Biology subjects

Huentelman, M. J.

Publications and source records attributed to Huentelman, M. J..

9 recordsLinked to original sources

bioRxiv2025

Transcriptomic and protein analysis of human cortex reveals genes and pathways linked to NPTX2 disruption in Alzheimer's disease

BackgroundCognitive resilience to Alzheimers disease (AD) pathology is associated with preserved expression of NPTX2, an activity-regulated synaptic protein involved in circuit plasticity, excitation-inhibition balance, and complement-linked synapse regulation. However, the broader molecular programs coordinated with NPTX2 in resilient individuals remain unclear. MethodsWe analyzed postmortem middle temporal gyrus tissue using targeted PRM-MS proteomics in 135 individuals and bulk RNA-seq in an expanded 575-sample cohort. NPTX2-associated molecular coordination was assessed within cognitively normal low-pathology controls (CN-Lo), cognitively normal high-pathology controls (CN-Hi), mild cognitive impairment (MCI), and AD. Correlation-based approaches were applied using NPTX2 protein and NPTX2 mRNA expression as anchors to define resilience mechanisms in CN-Hi subjects. ResultsNPTX2 protein abundance was preserved across all controls regardless of age and pathology but reduced in MCI and AD. NPTX2 mRNA expression was also invariant across pathology within controls and reduced in MCI and AD but decreased markedly with age. Targeted proteomics identified NPTX2 relationships with synaptic and inhibitory-circuit proteins that were preserved across control groups, alongside CN-Hi-specific recruitment of trafficking, lysosomal, metabolic, and proteostasis-associated proteins. Transcriptome-wide correlations with NPTX2 revealed differences in gene co-expression between groups, identifying a prominent activity-dependent program including BDNF, VGF, SCG2, SST, SERTM1, DUSP4, and EGR4, that was preserved in both CN-Lo and CN-Hi subjects, while genes recruited to the NPTX2 network specifically in CN-Hi implicated immune, neuroprotective, translation, and proteostasis-related pathways. Coupling differential gene expression analysis with co-expression, we further identified five candidate resilience genes whose expression and NPTX correlation was preserved across controls, but lost in MCI and AD: SST, MAL2, TAC1, SERTM1, and RFK. Expression of genes in distinct NPTX2 co-expression classes can be freely explored in our bulk RNA-seq data and other public AD transcriptomic datasets at NeMO Analytics. ConclusionFindings suggest that cognitive resilience in the context of AD neuropathology engages a coordinated molecular state distinct from both persevered cognition without pathology and MCI/AD, which is organized around preserved and selectively remodeled NPTX2-associations. Rather than reflecting broad transcript abundance changes, resilience was characterized by maintained synaptic and inhibitory programs, and adaptive proteostasis and trafficking pathways that distinguish resilient high-pathology individuals from low-pathology controls or symptomatic AD.

bioinformatics↗

bioRxiv2025

Transcriptomic profiling of the middle temporal gyrus reveals differential glial/neuronal dysregulation across Alzheimer disease and aging.

Alzheimers disease (AD), the most common cause of dementia, is characterized by amyloid-{beta} plaques, neurofibrillary tangles, and widespread neuronal dysfunction. Aging, the strongest risk factor for AD, is also associated with some overlapping processes, such as neuronal cell transcriptional downregulation and glial cell activation. The middle temporal gyrus (MTG) is a brain region that supports semantic processing and default-mode connectivity and shows early vulnerability in both aging and AD. Here we profile bulk RNA-seq from 606 postmortem MTG samples with the goal of understanding the transcriptional changes associated with AD and aging. In 217 clinical and neuropathologically confirmed AD versus 290 no-dementia controls donors, we identify 613 differentially expressed genes (390 up, 223 down; |log2 fold change| [≥] 0.5; BH P < 0.05), with NPNT and ADAMTS2 among the top upregulated signals. Cell set enrichment indicates reduced excitatory neuronal signatures together with increased microglial, astrocytic, endothelial, and pericyte programs. Gene-set analyses reveal strong activation of angiogenesis, extracellular-matrix organization, wound response, adaptive immunity, and coordinated suppression of neuronal and mitochondrial processes, including synaptic signaling and respiratory-chain complexes. Multiscale coexpression mapping resolves three disease clusters: a neuron-mitochondrial module suppressed in AD (M5; hub PJA2; key driver GABRB3), a microglial immune module upregulated in AD (M6; hub C1QC; key driver FCER1G), and an increased astrocyte-vascular extracellular-matrix module in AD (M8; hub ESAM; key driver TAGLN). Across 324 non-AD controls aged 24-108 years, aging is associated with declines in gene expression associated with translation, proteostasis, and mitochondrial function and increases in those linked to oligodendrocyte and myelination programs (for example M4; hub CNTN2; key driver MOBP); in a 65+ subset, neuronal and protein-folding modules show the strongest decrements with reduced glial gene expression upregulatio. Our results indicate that late-life aging involves increased glial responses and neuronal/proteostasis suppression, whereas AD is also associated with immune- vascular-ECM activation and suppression of neuronal programs.

genomics↗

bioRxiv2024

Characterizing CSNK2A1 Mutant-Induced Morphological Phenotypes in Zebrafish (Danio rerio): Insights into Okur-Chung Neurodevelopmental Syndrome (OCNDS)

Okur-Chung Neurodevelopmental Syndrome (OCNDS) is a rare, autosomal dominant disorder caused by heterozygous pathogenic variants in the CSNK2A1 gene. CSNK2A1 encodes the subunit of protein kinase CK2, involved in diverse biological processes. In 2016, Okur et al. reported the discovery of germline de novo missense and canonical splice site mutations in CSNK2A1 in five female patients with OCNDS. The syndrome is characterized by developmental delays, intellectual disability, hypotonia, feeding difficulties, dysmorphic facial features, and disrupted circadian rhythms, leading to sleep disturbances. The complex phenotypic spectrum of OCNDS underscores the need for robust model systems to investigate genotype-phenotype correlations, disease mechanisms, and potential therapies. In this study, we employed an overexpression strategy in a zebrafish model to investigate the functional consequences of select CSNK2A1 variants implicated in OCNDS. Our findings revealed distinct morphological phenotypes resulting from the overexpression of different CSNK2A1 mutants, indicating a direct correlation between genetic alterations and phenotypic manifestations. Notably, the CSNK2A1 p.Arg191Ter (R191X) mutation had a significant impact on the phenotype. Co-injection of wild-type CSNK2A1 mRNA with mutant CSNK2A1 mRNA rescued morphological abnormalities in zebrafish embryos. Overall our study highlights the utility of zebrafish as an adaptable model system for examining the functional impact of CSNK2A1 mutations and exploring novel therapeutic avenues.

neuroscience↗

bioRxiv2023

CELSR3 deficiency leads to tic-related behaviors and dopaminergic alterations in the striatum

The gene CELSR3 (Cadherin EGF LAG Seven-pass-G-type Receptor 3) has been recently recognized as a high-confidence risk factor for Tourette syndrome (TS). Additionally, Celsr3 mutant mice have been reported to exhibit TS-related behaviors and increased dopamine release in the striatum. Building on these findings, we further characterized the neurobehavioral and molecular profile of Celsr3 mutant mice to understand better the biological mechanisms connecting the deficiency of this gene and TS-related phenotypes. Our analyses confirmed that Celsr3 mutant mice displayed grooming stereotypies and tic-like jerks, as well as sensorimotor gating deficits, which were opposed by TS therapies. Spatial transcriptomic analyses revealed widespread extracellular matrix abnormalities in the striatum of Celsr3 mutants. Single-nucleus transcriptomics also showed significant upregulation of the Drd3 gene, encoding the dopamine D3 receptor, in striosomal D1-positive neurons. In situ hybridization and immunofluorescence confirmed dysregulated D3 receptor expression, with lower levels in presynaptic striatal fibers and higher levels in striatal D1-positive neurons. Activating and blocking D3 receptors amplified or decreased tic-like jerks and stereotypies in Celsr3-deficient mice, respectively. These findings suggest that modifications of D3 receptor distribution contribute to the tic-like responses associated with Celsr3 deficiency.

neuroscience↗

bioRxiv2022

Dynamic Transcriptomic Network Responses to Divergent Acute Exercise Challenges in Young Adults

Acute exercise elicits dynamic transcriptional changes that, when repeated, form the fundamental basis of adaptations in health, resilience, and performance. While moderate-intensity endurance training combined with conventional resistance training (traditional, TRAD) is often prescribed and recommended by public health guidance, high-intensity training combining maximal-effort intervals with intensive, limited-rest resistance training is a time-efficient alternative that may be used tactically (HITT) to seek whole body health benefits. Mechanisms of action of these distinct doses are incompletely characterized and have not been directly compared. We assessed transcriptome-wide responses in skeletal muscle and circulating extracellular vesicles (EVs) to a single exercise bout in young adults randomized to TRAD (n=21, 12M/9F, 22{+/-}3y) or HITT (n=19, 11M/8F, 22{+/-}2y). Next-generation sequencing captured small, long, and circular RNA in muscle and EVs. Analysis identified differentially expressed transcripts (|log2FC|>1, FDR[≤]0.05) immediately (h0, EVs only), h3, and h24 post-exercise within and between exercise doses. Additionally, all apparently responsive transcripts (FDR<0.2) underwent singular value decomposition to summarize data structures into latent variables (LVs) to deconvolve molecular expression circuits and inter-regulatory relationships. LVs were compared across time and exercise dose. TRAD generally elicited a stronger, more consistent transcriptional response than HITT, but considerable overlap and key differences existed. Findings reveal shared and unique molecular responses to divergent exercise stimuli and lay groundwork toward establishing relationships between protein-coding genes and lesser-understood transcripts that serve regulatory roles in response to exercise. Future work should advance the understanding of these circuits and whether they repeat in other populations or following other types of exercise/stress. NEW AND NOTEWORTHYWe examined small and long transcriptomics in skeletal muscle and serum-derived extracellular vesicles before and after a single exposure to traditional combined exercise (TRAD) and high-intensity tactical training (HITT). Across 40 young adults, we found more consistent protein-coding gene responses to TRAD, whereas HITT elicited differential expression of microRNA enriched in brain regions. Follow-up analysis revealed relationships and temporal dynamics across transcript networks, highlighting potential avenues for research into mechanisms of exercise response and adaptation.

bioinformatics↗

bioRxiv2020

Adenosine triphosphate Binding Cassette subfamily C member 1 (ABCC1) overexpression reduces APP processing and increases alpha- versus beta-secretase activity, in vitro

The organic anion transporter Adenosine triphosphate Binding Cassette subfamily C member 1 (ABCC1), also known as MRP1, has been demonstrated in murine models of Alzheimers disease (AD) to export amyloid beta (Abeta) from the endothelial cells of the blood-brain barrier to the periphery, and that pharmaceutical activation of ABCC1 can reduce amyloid plaque deposition in the brain. Here, we show that ABCC1 is not only capable of exporting Abeta from the cytoplasm of human cells, but also that its overexpression significantly reduces Abeta production and increases the ratio of alpha- versus beta-secretase mediated cleavage of the Amyloid Precursor Protein (APP), likely via indirect modulation of alpha-, beta-, and gamma-secretase activity.

molecular biology↗

bioRxiv2020

Association of common genetic variants in the CPSF7 and SDHAF2 genes with Canine Idiopathic Pulmonary Fibrosis in the West Highland White Terrier

Canine Idiopathic Pulmonary Fibrosis (CIPF) is a chronic fibrotic lung disease that is observed at a higher frequency in the West Highland White Terrier dog breed (WHWT) and may have molecular pathological overlap with human lung fibrotic disease. We conducted a Genome-Wide Association Study (GWAS) in the WHWT using Whole Genome Sequencing (WGS) to discover genetic variants associated with CIPF. Saliva-derived DNA samples were sequenced using the Riptide DNA library prep kit. After quality controls, 28 affected, 44 unaffected and 1,843,695 informative Single Nucleotide Polymorphisms (SNPs) were included in the GWAS. Data were analyzed both at the single SNP and gene levels using the GEMMA and GATES methods, respectively. We detected significant signals at the gene level in both the CPSF7 and SDHAF2 genes (adjusted p = 0.016 and p = 0.025, respectively), two overlapping genes located on chromosome 18. The top SNP for both genes was rs22669389, however it did not reach genome-wide significance in the GWAS (adjusted p = 0.078). Our studies provide, for the first time, candidate loci for CIPF in the WHWT. CPSF7 was recently associated with lung adenocarcinoma further highlighting the potential relevance of our results since IPF and lung cancer share several pathological mechanisms.

genomics↗

bioRxiv2020

Complex genetic network underlying the convergent of Rett Syndrome like (RTT-L) phenotype in neurodevelopmental disorders

Mutations of the X-linked gene encoding methyl-CpG-binding protein 2 (MECP2) cause classical forms of Rett syndrome (RTT) in girls. Patients with features of classical Rett syndrome, but do not fulfill all the diagnostic criteria (e.g. absence of a MECP2 mutation), are defined as atypical Rett syndrome. Genes encoding for cyclin-dependent kinase-like 5 (CDKL5) and forkhead box G1 (FOXG1) are more commonly found in patients with atypical Rett syndrome. Nevertheless, a subset of patients who are recognized to have an overlapping phenotype with RTT but are lacking a mutation in a gene that causes typical or atypical RTT are described as having Rett syndrome like phenotype (RTT-L). Whole Exome Sequencing (WES) of 8 RTT-L patients from our cohort revealed mutations in the genes GABRG2, GRIN1, ATP1A2, KCNQ2, KCNB1, TCF4, SEMA6B, and GRIN2A, which are seemingly unrelated to Rett syndrome genes. We hypothesized that the phenotypic overlap in RTT and RTT-L is caused by mutations in genes that affect common cellular pathways critical for normal brain development and function. We annotated the list of genes identified causing RTT-L from peer-reviewed articles and performed a protein-protein interaction (PPI) network analysis. We also investigated their interaction with RTT (typical or atypical) genes such as MECP2, CDKL5, NTNG1, and FOXG1. We found that the RTT-L-causing genes were enriched in the biological pathways such as circadian entrainment, the CREB pathway, and RET signaling, and neuronal processes like ion transport, synaptic transmission, and transcription. We conclude that genes that significantly interact with the PPI network established by RTT genes cause RTT-L, explaining the considerable feature overlap between genes that are indicated for RTT-L and RTT.

genomics↗

bioRxiv2017

Systems genetics identifies modifiers of Alzheimer’s disease risk and resilience

Identifying genes that modify symptoms of Alzheimers disease (AD) will provide novel therapeutic strategies to prevent, cure or delay AD. To discover genetic modifiers of AD, we combined a mouse model of AD with a genetically diverse reference panel to generate F1 mice harboring identical high-risk human AD mutations but which differ across the remainder of their genome. We first show that genetic variation profoundly modifies the impact of causal human AD mutations and validate this panel as an AD model by demonstrating a high degree of phenotypic, transcriptomic, and genetic overlap with human AD. Genetic mapping was used to identify candidate modifiers of cognitive deficits and amyloid pathology, and viral-mediated knockdown was used to functionally validate Trpc3 as a modifier of AD. Overall, work here introduces a humanized mouse population as an innovative and reproducible resource for the study of AD and identifies Trpc3 as a novel therapeutic target.\n\nHighlightsO_LINew transgenic mouse population enables mapping of AD risk and resilience factors\nC_LIO_LITranscriptomic and phenotypic profiles in diverse AD mice parallel those in humans\nC_LIO_LIApoe genotype and expression correlate with cognitive symptoms in mice\nC_LIO_LITrpc3 is a novel target to reduce amyloid load and cognitive symptoms in AD\nC_LI

genetics↗