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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.
- Source :
-
International journal of molecular sciences [Int J Mol Sci] 2021 Dec 20; Vol. 22 (24). Date of Electronic Publication: 2021 Dec 20. - Publication Year :
- 2021
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Abstract
- 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.
- Subjects :
- Aged
Aged, 80 and over
Alzheimer Disease genetics
Female
Frontotemporal Lobar Degeneration genetics
High-Throughput Nucleotide Sequencing
Humans
Lewy Body Disease genetics
Lysosomes metabolism
Male
Middle Aged
Sequence Analysis, DNA
Alzheimer Disease metabolism
Frontotemporal Lobar Degeneration metabolism
Genetic Predisposition to Disease
HSP40 Heat-Shock Proteins genetics
LDL-Receptor Related Proteins genetics
Lewy Body Disease metabolism
Membrane Transport Proteins genetics
Polymorphism, Single Nucleotide
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 22
- Issue :
- 24
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 34948429
- Full Text :
- https://doi.org/10.3390/ijms222413633