Biology subjects

Caron, N. S.

Publications and source records attributed to Caron, N. S..

7 recordsLinked to original sources

bioRxiv2026

Proteomic profiling of baseline CSF and serum from HDClarity identifies signatures for Huntington disease staging and stratification

Background: Sensitive biomarkers that objectively stage Huntington disease (HD) are needed to improve participant stratification and facilitate the enrichment of clinical trials with biologically and clinically homogeneous populations. The HDClarity study, an international longitudinal biofluid collection initiative for HD, provides a unique resource for large-scale proteomic profiling of matched CSF and serum samples from healthy controls and individuals across premanifest and manifest stages of HD. Here, we leveraged baseline proteomic data from HDClarity to characterize protein signatures associated with disease stage and clinical severity, compare measurements across analytical platforms and biofluid compartments, and identify candidate multi-protein panels for disease staging. Methods: Baseline proteomic data generated using Olink Explore (~3,000 proteins) and SomaScan (~7,000 proteins) were analyzed in matched CSF and serum samples from 315 HD gene-expansion carriers and 92 non-HD controls. A total of 2,119 proteins overlapped between Olink and SomaScan, enabling assessment of cross-platform concordance, while CSF-serum relationships were evaluated using all available protein measurements within each assay. Covariate-adjusted linear regression models were used to assess disease stage-associated differences in protein abundance, while partial correlation analyses evaluated relationships between protein abundance, clinical severity in HD gene-expansion carriers, and estimated years to disease onset in premanifest participants. A nested machine-learning pipeline incorporating univariate feature ranking, penalized regression-based feature selection, and repeated cross-validation was used to derive compact multi-protein classifiers for HD staging. Results: Cross-platform and CSF-serum correlations were highly protein-dependent, with some analytes showing strong concordance and others exhibiting weak or inverse relationships. These findings highlight substantial heterogeneity in biomarker behaviour across analytical platforms and biofluids. Adjusted models identified both known HD-associated markers (NEFL, GFAP, CHI3L1) and less well-characterized proteins in CSF (TNFRSF8, TPM3, NPPB) and serum (OMG, NPTXR, NCAN) whose baseline abundance differed across clinical and/or HD-Integrated Staging System (HD-ISS) stages. Partial correlation analyses revealed additional candidate biomarkers associated with clinical severity and years to predicted disease onset. Machine-learning models identified compact CSF and serum protein panels that achieved high classification accuracy (AUC > 0.9) across all clinical contrasts, with models distinguishing the transitions from HD-ISS stage 0 to 1 and from premanifest to early manifest disease demonstrating robust generalization to unseen data. Conclusions: This study provides the first large-scale comparison of matched CSF and serum proteomic profiles from the HDClarity cohort, identifying robust baseline proteomic signatures across the HD continuum. Our findings demonstrate the importance of considering both analytical platform and biofluid when interpreting protein biomarkers and identify compact protein panels with potential utility for objective disease staging, patient stratification, and clinical trial enrichment in HD.

neuroscience↗

bioRxiv2024

Identification of neurodevelopmental organization of the cell populations of juvenile Huntington's disease using dorso-ventral HD organoids and HD mouse embryos

Huntingtons disease (HD), especially juvenile-onset HD (JOHD), involves early neurodevelopmental pathogenesis alongside the gradual breakdown of the corticostriatal neural axis. To better understand this mechanism, we created fused dorsal-ventral forebrain organoids from induced pluripotent stem cells (iPSCs) from JOHD to mimic early corticostriatal interactions in the disease. We observed characteristic growth phenotypes in HD organoids and found that these phenotypes were influenced by paracrine signals from opposite regions (dorsal-ventral and ventral-dorsal). These phenotypes were only partially rescued by conditioning with medium in HD compared to control organoids. We also investigated humanized HD embryonic mouse forebrains at E13.5 to validate the phenotypes. Using single-cell RNA sequencing (scRNAseq) and immunofluorescence of the internal structure of HD organoids, we observed early neurodevelopmental signs, including stalling during the phase of increased progenitor cell growth, delayed neuron maturation, and disrupted patterning between pallial and subpallial regions. A consistent feature across in vitro and in vivo models was an abnormal expansion of transthyretin (TTR)-positive cells resembling choroid plexus (ChP), along with ectopic expression of neuronal factors in ChP and a reduction in populations expressing intermediate progenitor and interneuron markers. In mosaic organoids that combined healthy and JOHD tissues, the healthy environment helped reduce ChP overgrowth and restore normal progenitor and neuronal development. This suggests that some developmental defects caused by mutant HTT are reversible and influenced by non-cell-autonomous factors. Overall, these findings point to early ChP-related abnormalities as a key aspect of JOHD neurodevelopmental disturbance and propose the ChP-CSF environment as an important area for future mechanistic studies and potential therapies.

developmental biology↗

bioRxiv2023

Reduced S-acylation of SQSTM1/p62 in Huntington disease is associated with impaired autophagy

Disruption of macroautophagy/autophagy has emerged as a common feature in many neurodegenerative diseases. Autophagy is a membrane-dependent pathway that requires many key regulators to quickly localize on and off membranes during induction promoting membrane fusion. Previously, our bioinformatic approaches have shown that autophagy and Huntington disease (HD) are enriched in S-acylated proteins. S-acylation involves the reversible addition of long chain fatty acids to promote membrane binding. Herein, we show that inhibition of S-acylation regulates the abundance of several key regulators of autophagy and leads to a partial block of autophagic flux. We show that the autophagy receptor SQSTM1/p62 (sequestosome 1) is S-acylated and directed to the lysosome. Importantly, we see that SQSTM1 S-acylation is significantly reduced in HD patient and mouse model brains, thus providing a novel mechanism for the generation of empty autophagosomes previously seen in HD models and patient cells.

neuroscience↗

bioRxiv2021

Rescue of aberrant huntingtin palmitoylation ameliorates mutant huntingtin-induced toxicity

Huntington disease (HD) is a neurodegenerative disorder caused by a CAG expansion in the HTT gene that codes for an elongated polyglutamine tract in the huntingtin (HTT) protein. HTT is subject to multiple post-translational modifications (PTMs) that regulate its cellular function. Mutating specific PTM sites within mutant HTT (mHTT) in HD mouse models can modulate disease phenotypes, highlighting the key role of HTT PTMs in the pathogenesis of HD. These findings have led to increased interest in developing small molecules to modulate HTT PTMs in order to decrease mHTT toxicity. However, the therapeutic efficacy of pharmacological modulation of HTT PTMs in preclinical HD models remains largely unknown. HTT is palmitoylated at cysteine 214 by the huntingtin-interacting protein 14 (HIP14 or ZDHHC17) and 14-like (HIP14L or ZDHHC13) acyltransferases. Here, we assessed if HTT palmitoylation should be regarded as a therapeutic target to treat HD by (1) investigating palmitoylation dysregulation in rodent and human HD model systems, (2) measuring the impact of mHTT-lowering therapy on brain palmitoylation, and (3) evaluating if HTT palmitoylation can be pharmacologically modulate. We show that palmitoylation of mHTT and some HIP14/HIP14L-substrates is decreased early in multiple HD mouse models, and that aging further reduces HTT palmitoylation. Lowering mHTT in the brain of YAC128 mice is not sufficient to rescue aberrant palmitoylation. However, we demonstrate that mHTT palmitoylation can be normalized in COS-7 cells, in YAC128 cortico-striatal primary neurons and HD patient-derived lymphoblasts using an acyl-protein thioesterase (APT) inhibitor. Moreover, we show that modulating palmitoylation reduces mHTT aggregation and mHTT-induced cytotoxicity in COS-7 cells and YAC128 neurons. HighlightsO_LIPalmitoylation of mHTT is reduced in multiple transgenic HD mouse models C_LIO_LIHTT palmitoylation decreases with increasing polyQ length in HD patient cells C_LIO_LImHTT-lowering in mouse brains does not rescue aberrant palmitoylation C_LIO_LImHTT palmitoylation in HD patient-derived cells can be rescued via APT inhibition C_LIO_LIPromoting palmitoylation reduces mHTT aggregation and cytotoxicity in vitro C_LI

neuroscience↗

bioRxiv2019

The interaction of aging and oxidative stress contributes to pathogenesis in mouse and human Huntington disease neurons

Huntington disease (HD) is a fatal, inherited neurodegenerative disorder caused by a mutation in huntingtin (HTT). While mutant HTT is present ubiquitously throughout life, HD onset typically occurs in mid-life. Oxidative damage accumulates in the aging brain and is a feature of HD. We sought to interrogate the roles and interaction of age and oxidative stress in HD using primary Hu97/18 mouse neurons, neurons differentiated from HD patient induced pluripotent stem cells (iPSCs), and mice. We find that primary neurons must be matured in culture for canonical stress responses to occur. Furthermore, when aging is accelerated in mature HD neurons, mutant HTT accumulates and sensitivity to oxidative stress is selectively enhanced. Furthermore, we observe HD-specific phenotypes in iPSC-derived neurons and mouse brains that have undergone accelerated aging. These findings suggest a role for aging in HD pathogenesis and interaction between biological age of HD neurons and sensitivity to exogenous stress.

neuroscience↗

bioRxiv2019

Gene expression profiles complement the analysis of genomic modifiers of the clinical onset of Huntington disease

Huntington disease (HD) is a neurodegenerative disorder that is caused by a CAG repeat expansion in the HTT gene. In an attempt to identify genomic modifiers that contribute towards the age of onset of HD, we performed a transcriptome wide association study assessing heritable differences in genetically determined expression in diverse tissues, employing genome wide data from over 4,000 patients. This identified genes that showed evidence for colocalization and replication, with downstream functional validation being performed in isogenic HD stem cells and patient brains. Enrichment analyses detected associations with various biologically-relevant gene sets and striatal coexpression modules that are mediated by CAG length. Further, cortical coexpression modules that are relevant for HD onset were also associated with cognitive decline and HD-related traits in a longitudinal cohort. In summary, the combination of population-scale gene expression information with HD patient genomic data identified novel modifier genes for the disorder.

genomics↗

bioRxiv2017

Feeding Schedule And Proteolysis Regulate Autophagic Clearance Of Mutant Huntingtin

The expression of mutant huntingtin (mHTT) causes Huntington disease (HD), and lowering its levels is therefore an attractive therapeutic strategy. Here we show that scheduled feeding significantly decreases mHTT protein levels through enhanced autophagy in the CNS of an HD mouse model, while short term fasting is sufficient to observe similar effects in peripheral tissue. Furthermore, preventing proteolysis at the caspase-6 cleavage site D586 (C6R) makes mHTT a better substrate for autophagy, additionally increasing its clearance. Mice expressing mutant C6R also exhibit increased autophagy at baseline compared to an HD model with cleavable mHTT, suggesting that the native function of HTT in promoting autophagy is disrupted upon cleavage and re-established by prevention of cleavage by caspase-6. In HD patients, mHTT clearance and autophagy may therefore become increasingly impaired as a function of age and disease stage by gradually increased activity of mHTT-processing enzymes.

neuroscience↗