Biology subjects

Monti, G.

Publications and source records attributed to Monti, G..

4 recordsLinked to original sources

bioRxiv2026

Microexon alternative splicing and feeding behavior in C. elegans.

Microexons are short alternative exons up to 51 nucleotides long that are highly enriched in neuronal genes. Their dysregulation has been linked to human neurodevelopmental disorders, including autism spectrum disorders. In the nematode Caenorhabditis elegans, global regulation of microexons is also critical for proper development. Here we show that microexon alternative splicing (AS) changes between C. elegans larval and adult stages and that microexon inclusion is differentially regulated among distinct neuronal types. Consistently with previous evidence that C. elegans splicing is regulated in response to environmental stimuli, we found here that specific microexons are modulated upon food availability. Both the inclusion levels of these microexons and the feeding behavior seem to depend on the DNA topology, which may affect transcription dynamics, as revealed by the effects of the topoisomerase I (TOP1) inhibitor, camptothecin (CPT). CPT treatment alters responses related to food availability such as speed reduction and exploration. Furthermore, animals carrying a mutation in the global regulator of microexon splicing prp-40 exhibit altered food preference, independently demonstrating that disruption of microexon AS has important consequences on animal behavior.

molecular biology↗

bioRxiv2025

Soluble SORL1 in cerebrospinal fluid as a marker for functional impact of rare SORL1 variants.

BackgroundAs part of the retromer, sortilin-related receptor (SORL1) sorts cargo proteins away from the endosome to the trans-Golgi network or to the cell surface, where SORL1 is cleaved into sSORL1 and shed into the interstitial fluid and CSF. SORL1s cargo includes APP and A{beta}, which may explain why protein-truncating genetic variants (PTVs) in SORL1 are observed almost exclusively in Alzheimers Disease (AD) patients, and that rare, predicted pathogenic missense variants have been associated with a 10-fold increased risk of AD. However, functional evidence supporting variant pathogenicity is warranted. Here we investigated whether soluble SORL1 (sSORL1) concentrations in cerebrospinal fluid (CSF) offer a potential in vivo biomarker to support impaired SORL1 function in variant carriers. MethodsUsing an ELISA assay for SORL1 (ABCAM), we determined sSORL1 concentrations in CSF from 218 participants of the Alzheimer Dementia Cohort (ADC) (54% females). We compared sSORL1 in CSF derived from 90 carriers of diverse SORL1 variants with concentrations observed in 78 SORL1-WT AD patients, and 50 SORL1-WT controls for whom CSF-pTau-181, CSF-tTau, CSF-A{beta}42 concentrations were available. In a subset of 36 individuals, we used Western blotting (WB) to validate sSORL1 concentrations as determined by ELISA. ResultsCSF-sSORL1 concentrations did not differ between SORL1-WT AD patients and controls. While CSF-sSORL1 did not correlate with CSF-A{beta}42 concentrations in SORL1-WT AD patients (p=0.62), it correlated with sCSF-ptau-181 (p=9.7x10-6). The mean CSF-sSORL1 concentration in the SORL1 WT AD cases and controls was 466 pg/ml, with wide variance (SD = 133). Comparatively, concentrations were significantly lower in PTV carriers (260 pg/ml, p=3.2x10-7) and in carriers of predicted damaging SORL1 missense variants (323 pg/ml, p=2.4x10-7). CSF-sSORL1 concentrations measured by ELISA correlated strongly with concentrations estimated by WB ({rho}=0.552; p=5.0x10-4). ConclusionCSF-sSORL1 increases with CSF-ptau, suggesting that increased SORL1-retromer activity may serve to rescue cellular stress associated with AD-related processes. However, impairing SORL1 genetic variants may preclude SORL1 trafficking to the cell surface, as supported by lower CSF-sSORL1 protein concentrations in carriers. While further refinements are necessary, we present first evidence for the applicability of ELISA-based quantification of sSORL1 in CSF to evaluate the functional impact of rare SORL1 variants.

neuroscience↗

bioRxiv2023

Relying on the relationship with known disease-causing variants in homologous proteins to predict pathogenicity of SORL1 variants in Alzheimer's disease

SORL1 encodes the retromer-associated receptor SORLA that functions in endosomal recycling. Rare variants in SORL1 have been associated with Alzheimers disease (AD) and rare pathogenic variants are estimated to occur in up to 2.75% of early onset AD patients and in 1.5% of unrelated late onset AD patients. While truncation mutations are observed almost exclusively in AD patients, it is currently unknown which among the hundreds of rare missense variants identified in SORL1, are pathogenic. Here we address this question by relying on SORLAs distinct molecular architecture. First, we completed a structure-guided sequence alignment for all the protein domains. Next, we identified proteins that contain domains homologous to those of SORLA, which include pathogenic variants for monogenic diseases. We identified the analogous domain positions of these variants in the SORLA protein sequence and showed that variants in these positions similarly impair SORL1, and lead to AD. Together, our findings represent a comprehensive compendium on SORLA protein variation and functional effects, which allowed us to prioritize SORL1 genetic variants into high or moderate priority mutations. We envision that this compendium will be used by clinical geneticists for assessing variants they identify in patients, allowing further development of diagnostic procedures and patient counseling strategies. Utimately, this compendium will inform investigations into the molecular mechanisms of endosomal recycling which will support the development of therapeutic treatment strategies for SORL1 variant-carrying patients.

biochemistry↗

bioRxiv2021

In vivo evidence that SORL1, encoding the endosomal recycling receptor SORLA, can function as a causal gene in Alzheimer's Disease

The few established causal genes in Alzheimers disease (AD), mutations in APP and PSENs, have been functionally characterized using biomarkers, capturing an in vivo profile reflecting the diseases initial preclinical phase. SORL1, a gene encoding the endosome recycling receptor SORLA, epidemiologically behaves as a causal gene when truncating mutations lead to partial loss of protein function. Here, in an effort to test whether SORL1 can indeed function as an AD causal gene, we used CRISPR-Cas9-based gene editing to develop a novel model of SORL1 haploinsufficiency in Gottingen Minipigs taking advantage of porcine models for biomarker investigations. SORL1 haploinsufficiency in young minipigs was found to phenocopy the preclinical in vivo profile of AD observed with other causal genes, resulting in spinal fluid abnormalities in A{beta} and tau, with no evident neurodegeneration or amyloid plaque formation. These studies provide functional support that SORL1 is a bona fide causal gene in AD, and when taken together with recent insight on other AD-causal genes, support the idea that dysfunctional endosomal recycling is a dominant pathogenic pathway in the disease.

neuroscience↗