Biology subjects

Huentelman, M.

Publications and source records attributed to Huentelman, M..

7 recordsLinked to original sources

bioRxiv2026

Pseudotime analysis of 2,106 brains across nine regions reveals conserved immune, neuronal, and myelin regulatory programs in Alzheimer's disease

Pseudotime trajectories can reconstruct latent disease progression from cross-sectional transcriptomic data. However, whether Alzheimer's disease (AD) progression follows a conserved molecular architecture across brain regions remains unclear. We applied pseudotime analysis to harmonized bulk RNA-seq data from 2,106 postmortem brain samples (1,364 AD, 742 controls) across nine brain regions from three AMP-AD cohorts (ROSMAP, Mayo, MSBB). Pseudotime was significantly associated with AD diagnosis in all nine regions and with Braak stage in seven of nine. We identified 21 genes with concordant pseudotime associations across all regions, increasing to 234 when the cerebellum was excluded. Pathway analysis revealed 1,268 significant associations, with synaptic deregulation as the most conserved process, and immune/ECM programs showing greater regional specificity. The cerebellum followed a distinct pattern, with enrichment for protein refolding and chaperone pathways rather than neurodegeneration. Co-expression network analysis identified six conserved metamodules, including immune/glial (MM1) and excitatory neuronal (MM2) programs spanning all nine regions, and an oligodendrocyte/myelin program (MM3) in seven cortical regions. Key driver analysis identified 76 unique genes across 35 modules, with HCK and LAPTM5 as the most broadly replicated immune regulators in seven regions. Oligodendrocyte-associated key drivers (MYRF, CNP, MOBP) increased along pseudotime in cortical regions, supporting active myelin remodeling during AD progression. These findings reveal a conserved transcriptional architecture underlying AD progression, organized around coordinated immune activation, synaptic loss, and myelin remodeling, with the cerebellum following a distinct trajectory.

neuroscience↗

bioRxiv2026

Integrative synaptosome multi-omics reveals disrupted synapse organization and localized cryptic transcripts in C9ORF72-Frontotemporal Dementia

Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) are linked neurodegenerative diseases characterized by both synaptic dysfunction and TDP-43 pathology. A hexanucleotide repeat expansion (HRE) in the C9ORF72 (C9) gene represents the most common genetic cause of FTD and ALS, yet the synapse-specific mechanisms underlying disease pathogenesis remain poorly understood. Here, we performed integrated multi-omic profiling of synaptosomes enriched from postmortem frontal cortex and patient-derived induced pluripotent stem cell (iPSC)-derived cortical neurons to define molecular alterations associated with C9-FTD-mediated synaptic dysfunction. Proteomic profiling of frontal cortex-derived synaptosomes identified 1,324 differentially abundant proteins (p<0.05) enriched in pathways regulating synaptic vesicle transport and synapse organization, while synaptosomal RNA sequencing revealed 2,835 differentially expressed protein-coding genes. C9-FTD iPSC-cortical neurons exhibited reductions in excitatory and inhibitory postsynaptic markers, accompanied by progressive impairment of neuronal network activity, supporting both structural and functional deficits. iPSC-derived synaptosomes recapitulated key molecular pathways observed in patient brain, revealing convergent dysregulation of synaptic signaling pathways. Comparative analyses revealed divergence between protein and RNA alterations, consistent with the disruption of regulatory processes that link RNA and protein abundance diseased synapses. Consistent with TDP-43 loss-of-function pathology we identified cryptic exon (CE)-containing transcripts within C9-FTD frontal cortex-derived synaptosomes, including KALRN and STMN2, providing evidence that aberrantly spliced RNAs localize to synaptic compartments. Together, these findings define convergent molecular pathways underlying synapse vulnerability in both C9-FTD model systems and identify synaptic localization of CE-containing transcripts as a previously unrecognized feature of TDP-43 proteinopathy.

neuroscience↗

bioRxiv2026

The TREM2-R47H Variant Drives Alzheimer's-Relevant Alterations in Forebrain Organoids Beyond Microglial Populations

Recent genetic studies highlight microglia as central drivers of Alzheimers disease (AD), yet how specific risk variants like TREM2-R47H influence broader neurocellular networks remains elusive. Here, we utilize an iPSC-derived forebrain organoid co-culture system to investigate the multi-lineage impact of the TREM2-R47H variant. High-resolution transcriptomic profiling, paired with confocal imaging, demonstrate that mutant organoids recapitulate AD-specific pathological signatures. Representative confocal imaging revealed phosphorylated-Tau (pTau) and amyloid-beta (A{beta}) internalization by WT microglia, while R47H variants showed a qualitative reduction in pTau accumulation. Single-cell RNA sequencing (scRNA-seq) revealed neurodegenerative transcriptional profiles in TREM2-R47H neurons as early as day 139, occurring independently of microglia presence. By day 173, these cell-intrinsic signatures intensified, characterized by disrupted oxidative phosphorylation and impaired maturation trajectories. Interaction analysis further demonstrated that the addition of microglia exacerbated this phenotype; while WT cells adapted to the microglia niche by activating homeostatic, neuro-supportive programs, TREM2-R47H cells underwent identity erosion and failed to transition into HLA-enriched activation states. This state was characterized by a failure to adopt brain-resident signatures and a divergent shift toward inflammatory myeloid phenotypes. These findings reveal that the TREM2-R47H mutation exerts a dual burden: it drives a baseline neurodegenerative state in neural lineages and renders them incapable of proper niche integration. Our study provides an in vitro human platform to dissect the interplay between genetic risk and multi-cellular dysfunction, establishing a scalable system for evaluating novel therapeutic interventions and drug screening aimed at restoring neuro-immune homeostasis in AD.

neuroscience↗

bioRxiv2020

Residual-matching: An efficient alternative to random sampling in human subjects research recruitment

ABSTRACTGiven the time- and resource-intense nature of human subjects research, we have developed a more intelligent approach to participant recruitment above and beyond random sampling that leverages pilot or preliminary results to reduce the overall number of participants needed for recruitment from an existing electronic cohort or database. Using open-access data from the General Social Survey (GSS) of the National Opinion Research Center, we generated pilot and validation datasets through a simulation to establish moderate and weak relationships based on linear regression. We then compared the performance of our residual-matching method against random sampling in their probabilities of achieving a given level of statistical power as well as their prediction accuracies. Results showed that the residual-matching method was superior to random sampling, yielding smaller sample sizes with equivalent mean square error. We therefore advocate the use of residual matching when scaling up pilot studies to conserve time and resources in larger follow-up studies.Competing Interest StatementThe authors have declared no competing interest.View Full Text

scientific communication and education↗

bioRxiv2020

Transcriptional profiling of Multiple System Atrophy cerebellar tissue highlights differences between the parkinsonian and cerebellar sub-types of the disease

Multiple system atrophy (MSA) is a rare adult-onset neurodegenerative disease of unknown cause, with no effective therapeutic options, and no cure. Limited work to date has attempted to characterize the transcriptional changes associated with the disease, which presents as either predominating parkinsonian (MSA-P) or cerebellar (MSC-C) symptoms. We report here the results of RNA expression profiling of cerebellar white matter (CWM) tissue from two independent cohorts of MSA patients (n=66) and healthy controls (HC; n=66). RNA samples from bulk brain tissue and from oligodendrocytes obtained by laser capture microdissection (LCM) were sequenced. Differentially expressed genes (DEGs) were obtained and were examined before and after stratifying by MSA clinical sub-type. We detected the highest number of DEGs in the MSA-C group (n = 747) while only one gene was noted in MSA-P, highlighting the larger dysregulation of the transcriptome in the MSA-C CWM. Results from both bulk tissue and LCM analysis of MSA-C showed a downregulation of oligodendrocyte genes and an enrichment for myelination processes with a key role noted for the QKI gene. Additionally, we observed a significant upregulation of neuron-specific gene expression in MSA-C and an enrichment for synaptic processes. A third cluster of genes was associated with the upregulation of astrocyte and endothelial genes, two cell types with a key role in inflammation processes. Finally, network analysis in MSA-C showed enrichment for {beta}-amyloid related functional classes, including the known Alzheimers disease (AD) genes, APP and PSEN1. This is the largest RNA profiling study ever conducted on post-mortem brain tissue from MSA patients. We were able to define specific gene expression signatures for MSA-C highlighting the different stages of the complex neurodegenerative cascade of the disease that included alterations in several cell-specific transcriptional programs. Finally, several results suggest a common transcriptional dysregulation between MSA and AD-related genes despite the clinical and neuropathological distinctions between the two diseases.

genomics↗

bioRxiv2017

Somatic inactivating PTPRJ mutations and dysregulated pathways identified in canine melanoma by integrated comparative genomic analysis

Canine malignant melanoma, a significant cause of mortality in domestic dogs, is a powerful comparative model for human melanoma, but little is known about its genetic etiology. We mapped the genomic landscape of canine melanoma through multi-platform analysis of 37 tumors (31 mucosal, 3 acral, 2 cutaneous, and 1 uveal) and 17 matching constitutional samples including long- and short-insert whole genome sequencing, RNA sequencing, array comparative genomic hybridization, single nucleotide polymorphism array, and targeted Sanger sequencing analyses. We identified novel predominantly truncating mutations in the putative tumor suppressor gene PTPRJ in 19% of cases. No BRAF mutations were detected, but activating RAS mutations (24% of cases) occurred in conserved hotspots in all cutaneous and acral and 13% of mucosal subtypes. MDM2 amplifications (24%) and TP53 mutations (19%) were mutually exclusive. Additional low-frequency recurrent alterations were observed amidst low point mutation rates, an absence of ultraviolet light mutational signatures, and an abundance of copy number and structural alterations. Mutations that modulate cell proliferation and cell cycle control were common and highlight therapeutic axes such as MEK and MDM2 inhibition. This mutational landscape resembles that seen in BRAF wild-type and sun-shielded human melanoma subtypes. Overall, these data inform biological comparisons between canine and human melanoma while suggesting actionable targets in both species.\n\nAUTHOR SUMMARYMelanoma, an aggressive cancer arising from transformed melanocytes, commonly occurs in pet dogs. Unlike human melanoma, which most often occurs in sun-exposed cutaneous skin, canine melanoma typically arises in sun-shielded oral mucosa. Clinical features of canine melanoma resemble those of human melanoma, particularly the less common sun-shielded human subtypes. However, whereas the genomic basis of diverse human melanoma subtypes is well understood, canine melanoma genomics remain poorly defined. Similarly, although diverse new treatments for human melanoma based on a biologic disease understanding have recently shown dramatic improvements in outcomes for these patients, treatments for canine melanoma are limited and outcomes remain universally poor. Detailing the genomic basis of canine melanoma thus provides untapped potential for improving the lives of pet dogs while also helping to establish canine melanoma as a comparative model system for informing human melanoma biology and treatment. In order to better define the genomic landscape of canine melanoma, we performed multi-platform characterization of 37 tumors. Our integrated analysis confirms that these tumors commonly contain mutations in canine orthologs of human cancer genes such as RAS, MDM2, and TP53 as well mutational patterns that share important similarities with human melanoma subtypes. We have also found a new putative cancer gene, PTPRJ, frequently mutated in canine melanoma. These data will guide additional biologic and therapeutic studies in canine melanoma while framing the utility of comparative studies of canine and human cancers more broadly.

cancer biology↗

bioRxiv2017

Do Candidate Genes Affect the Brain’s White Matter Microstructure? Large-Scale Evaluation of 6,165 Diffusion MRI Scans

AbstractSusceptibility genes for psychiatric and neurological disorders - including APOE, BDNF, CLU,CNTNAP2, COMT, DISC1, DTNBP1, ErbB4, HFE, NRG1, NTKR3, and ZNF804A - have been reported to affect white matter (WM) microstructure in the healthy human brain, as assessed through diffusion tensor imaging (DTI). However, effects of single nucleotide polymorphisms (SNPs) in these genes explain only a small fraction of the overall variance and are challenging to detect reliably in single cohort studies. To date, few studies have evaluated the reproducibility of these results. As part of the ENIGMA-DTI consortium, we pooled regional fractional anisotropy (FA) measures for 6,165 subjects (CEU ancestry N=4,458) from 11 cohorts worldwide to evaluate effects of 15 candidate SNPs by examining their associations with WM microstructure. Additive association tests were conducted for each SNP. We used several meta-analytic and mega-analytic designs, and we evaluated regions of interest at multiple granularity levels. The ENIGMA-DTI protocol was able to detect single-cohort findings as originally reported. Even so, in this very large sample, no significant associations remained after multiple-testing correction for the 15 SNPs investigated. Suggestive associations (1.3x10-4 < p < 0.05, uncorrected) were found for BDNF, COMT, and ZNF804A in specific tracts. Meta-and mega-analyses revealed similar findings. Regardless of the approach, the previously reported candidate SNPs did not show significant associations with WM microstructure in this largest genetic study of DTI to date; the negative findings are likely not due to insufficient power. Genome-wide studies, involving large-scale meta-analyses, may help to discover SNPs robustly influencing WM microstructure.

neuroscience↗