AD- and PD-related genes, respectively; (ii) three predicted null variants in AD patients in the SORL1 (p.R985X in early onset familial AD, p.R1207X) and PPT1 (p.R48X in early onset familial AD) genes, where loss of function is a known disease mechanism. A single variant and gene burden analysis revealed some nominally significant results of potential interest for SORL1 and DNAJC6 genes. Our data highlight that genes controlling key endo-lysosomal processes (i.e., protein sorting/transport, clathrin-coated vesicle uncoating, lysosomal enzymatic activity regulation) might be involved in AD, FTLD and DLB pathogenesis, thus suggesting an etiological link behind these diseases. |
| first_indexed | 2024-03-10T03:54:51Z |
| format | Article |
| id | doaj.art-a4308e122d324471877fb0d8ce6d7d02 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T03:54:51Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-a4308e122d324471877fb0d8ce6d7d022023-11-23T08:49:15ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-12-0122241363310.3390/ijms222413633Investigating the Endo-Lysosomal System in Major Neurocognitive Disorders Due to Alzheimer’s Disease, Frontotemporal Lobar Degeneration and Lewy Body Disease: Evidence for SORL1 as a Cross-Disease GeneLuisa Benussi0Antonio Longobardi1Cemile Kocoglu2Matteo Carrara3Sonia Bellini4Clarissa Ferrari5Roland Nicsanu6Claudia Saraceno7Cristian Bonvicini8Silvia Fostinelli9Roberta Zanardini10Marcella Catania11Matthieu Moisse12Philip Van Damme13Giuseppe Di Fede14Giuliano Binetti15Christine Van Broeckhoven16Julie van der Zee17Roberta Ghidoni18Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, I-25125 Brescia, ItalyMolecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, I-25125 Brescia, ItalyNeurodegenerative Brain Diseases, VIB Center for Molecular Neurology, VIB, B-2610 Antwerp, BelgiumService of Statistics, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, I-25125 Brescia, ItalyMolecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, I-25125 Brescia, ItalyService of Statistics, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, I-25125 Brescia, ItalyMolecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, I-25125 Brescia, ItalyMolecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, I-25125 Brescia, ItalyMolecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, I-25125 Brescia, ItalyMAC-Memory Clinic and Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, I-25125 Brescia, ItalyMolecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, I-25125 Brescia, ItalyNeurology 5/Neuropathology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, I-20133 Milan, ItalyDepartment of Neurosciences and Leuven Brain Institute (LBI), KU Leuven-University of Leuven, B-3000 Leuven, BelgiumDepartment of Neurosciences and Leuven Brain Institute (LBI), KU Leuven-University of Leuven, B-3000 Leuven, BelgiumNeurology 5/Neuropathology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, I-20133 Milan, ItalyMAC-Memory Clinic and Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, I-25125 Brescia, ItalyNeurodegenerative Brain Diseases, VIB Center for Molecular Neurology, VIB, B-2610 Antwerp, BelgiumNeurodegenerative Brain Diseases, VIB Center for Molecular Neurology, VIB, B-2610 Antwerp, BelgiumMolecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, I-25125 Brescia, ItalyDysfunctions in the endo-lysosomal system have been hypothesized to underlie neurodegeneration in major neurocognitive disorders due to Alzheimer’s disease (AD), Frontotemporal Lobar Degeneration (FTLD), and Lewy body disease (DLB). The aim of this study is to investigate whether these diseases share genetic variability in the endo-lysosomal pathway. In AD, DLB, and FTLD patients and in controls (948 subjects), we performed a targeted sequencing of the top 50 genes belonging to the endo-lysosomal pathway. Genetic analyses revealed (i) four previously reported disease-associated variants in the SORL1 (p.N1246K, p.N371T, p.D2065V) and DNAJC6 genes (p.M133L) in AD, FTLD, and DLB, extending the previous knowledge attesting SORL1 and DNAJC6 as AD- and PD-related genes, respectively; (ii) three predicted null variants in AD patients in the SORL1 (p.R985X in early onset familial AD, p.R1207X) and PPT1 (p.R48X in early onset familial AD) genes, where loss of function is a known disease mechanism. A single variant and gene burden analysis revealed some nominally significant results of potential interest for SORL1 and DNAJC6 genes. Our data highlight that genes controlling key endo-lysosomal processes (i.e., protein sorting/transport, clathrin-coated vesicle uncoating, lysosomal enzymatic activity regulation) might be involved in AD, FTLD and DLB pathogenesis, thus suggesting an etiological link behind these diseases.https://www.mdpi.com/1422-0067/22/24/13633SORL1DNAJC6PPT1endo-lysosomal genesNGScross-disease |
| spellingShingle | Luisa Benussi Antonio Longobardi Cemile Kocoglu Matteo Carrara Sonia Bellini Clarissa Ferrari Roland Nicsanu Claudia Saraceno Cristian Bonvicini Silvia Fostinelli Roberta Zanardini Marcella Catania Matthieu Moisse Philip Van Damme Giuseppe Di Fede Giuliano Binetti Christine Van Broeckhoven Julie van der Zee Roberta Ghidoni Investigating the Endo-Lysosomal System in Major Neurocognitive Disorders Due to Alzheimer’s Disease, Frontotemporal Lobar Degeneration and Lewy Body Disease: Evidence for SORL1 as a Cross-Disease Gene International Journal of Molecular Sciences SORL1 DNAJC6 PPT1 endo-lysosomal genes NGS cross-disease |
| title | Investigating the Endo-Lysosomal System in Major Neurocognitive Disorders Due to Alzheimer’s Disease, Frontotemporal Lobar Degeneration and Lewy Body Disease: Evidence for SORL1 as a Cross-Disease Gene |
| title_full | Investigating the Endo-Lysosomal System in Major Neurocognitive Disorders Due to Alzheimer’s Disease, Frontotemporal Lobar Degeneration and Lewy Body Disease: Evidence for SORL1 as a Cross-Disease Gene |
| title_fullStr | Investigating the Endo-Lysosomal System in Major Neurocognitive Disorders Due to Alzheimer’s Disease, Frontotemporal Lobar Degeneration and Lewy Body Disease: Evidence for SORL1 as a Cross-Disease Gene |
| title_full_unstemmed | Investigating the Endo-Lysosomal System in Major Neurocognitive Disorders Due to Alzheimer’s Disease, Frontotemporal Lobar Degeneration and Lewy Body Disease: Evidence for SORL1 as a Cross-Disease Gene |
| title_short | Investigating the Endo-Lysosomal System in Major Neurocognitive Disorders Due to Alzheimer’s Disease, Frontotemporal Lobar Degeneration and Lewy Body Disease: Evidence for SORL1 as a Cross-Disease Gene |
| title_sort | investigating the endo lysosomal system in major neurocognitive disorders due to alzheimer s disease frontotemporal lobar degeneration and lewy body disease evidence for sorl1 as a cross disease gene |
| topic | SORL1 DNAJC6 PPT1 endo-lysosomal genes NGS cross-disease |
| url | https://www.mdpi.com/1422-0067/22/24/13633 |
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