Alzheimer's disease: the large gene instability hypothesis

Abstract

23All of the drug trials of the Alzheimer's disease (AD) have failed to slow progression of 24 dementia in phase III studies, and the most effective therapeutic approach still remains 25 controversial due to our incomplete understanding of AD pathophysiology. Amyloid beta (Aβ) 26 and its cascade have been the primary focus of drug design efforts for more than a decade. 27However, mounting evidence indicates that mechanisms of AD etiopathogenesis are probably 28 more complex than the previous reductionist models. 29Several genome-wide association studies (GWAS) have recently shed light on dark aspects of 30AD from a hypothesis-free point of view. While the newly-identified AD risk genes rather raise 31 more questions than they answer in deciphering the amyloid cascade, as a potentially overlooked 32 finding, many of them code for receptors and transducers of cell adhesion signaling cascades. 33Remarkably, the hallmark genetic factors of AD, including the amyloid precursor protein (APP), 34 presenilins (PSEN) and APOE also take part in highly similar pathways of cell adhesion 35 regulation and coordinate contact-guidance of neuronal growth cones in brain development, 36 albeit these Aβ-independent roles remain highly underexplored. 37Here, we have revisited function of 27 AD risk genes in pathways of normal cell physiology. Our

A CRISPR-del-based pipeline for complete gene knockout in human diploid cells

“…These analyses demonstrate that successful deletions were achieved for almost an entire locus in both CEP128 alleles in RPE1 cells. In the human genome more than 95% of the protein-coding sequences have a length shorter than the here demonstrated possible deletion of 440 kb (Soheili-Nezhad, 2017). Our data therefore indicate that most of the human genes could be completely deleted by the CRISPR-del pipeline.…”

“…To prove that our optimized CRISPR-del pipeline can be used for gene knockout in RPE1 cells, we applied it to target the CEP128 gene, which encodes a centrosomal protein. The length of this gene is 502.54-kb, which is longer than 95% of the human protein-coding genes (Soheili-Nezhad, 2017). We first designed two sgRNAs (named as CEP128 sgRNA#1 and #2) to delete a 20-kb region ranging from 35 bp downstream of the first ATG in exon 3 to the middle of intron 8 of the longest CEP128 transcript variant (NM_152446) (Fig.…”

“…Although the length of the chromosomal deletion that can be introduced is a critical factor in performing a “complete” gene knockout by CRISPR-del, our optimized method successfully achieved deletions of very long regions of genomic DNA: 440-kb for the CEP128 gene, 1000-kb for the region around the HNRNPA1 gene and 650-kb for the chromosomal region 9p21.3. This range covers the length of more than 95 % of the human genes encoding proteins (Soheili-Nezhad, 2017), indicating that the CRISPR-del pipeline can be used to generate “complete” knockout cell lines for most of the human protein-coding genes as routine lab work.…”

MiR-15b and let-7a as Non-invasive Diagnostic Biomarkers of Alzheimer’s Disease Using an Artificial Neural Network

“…The GO enrichment analysis indicated that chemical synaptic transmission, neurotransmitter secretion, glutamate secretion, inflammatory response, neuropeptide signaling pathway, calcium ion binding, calmodulin binding, and neuropeptide hormone activity terms were significantly enriched. The results of similar studies revealed that chemical synaptic transmission, neurotransmitter secretion (38), inflammatory response (39), neuropeptide signaling pathway (40), calcium ion binding (41), calmodulin binding (42), and neuropeptide hormone activity (43) were associated with AD.…”

The Road Less Traveled: Uncovering the Convergence Toward Specific Pleiotropic Phenotypes in Aging

“…Moreover, length-correlated changes in the transcriptome have been observed in Alzheimer ‘s disease 56,57 , and the potential duality with length-correlated changes in aging was first proposed by Sourena Soheili-Nezhad in 2018 58 . The length correlation may therefore represent a promising avenue for understanding the age-dependency of age-related diseases.…”