Biology subjects

Naymik, M.

Publications and source records attributed to Naymik, M..

4 recordsLinked to original sources

bioRxiv2026

Pseudotime analysis of 2,106 brains across nine regions reveals conserved immune, neuronal, and myelin regulatory programs in Alzheimer's disease

Pseudotime trajectories can reconstruct latent disease progression from cross-sectional transcriptomic data. However, whether Alzheimer's disease (AD) progression follows a conserved molecular architecture across brain regions remains unclear. We applied pseudotime analysis to harmonized bulk RNA-seq data from 2,106 postmortem brain samples (1,364 AD, 742 controls) across nine brain regions from three AMP-AD cohorts (ROSMAP, Mayo, MSBB). Pseudotime was significantly associated with AD diagnosis in all nine regions and with Braak stage in seven of nine. We identified 21 genes with concordant pseudotime associations across all regions, increasing to 234 when the cerebellum was excluded. Pathway analysis revealed 1,268 significant associations, with synaptic deregulation as the most conserved process, and immune/ECM programs showing greater regional specificity. The cerebellum followed a distinct pattern, with enrichment for protein refolding and chaperone pathways rather than neurodegeneration. Co-expression network analysis identified six conserved metamodules, including immune/glial (MM1) and excitatory neuronal (MM2) programs spanning all nine regions, and an oligodendrocyte/myelin program (MM3) in seven cortical regions. Key driver analysis identified 76 unique genes across 35 modules, with HCK and LAPTM5 as the most broadly replicated immune regulators in seven regions. Oligodendrocyte-associated key drivers (MYRF, CNP, MOBP) increased along pseudotime in cortical regions, supporting active myelin remodeling during AD progression. These findings reveal a conserved transcriptional architecture underlying AD progression, organized around coordinated immune activation, synaptic loss, and myelin remodeling, with the cerebellum following a distinct trajectory.

neuroscience↗

bioRxiv2020

Adenosine triphosphate Binding Cassette subfamily C member 1 (ABCC1) overexpression reduces APP processing and increases alpha- versus beta-secretase activity, in vitro

The organic anion transporter Adenosine triphosphate Binding Cassette subfamily C member 1 (ABCC1), also known as MRP1, has been demonstrated in murine models of Alzheimers disease (AD) to export amyloid beta (Abeta) from the endothelial cells of the blood-brain barrier to the periphery, and that pharmaceutical activation of ABCC1 can reduce amyloid plaque deposition in the brain. Here, we show that ABCC1 is not only capable of exporting Abeta from the cytoplasm of human cells, but also that its overexpression significantly reduces Abeta production and increases the ratio of alpha- versus beta-secretase mediated cleavage of the Amyloid Precursor Protein (APP), likely via indirect modulation of alpha-, beta-, and gamma-secretase activity.

molecular biology↗

bioRxiv2020

Transcriptional profiling of Multiple System Atrophy cerebellar tissue highlights differences between the parkinsonian and cerebellar sub-types of the disease

Multiple system atrophy (MSA) is a rare adult-onset neurodegenerative disease of unknown cause, with no effective therapeutic options, and no cure. Limited work to date has attempted to characterize the transcriptional changes associated with the disease, which presents as either predominating parkinsonian (MSA-P) or cerebellar (MSC-C) symptoms. We report here the results of RNA expression profiling of cerebellar white matter (CWM) tissue from two independent cohorts of MSA patients (n=66) and healthy controls (HC; n=66). RNA samples from bulk brain tissue and from oligodendrocytes obtained by laser capture microdissection (LCM) were sequenced. Differentially expressed genes (DEGs) were obtained and were examined before and after stratifying by MSA clinical sub-type. We detected the highest number of DEGs in the MSA-C group (n = 747) while only one gene was noted in MSA-P, highlighting the larger dysregulation of the transcriptome in the MSA-C CWM. Results from both bulk tissue and LCM analysis of MSA-C showed a downregulation of oligodendrocyte genes and an enrichment for myelination processes with a key role noted for the QKI gene. Additionally, we observed a significant upregulation of neuron-specific gene expression in MSA-C and an enrichment for synaptic processes. A third cluster of genes was associated with the upregulation of astrocyte and endothelial genes, two cell types with a key role in inflammation processes. Finally, network analysis in MSA-C showed enrichment for {beta}-amyloid related functional classes, including the known Alzheimers disease (AD) genes, APP and PSEN1. This is the largest RNA profiling study ever conducted on post-mortem brain tissue from MSA patients. We were able to define specific gene expression signatures for MSA-C highlighting the different stages of the complex neurodegenerative cascade of the disease that included alterations in several cell-specific transcriptional programs. Finally, several results suggest a common transcriptional dysregulation between MSA and AD-related genes despite the clinical and neuropathological distinctions between the two diseases.

genomics↗

bioRxiv2020

Complex genetic network underlying the convergent of Rett Syndrome like (RTT-L) phenotype in neurodevelopmental disorders

Mutations of the X-linked gene encoding methyl-CpG-binding protein 2 (MECP2) cause classical forms of Rett syndrome (RTT) in girls. Patients with features of classical Rett syndrome, but do not fulfill all the diagnostic criteria (e.g. absence of a MECP2 mutation), are defined as atypical Rett syndrome. Genes encoding for cyclin-dependent kinase-like 5 (CDKL5) and forkhead box G1 (FOXG1) are more commonly found in patients with atypical Rett syndrome. Nevertheless, a subset of patients who are recognized to have an overlapping phenotype with RTT but are lacking a mutation in a gene that causes typical or atypical RTT are described as having Rett syndrome like phenotype (RTT-L). Whole Exome Sequencing (WES) of 8 RTT-L patients from our cohort revealed mutations in the genes GABRG2, GRIN1, ATP1A2, KCNQ2, KCNB1, TCF4, SEMA6B, and GRIN2A, which are seemingly unrelated to Rett syndrome genes. We hypothesized that the phenotypic overlap in RTT and RTT-L is caused by mutations in genes that affect common cellular pathways critical for normal brain development and function. We annotated the list of genes identified causing RTT-L from peer-reviewed articles and performed a protein-protein interaction (PPI) network analysis. We also investigated their interaction with RTT (typical or atypical) genes such as MECP2, CDKL5, NTNG1, and FOXG1. We found that the RTT-L-causing genes were enriched in the biological pathways such as circadian entrainment, the CREB pathway, and RET signaling, and neuronal processes like ion transport, synaptic transmission, and transcription. We conclude that genes that significantly interact with the PPI network established by RTT genes cause RTT-L, explaining the considerable feature overlap between genes that are indicated for RTT-L and RTT.

genomics↗