Biology subjects

Ndayisaba, A.

Publications and source records attributed to Ndayisaba, A..

3 recordsLinked to original sources

bioRxiv2026

tRNA-derived fragments are elevated in the aging brain and may contribute to neurodegeneration

tRNA-derived fragments (tRFs) are a class of small noncoding RNAs with emerging roles in stress responses and gene regulation, yet their dynamics across tissues and brain regions during aging remain poorly understood. Here, we systematically profiled age-associated changes in tRFs using three independent mouse small RNA-seq datasets spanning multiple organs and brain regions. Nuclear-encoded tRFs were the only small RNA class showing a strong, progressive accumulation with age, a pattern that was specific to the brain and broadly distributed across brain regions. Fragment length distributions, boundary profiles, and coverage maps were consistent with amplified cleavage at conserved sites, implicating angiogenin as a primary driver. Age-associated increases in specific tRF species, including 5CysGCA, 5GluCTC, and 5GlyGCC, were validated by northern blotting and RT-qPCR. Analogous upregulation was observed in human frontal lobe tissue from frontotemporal dementia patients and in cerebrospinal fluid from traumatic brain injury patients, suggesting that tRF accumulation is further amplified under neurological stress. Together, these findings establish nuclear-encoded tRFs as a small RNA class that accumulates selectively in the aging brain, with potential roles in neurodegeneration, and as biomarkers and targets for therapeutic intervention.

neuroscience↗

bioRxiv2025

Cholesterol-mediated Lysosomal Dysfunction in APOE4 Astrocytes Promotes α-Synuclein Pathology in Human Brain Tissue

The pathological hallmarks of neurodegeneration are the aberrant post-translational modification and aggregation of proteins. Genetic factors, like APOE4, increase the prevalence and severity of tau, amyloid, and -synuclein pathologies. However, the human brain is largely inaccessible during this process, limiting mechanistic understanding. Here, we developed an iPSC-based 3D model that integrates neurons, glia, myelin, and cerebrovascular cells into a human brain-like tissue ("miBrain"). Single-nucleus RNA sequencing of miBrains confirmed the presence of diverse cell populations and revealed transcriptional responses to -synuclein pathology. Like the human brain, pathogenic -synuclein is increased in APOE4/4 miBrains. Combinatorial experiments revealed that endolysosomal dysfunction caused by cholesterol accumulation in APOE4/4 astrocytes impairs the degradation of soluble -synuclein leading to a pathogenic transformation that seeds -synuclein inclusions in neurons. Collectively, this study establishes a robust model for investigating protein inclusions in human iPSC-derived brain tissue and highlights the role of astrocytes and cholesterol in APOE4-mediated pathologies.

neuroscience↗

bioRxiv2022

Rapid iPSC inclusionopathy models shed light on formation, consequence and molecular subtype of alpha-synuclein inclusions

Intracellular inclusions accompanying neurodegeneration are histopathologically and ultrastructurally heterogeneous but the significance of this heterogeneity is unclear. iPSC models, while promising for disease modeling, do not form inclusions in a reasonable timeframe and suffer from limited tractability. Here, we developed an iPSC toolbox utilizing piggyBac-based or targeted transgenes to rapidly induce CNS cells with concomitant expression of aggregation-prone proteins. This system is amenable to screening and longitudinal tracking at single-cell and single-inclusion resolution. For proof-of-principle, cortical neuron -synuclein "inclusionopathy" models were engineered to form inclusions through exogenous seeding or -synuclein mutation. These models recapitulated known fibril- and lipid-rich inclusion subtypes, uncovering dynamic interactions between them, and refined the classification of inclusions in postmortem brain. Genetic-modifier and protein-interaction screens pinpointed proteins like RhoA whose sequestration into specific inclusion subtypes is likely to be toxic. This iPSC platform should enhance our understanding of proteinaceous pathologies in neurodegeneration and facilitate therapeutics development.

neuroscience↗