Biology subjects

Piras, I.

Publications and source records attributed to Piras, I..

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↗

bioRxiv2026

Integrative synaptosome multi-omics reveals disrupted synapse organization and localized cryptic transcripts in C9ORF72-Frontotemporal Dementia

Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) are linked neurodegenerative diseases characterized by both synaptic dysfunction and TDP-43 pathology. A hexanucleotide repeat expansion (HRE) in the C9ORF72 (C9) gene represents the most common genetic cause of FTD and ALS, yet the synapse-specific mechanisms underlying disease pathogenesis remain poorly understood. Here, we performed integrated multi-omic profiling of synaptosomes enriched from postmortem frontal cortex and patient-derived induced pluripotent stem cell (iPSC)-derived cortical neurons to define molecular alterations associated with C9-FTD-mediated synaptic dysfunction. Proteomic profiling of frontal cortex-derived synaptosomes identified 1,324 differentially abundant proteins (p<0.05) enriched in pathways regulating synaptic vesicle transport and synapse organization, while synaptosomal RNA sequencing revealed 2,835 differentially expressed protein-coding genes. C9-FTD iPSC-cortical neurons exhibited reductions in excitatory and inhibitory postsynaptic markers, accompanied by progressive impairment of neuronal network activity, supporting both structural and functional deficits. iPSC-derived synaptosomes recapitulated key molecular pathways observed in patient brain, revealing convergent dysregulation of synaptic signaling pathways. Comparative analyses revealed divergence between protein and RNA alterations, consistent with the disruption of regulatory processes that link RNA and protein abundance diseased synapses. Consistent with TDP-43 loss-of-function pathology we identified cryptic exon (CE)-containing transcripts within C9-FTD frontal cortex-derived synaptosomes, including KALRN and STMN2, providing evidence that aberrantly spliced RNAs localize to synaptic compartments. Together, these findings define convergent molecular pathways underlying synapse vulnerability in both C9-FTD model systems and identify synaptic localization of CE-containing transcripts as a previously unrecognized feature of TDP-43 proteinopathy.

neuroscience↗

bioRxiv2021

West Nile virus in crocodiles and mosquitoes in Zimbabwe

We detected, for the first time, West Nile virus lineages 1 and 2 in Zimbabwe in mosquitoes and crocodile tissue samples, including fluid from egg waste. Our results provide evidence of WNV circulation in Zimbabwe, suggesting that an evaluation of the risk to humans and susceptible animals should be considered.

microbiology↗

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↗