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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, International Journal of Molecular Sciences, International Journal of Molecular Sciences, Vol 22, Iss 13633, p 13633 (2021), International Journal of Molecular Sciences; Volume 22; Issue 24; Pages: 13633
- Publication Year :
- 2021
-
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. ispartof: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES vol:22 issue:24 ispartof: location:Switzerland status: published
- Subjects :
- Lewy Body Disease
Male
QH301-705.5
DNAJC6
Polymorphism, Single Nucleotide
Article
Catalysis
Inorganic Chemistry
PPT1
Alzheimer Disease
SORL1
mental disorders
allele dose effect
Humans
Genetic Predisposition to Disease
cross-disease
endo-lysosomal genes
Biology (General)
Physical and Theoretical Chemistry
QD1-999
Molecular Biology
Biology
LDL-Receptor Related Proteins
Spectroscopy
Aged
Aged, 80 and over
Organic Chemistry
High-Throughput Nucleotide Sequencing
Membrane Transport Proteins
NGS
loss of function
multicarrier
Sequence Analysis, DNA
General Medicine
HSP40 Heat-Shock Proteins
Middle Aged
Computer Science Applications
nervous system diseases
Chemistry
Female
Frontotemporal Lobar Degeneration
Lysosomes
Subjects
Details
- Language :
- English
- ISSN :
- 14220067
- Database :
- OpenAIRE
- Journal :
- International journal of molecular sciences
- Accession number :
- edsair.doi.dedup.....da00cc74d91ea8b205de0c6574d32baf