Apoptotic factors and pathways across tissues and species in health and Alzheimer's disease

Abstract

Alzheimer’s disease (AD) is a hard neurodegeneration disease without cure. One of the provisional mechanisms by which the damage occurs is apoptosis gone aberrant. Both cell-intrinsic and cell-extrinsic factors affect its flow, biochemical as well as physical. A gene that has been attracting intensified attention in relation to both apoptosis and AD, is HNRNP A1, and its link to both was brought to focus. This work applied the unified set of bioinformatics tools from several angles to study intrinsic apoptosis factors: differential gene expression analysis, SNP and gene transcript analysis, splicing analysis, RNA binding analysis with gene interaction and co-expression with HNRNP A1 gene, and gene ontology analysis. This set was used on various levels: whole-genome, individual cell type, and intra-cell. Whole-genome sequencing data of murine HNRNP A1 +/- models with AD was clustered with WGCNA, analyzed for differentially expressed genes and splicing events. Following the results of this first stage, the next step of analysis took research to the microglia domain of human specimen from ROSMAP database. 7000 AD risk genes were put through the AD-trained gene embedding. The 16 outcome genes were then analyzed for gene ontology, binding to HNRNP A1, and capability to affect splicing, and also put on a velocity graph as nodes for biological process translation. Finally, meta-analysis of 1654 ROSMAP nervous tissue datasets was investigated for metabolic communication, AD risk genes, and DNA repair hotspots overlapping with BIN1 gene. Additionally, to study what can influence apoptosis extrinsically, caspase, the crucial trigger of apoptosis, was activated optogenetically in vivo, after which cells surviving high caspase activation were investigated to extract other factors they sustained. The results suggested potential role of mechanical force as factor in cell-death decision making. As a result, gene ontology and marker analysis linked cell types to genetic factors, typical for mechanotransduction processes, and cell communication analysis yielded stages that identify mechanotransduction aberrations. A link between these genetic factors interacting or binding with HNRNP A1 and association with AD was proposed. HNRNP A1 effect on specific isoforms CSF1 ENSMUST00000156820.1 (pVal = 0.0266, x̄(log2Fold) = 1.8654, σ = 0.9244); MAPK3 ENSMUSE00000477246 (pVal = 0.0379, x̄(log2Fold) = 4.5982, σ = 1.9235); NOS1 ENSMUSE00000689840 (pVal = 0.0166, x̄(log2Fold) = 1.7665, σ = 1.3768); RTN4 ENSMUSE00000279552 (pVal = 0.036, x̄(log2Fold) = 5.0128, σ = 0.4743), ENSMUSE00001278129 (pVal = 0.0128, x̄(log2Fold) = 3.6109, σ = 0.3431), ENSMUSE00001313485 (pVal = 0.0293, x̄(log2Fold) = 1.7891, σ = 0.0979), ENSMUSE00001280062 (pVal = 0.0123, x̄(log2Fold) = 6.5235, σ = 0.8453); SLC39A2 ENSMUSE00000854217 (pVal = 0.0025, x̄(log2Fold) = 3.6789, σ = 1.5867). by AD was highlighted. Role of factors aside from caspase in apoptosis was implicated. RABGAP1L SNP rs114162361 accumulated evidence to be implicated in AD manifestations in microglia through binding to HNRNP A1 (Z = 1.672, with pVal = 4.73e-02). The BIN1 neuronal isoform rs78710909C is significantly downregulated in the AD in microglia-communicating excitatory neurons (beta = –0 .7), highly susceptible to neurodegeneration. This work opens perspective for novel avenues of research in AD-associated role of HNRNP A1 in apoptosis.