Biology subjects

Gasparini, L.

Publications and source records attributed to Gasparini, L..

4 recordsLinked to original sources

bioRxiv2025

New Insights on Bridging Integrator 1 Protein Isoforms as a Risk Increasing Gene in Alzheimer's Disease

INTRODUCTIONGenome-wide association studies (GWAS) have identified Bridging Integrator 1 (BIN1) as the second-most significant genetic risk factor for Alzheimers disease (AD). We performed GWAS by proxy (GWAX) using UKBiobank and replicated this finding. However, the mechanism by which BIN1 impacts AD risk is largely unknown. METHODSTo address this, we first measured the expression of BIN1 isoforms in a human induced pluripotent stem cells (hiPSC) model and further evaluated whether the BIN1 risk loci associated with the expression of BIN1 isoforms in a Phase 2 AD clinical trial. RESULTSOur data indicated BIN1 isoform expression patterns associated with the differentiation of hiPSC into neurons or microglia and found the variant rs35103166 impacts the expression of the BIN1 microglia-specific isoforms. DISCUSSIONGiven the strong association with susceptibility to AD, exploring the mechanisms of BIN1 genetic variants and their impacts on cell-type specific expression could serve as a valuable resource for novel drug discovery. HighlightsO_LIBIN1 variants are significantly associated with AD risk in GWAX analysis from UKBB. C_LIO_LIBIN1 isoforms show a cell-type-specific expression pattern during hiPSC differentiation into neurons or microglia. C_LIO_LIBIN1 risk alleles associate with BIN1 isoform expression in a Phase 2 AD trial (NCT02880956). C_LI

neuroscience↗

bioRxiv2024

A Novel C. elegans Model for Tau spreading Reveals Genes Critical for Endolysosomal Integrity and Seeded Tau Aggregation

The spreading of Tau pathology is closely associated with the progression of neurodegeneration and cognitive decline in Alzheimers disease and other tauopathies. A key event in this process is the rupture of endolysosomal vesicles following the intercellular transfer of Tau aggregates, releasing the transferred Tau species into the cytosol where they can promote the aggregation of endogenous Tau. However, understanding of the cellular pathways involved in this process remains limited. In this study, we investigated cellular pathways that prevent endolysosomal vesicle rupture. We established a new C. elegans model of Tau spreading by introducing an mCherry-labelled, disease-associated aggregation-prone fragment of human Tau (F3{Delta}K281::mCh) into the six touch receptor neurons. F3{Delta}K281::mCh transgenic animals exhibited significant neurotoxicity and mechanosensory deficits due to the accumulation of this Tau fragment. In addition, its intercellular transmission compromised the endolysosomal system in receiving hypodermal cells. Using this model, we conducted an unbiased genome-wide RNAi screen and identified 59 genes critical for maintaining endolysosomal integrity. GO-term analysis revealed an enrichment of genes related to the ESCRT complex, the ubiquitin-proteasome system, mRNA splicing, and fatty acid metabolism. Silencing of selected conserved genes exacerbated seeded Tau aggregation in a human induced pluripotent stem cell (hiPSC)-derived cortical neuron model and triggered endolysosomal rupture in HEK293T cells, confirming the crucial role of endolysosomal damage in seeded Tau aggregation. Overall, this study discovered novel cellular pathways that safeguard endolysosomal integrity. These findings may guide the development of therapeutics that improve endolysosomal integrity to halt the progression of Tau pathology.

cell biology↗

bioRxiv2020

Tau in the brain interstitial fluid is fragmented and seeding-competent

In Alzheimer disease, Tau pathology is thought to propagate from cell to cell throughout interconnected brain areas. However, the forms of Tau released into the brain interstitial fluid (ISF) in vivo during the development of Tauopathy and their pathological relevance remain unclear. Combining in vivo microdialysis and biochemical analysis, we find that in Tau transgenic mice, human Tau (hTau) present in brain ISF is truncated and comprises at least 10 distinct fragments spanning the entire Tau protein. The fragmentation pattern is similar across different Tau transgenic models, pathological stages and brain areas. ISF hTau concentration decreases during Tauopathy progression, while its phosphorylation increases. ISF from mice with established Tauopathy induces Tau aggregation in HEK293-Tau biosensor cells. Notably, immunodepletion of ISF phosphorylated Tau, but not Tau fragments, significantly reduces its ability to seed Tau aggregation and only a fraction of Tau, separated by ultracentrifugation, is seeding competent. These results indicate that ISF seeding competence is driven by a small subset of Tau, which potentially contribute to the propagation of Tau pathology. HighlightsO_LIIn interstitial fluid (ISF) of transgenic mice, Tau comprises >10 distinct fragments C_LIO_LIISF Tau decreases with Tauopathy progression, while its phosphorylation increases C_LIO_LIOnly ISF from mice with established Tauopathy is seeding competent in vitro C_LIO_LIRemoval of phospho-Tau reduces ISF seeding competence C_LIO_LIISF seeding competence is driven by less soluble, aggregated and phosphorylated Tau C_LI Graphical abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

neuroscience↗

bioRxiv2020

SETD7-mediated lysine monomethylation is abundant on non-hyperphosphorylated nuclear Tau

Human tauopathies including Alzheimers disease (AD) are characterized by alterations in the post-translational modification (PTM) pattern of Tau, leading to the formation of insoluble aggregates, neuronal dysfunction and degeneration. Using a mass spectrometry approach, we identified multiple sites of lysine monomethylation on Tau isolated from a detergent-soluble fraction of human brain, some of which were increased in early AD samples. Brain tissues derived from a mouse model of tauopathy demonstrate an age-dependent increase in methylation at specific sites, with methylated Tau enriched in the soluble nuclear fraction and not associated with hyperphosphorylated, insoluble Tau species. Furthermore, we show that the protein lysine methyltransferase SETD7 methylates Tau at K132 and demonstrate an interaction with K130, an additional methylation site in close vicinity. These findings shed light on the function of a novel type of PTM on Tau that provide a potential signal for its translocation to different subcellular sites. Since the mislocalization and depletion of Tau from axons is associated with tauopathies, our findings may furthermore provide insight into this disease-associated phenomenon.

neuroscience↗