Biology subjects

Rizzu, P.

Publications and source records attributed to Rizzu, P..

7 recordsLinked to original sources

bioRxiv2025

Piccolo Regulates Secretion of the Extracellular Matrix Components Brevican and Tenascin R from Astrocytes to Drive Synapse Formation: Implications for Pontocerebellar Hypoplasia Type 3 (PCH3)

BackgroundAstrocytes are crucial for CNS health, for instance via the secretion of extracellular matrix (ECM) components that are vital for synapse formation and maturation. While the scaffolding protein Piccolo is known for its role at synapses, its function in astrocytes and contribution to neurodegenerative disorders like Pontocerebellar Hypoplasia Type 3 (PCH3) are largely unknown. Understanding these mechanisms is key to elucidating PCH3 pathology. MethodsWe used a multi-faceted approach with a Pclogt/gtrat model. Methods included RNA-sequencing for gene expression and GO analysis. Immunohistochemistry and immunocytochemistry assessed Piccolo localization, ECM component (Brevican [Bcan], Tenascin-R [TNR]) levels, distribution, and secretion in brain sections and primary astrocytes. Golgi morphology was evaluated via GM130 staining. Neuronal network formation and function were investigated by co-culturing wild-type neurons with Pclowt/wt or Pclogt/gt astrocytes in a Banker setup, assessing synapse density (immunostaining, RRP electrophysiology) and spontaneous activity (mEPSCs, mIPSCs). Astrocyte-conditioned media (ACM) experiments determined secreted factor roles. ResultsRNA-seq showed significant DEG increases in older versus young Pclogt/gt rats (P25 vs. P5), which were strongly enriched in cell communication, signaling, and ECM GO terms. We identified a novel astrocyte-specific Piccolo isoform that partially localizes at the Golgi. Piccolo gene trap transposon mutation led to impaired ECM secretion (reduced extracellular Bcan, altered TNR) from astrocytes, correlating with a fragmented Golgi in Pclogt/gt astrocytes. Functionally, Pclogt/gt astrocytes significantly reduced synapse density and altered intrinsic activity (increased mEPSC frequency) in neuronal networks. This synaptic deficit was substantially rescued by Pclowt/wtastrocyte conditioned media (ACM). ConclusionOur findings reveal a critical, unrecognized role for Piccolo in regulating astrocytic ECM secretion, essential for proper neuronal network formation and activity. Astrocytic Piccolo dysfunction disrupts this process, causing impaired synaptogenesis and altered intrinsic network activity, providing a novel cellular and molecular mechanism for neurodegenerative diseases like PCH3 and highlights astrocytes as potential therapeutic targets.

neuroscience↗

bioRxiv2025

The Insertion of an ATTTC Repeat in an Alu Element Hyperactivates a Primate-Specific Neurodevelopmental Enhancer in Spinocerebellar Ataxia Type 37

Alu are evolutionarily very old primate-specific interspersed repeat elements that constitute [~]11% of the human genome. They are a source of short tandem repeats (STRs), which often expand in size and originate inherited neuromuscular and neurodegenerative disorders. How expanded STR insertion mutations within Alu STRs culminate in disease remains unknown. Here we report an Alu STR located in an intron of DAB1 that functions as a neurodevelopmental enhancer. We demonstrated that an ATTTC repeat insertion in this DAB1 Alu STR, known to cause spinocerebellar ataxia type 37 (SCA37), hyperactivates a neurodevelopmental DAB1 enhancer. Importantly, we showed that neurons derived from SCA37 subjects have higher levels of DAB1 expression and DAB1 overexpression causes abnormal axonal pathfinding in vivo. Overall, these results establish that neuronal dysregulation of a developmental DAB1 Alu STR enhancer contributes to SCA37 pathogenesis, an unexplored mechanism likely acting in many Alu STR diseases, potentially reshaping the therapeutic landscape.

genetics↗

bioRxiv2023

Epigenetic age acceleration in frontotemporal lobar degeneration: a comprehensive analysis in the blood and brain

Frontotemporal lobar degeneration (FTLD) includes a heterogeneous group of disorders pathologically characterized by the degeneration of the frontal and temporal lobes. In addition to major genetic contributors of FTLD such as mutations in MAPT, GRN, and C9orf72, recent work has identified several epigenetic modifications including significant differential DNA methylation in DLX1, and OTUD4 loci. As aging remains to be one of the major risk factors for FTLD, we investigated the presence of accelerated epigenetic aging in FTLD compared to controls. We calculated epigenetic age in both peripheral blood and brain tissues of multiple FTLD subtypes using several DNA methylation clocks, i.e., DNAmClockMulti, DNAmClockHannum, DNAmClockCortical, GrimAge and PhenoAge, and determined age acceleration and its association with different cellular proportions and clinical traits. Significant epigenetic age acceleration was observed in the peripheral blood of both frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP) patients compared to controls with DNAmClockHannum, even after accounting for confounding factors. A similar trend was observed with both DNAmClockMulti and DNAmClockCortical in post-mortem frontal cortex tissue of PSP patients and in FTLD cases harboring GRN mutations. Our findings support that increased epigenetic age acceleration in the peripheral blood could be an indicator for PSP and to a smaller extent, FTD.

neuroscience↗

bioRxiv2022

Rescue of the increased susceptibility to Mild Chronic Oxidative Stress of iNeurons carrying the MAPT Chromosome 17q21.3 H1/H1 risk allele by FDA-approved compounds

The microtubule associated protein tau (MAPT) chromosome 17q21.31 locus lies within a region of high linkage disequilibrium (LD) conferring two extended haplotypes commonly referred to as H1 and H2. The major haplotype, H1 has been genetically associated with an increased risk for multiple neurodegenerative disorders, including Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), APOE {varepsilon}4-negative Alzheimers disease (AD) and Parkinsons disease (PD). The mechanism causing this increased risk is largely unknown. Here, we investigated the role of Mild Chronic Oxidative Stress (MCOS) in neurogenin 2 (NGN2) induced neurons (iNeurons) derived from iPS (induced pluripotent stem cells) from carriers of both haplotypes. We identified that iNeurons of the H1 homozygous haplotype showed an increased susceptibility to MCOS compared to homozygous H2 carriers, leading to cell death through ferroptosis. We performed a cellular screen in H1 iNeurons using a FDA-approved Drug Library and identified candidate molecules that rescued the increased susceptibility to MCOS and prevented ferroptosis in H1 iNeurons. HighlightsO_LIMild Chronic Oxidative Stress induces neurotoxicity via ferroptosis on iNGN2 neurons C_LIO_LIAxonal degeneration, disordered microtubules, blebs precede neurotoxicity C_LIO_LIMAPT-17q21.3 locus H1/H1, risk allele for NDD is more vulnerable to MCOS C_LIO_LIFDA-approved drugs reverse MCOS induced ferroptosis on H1/H1 risk allele C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=158 SRC="FIGDIR/small/515284v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@eddb2eorg.highwire.dtl.DTLVardef@1d0c00dorg.highwire.dtl.DTLVardef@1f0b00eorg.highwire.dtl.DTLVardef@b68f1b_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

Brain DNA methylomic analysis of frontotemporal lobar degeneration reveals OTUD4 and CEBPZ in shared dysregulated signatures across pathological subtypes

Frontotemporal lobar degeneration (FTLD) is an umbrella term describing the neuropathology of a clinically, genetically and pathologically heterogeneous group of diseases, including frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP). Among the major FTLD pathological subgroups, FTLD with TDP-43 positive inclusions (FTLD-TDP) and FTLD with tau positive inclusions (FTLD-tau) are the most common, representing about 90% of the cases. Although alterations in DNA methylation have been consistently associated with neurodegenerative diseases, including Alzheimers disease and Parkinsons disease, little is known for FTLD and its heterogeneous subgroups and subtypes. The main goal of this study was to investigate DNA methylation variation in FTLD-TDP and FTLD-tau. We used frontal cortex genome-wide DNA methylation profiles from three FTLD cohorts (234 individuals), generated using the Illumina 450K or EPIC microarray. We performed epigenome-wide association studies (EWAS) for each cohort followed by meta-analysis to identify shared differential methylated loci across FTLD subgroups/subtypes. Additionally, we used weighted gene correlation network analysis to identify co-methylation signatures associated with FTLD and other disease-related traits. Wherever possible, we also incorporated relevant gene/protein expression data. After accounting for a conservative Bonferroni multiple testing correction, the EWAS meta-analysis revealed two differentially methylated loci in FTLD, one annotated to OTUD4 (5UTR-shore) and the other to NFATC1 (gene body-island). Of these loci, OTUD4 showed consistent upregulation of mRNA and protein expression in FTLD. Additionally, in the three independent co-methylation networks, OTUD4-containing modules were enriched for EWAS meta-analysis top loci and were strongly associated with the FTLD status. These co-methylation modules were enriched for genes implicated in the ubiquitin system, RNA/stress granule formation and glutamatergic synaptic signalling. Altogether, our findings identified novel FTLD-associated loci, and support a role for DNA methylation as a mechanism involved in the dysregulation of biological processes relevant to FTLD, highlighting novel potential avenues for therapeutic development.

neuroscience↗

bioRxiv2021

The Foundational data initiative for Parkinsons disease (FOUNDIN-PD): enabling efficient translation from genetic maps to mechanism

The FOUNdational Data INitiative for Parkinsons Disease (FOUNDIN-PD) is an international collaboration producing fundamental resources for Parkinsons disease (PD). FOUNDIN-PD generated a multi-layered molecular dataset in a cohort of induced pluripotent stem cell (iPSC) lines differentiated to dopaminergic (DA) neurons, a major affected cell type in PD. The lines were derived from the Parkinsons Progression Markers Initiative study including participants with PD carrying monogenic PD (SNCA) variants, variants with intermediate effects and variants identified by genome-wide association studies and unaffected individuals. We generated genetic, epigenetic, regulatory, transcriptomic, and longitudinal cellular imaging data from iPSC-derived DA neurons to understand molecular relationships between disease associated genetic variation and proximate molecular events. These data reveal that iPSC-derived DA neurons provide a valuable cellular context and foundational atlas for modelling PD genetic risk. We have integrated these data into a FOUNDIN-PD data browser (https://www.foundinpd.org) as a resource for understanding the molecular pathogenesis of PD.

genomics↗

bioRxiv2020

Integrated multi-omics analysis reveals common and distinct dysregulated pathways for genetic subtypes of Frontotemporal Dementia

Understanding the molecular mechanisms underlying frontotemporal dementia (FTD) is essential for the development of successful therapies. Systematic studies on human post-mortem brain tissue of patients with genetic subtypes of FTD are currently lacking. The Risk and Modyfing Factors of Frontotemporal Dementia (RiMod-FTD) consortium therefore has generated a multi-omics dataset for genetic subtypes of FTD to identify common and distinct molecular mechanisms disturbed in disease. Here, we present multi-omics datasets generated from the frontal lobe of post-mortem human brain tissue from patients with mutations in MAPT, GRN and C9orf72 and healthy controls. This data resource consists of four datasets generated with different technologies to capture the transcriptome by RNA-seq, and small RNA-seq, and supplemented this date with CAGE-seq, and methylation profiling. We show concrete examples on how to use the resulting data and confirm current knowledge about FTD and identify new processes for further investigation. This extensive multi-omics dataset holds great value to reveal new research avenues for this devastating disease.

neuroscience↗