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PTMs as molecular encoders: reprogramming chaperones into epichaperomes for network control in disease
Chu, Feixia; Sharma, Sahil; Ginsberg, Stephen D; Chiosis, Gabriela
Recent discoveries reveal that post-translational modifications (PTMs) do more than regulate protein activity - they encode conformational states that transform chaperones into epichaperomes: multimeric scaffolds that rewire protein-protein interaction networks. This emerging paradigm expands the framework of chaperone biology in disease and provides a structural basis for systems-level dysfunction in disorders such as cancer and Alzheimer's disease. This review explores how PTMs within intrinsically disordered regions drive epichaperome formation, how these scaffolds selectively regulate disease-enabling functions, and why their disruption normalizes pathological networks. By highlighting PTMs as molecular encoders of supramolecular assemblies, we propose a shift from targeting proteins to targeting network architectures that sustain and perpetuate disease - a concept with broad implications for cell biology, disease propagation, and therapeutic design.
PMID: 40877054
ISSN: 0968-0004
CID: 5910612
Benefits of Maternal Choline Supplementation on Aged Basal Forebrain Cholinergic Neurons (BFCNs) in a Mouse Model of Down Syndrome and Alzheimer's Disease
Alldred, Melissa J; Pidikiti, Harshitha; Ibrahim, Kyrillos W; Lee, Sang Han; Heguy, Adriana; Chiosis, Gabriela; Mufson, Elliott J; Stutzmann, Grace E; Ginsberg, Stephen D
Down syndrome (DS), stemming from the triplication of human chromosome 21, results in intellectual disability, with early mid-life onset of Alzheimer's disease (AD) pathology. Early interventions to reduce cognitive impairments and neuropathology are lacking. One modality, maternal choline supplementation (MCS), has shown beneficial effects on behavior and gene expression in neurodevelopmental and neurodegenerative disorders, including trisomic mice. Loss of basal forebrain cholinergic neurons (BFCNs) and other DS/AD relevant hallmarks were observed in a well-established trisomic model (Ts65Dn, Ts). MCS attenuates these endophenotypes with beneficial behavioral effects in trisomic offspring. We postulate MCS ameliorates dysregulated cellular mechanisms within vulnerable BFCNs, with attenuation driven by novel gene expression. Here, choline acetyltransferase immunohistochemical labeling identified BFCNs in the medial septal/ventral diagonal band nuclei of the basal forebrain in Ts and normal disomic (2N) offspring at ~11 months of age from dams exposed to MCS or normal choline during the perinatal period. BFCNs (~500 per mouse) were microisolated and processed for RNA-sequencing. Bioinformatic assessment elucidated differentially expressed genes (DEGs) and pathway alterations in the context of genotype (Ts, 2N) and maternal diet (MCS, normal choline). MCS attenuated select dysregulated DEGs and relevant pathways in aged BFCNs. Trisomic MCS-responsive improvements included pathways such as cognitive impairment and nicotinamide adenine dinucleotide signaling, among others, indicative of increased behavioral and bioenergetic fitness. Although MCS does not eliminate the DS/AD phenotype, early choline delivery provides long-lasting benefits to aged trisomic BFCNs, indicating that MCS prolongs neuronal health in the context of DS/AD.
PMCID:12384390
PMID: 40867575
ISSN: 2218-273x
CID: 5910322
Frontal cortex pyramidal neuron expression profiles differentiate the prodromal stage from progressive degeneration across the Alzheimer's disease spectrum
Labuza, Amanda; Alldred, Melissa J; Pidikiti, Harshitha; Malek-Ahmadi, Michael H; Lee, Sang Han; Heguy, Adriana; Coleman, Paul D; Chakrabarty, Souparna; Chiosis, Gabriela; Mufson, Elliott J; Ginsberg, Stephen D
INTRODUCTION/BACKGROUND:Underlying causes of Alzheimer's disease (AD) remain unknown, making it imperative to identify molecular mechanisms driving the pathobiology of AD onset and progression. METHODS:Laser capture microdissection was used to isolate layer III pyramidal neurons from post mortem human prefrontal cortex (Brodmann area 9). Single population RNA sequencing was conducted using tissue from subjects with no cognitive impairment (NCI), mild cognitive impairment (MCI), and AD. Differentially expressed genes (DEGs) were compared across groups. RESULTS:DEGs increased from prodromal (MCI vs. NCI) to progression (AD vs. MCI) to frank AD (AD vs. NCI). The majority of DEGs and pathways shared between prodromal and progression exhibited a change in the direction of dysregulation unlike pathways between progression and frank AD. DISCUSSION/CONCLUSIONS:Candidate genes and pathways were identified that demarcate early-stage AD onset from AD progression, providing a roadmap to study cortical cellular vulnerability and key targets for intervention at early stages of AD. HIGHLIGHTS/CONCLUSIONS:Pyramidal neuron differentially expressed genes (DEGs) are directionally divergent between prodromal, progression, and frank Alzheimer's disease (AD). Pyramidal neuron DEGs are directionally convergent between progression and frank AD. Dysfunctional bioenergetic pathways increased dysregulation as the AD spectrum progressed. Immune response pathways were more dysregulated in frank AD than prodromal stages. DEGs, = biological pathways, and interactomes demarcate specific stages across the AD spectrum.
PMID: 40709510
ISSN: 1552-5279
CID: 5901932
Profiling lamina specific pyramidal neurons using postmortem human formalin fixed paraffin embedded frontal cortex tissue in combination with digital spatial profiling
Stanisavljevic, Aleksandra; Ibrahim, Kyrillos W; Stavrides, Philip H; Bare, Christopher; Alldred, Melissa J; Heguy, Adriana; Nixon, Ralph A; Ginsberg, Stephen D
BACKGROUND:/calmodulin-dependent protein kinase II and selected for probe collection. RESULTS:This approach significantly reduced the amount of FFPE tissue needed for robust single population RNA-seq. We demonstrate ~20 identified L3 or L5 pyramidal neurons or one lamina-specific cortical ribbon from a single 5µm thick section is sufficient to generate robust RNA-seq reads. Bioinformatic analysis of neurons and ribbons showed notable similarities and differences reflective of the single neuron and multiple admixed cell types within the former and latter, respectively. Comparison with existing methods Protocols exist for DSP of postmortem human FFPE brain tissue. However, this new approach enables profiling small groups of ~14-21 pyramidal neurons using the GeoMx DSP platform. CONCLUSIONS:This optimized DSP assay provides high resolution RNA-seq data demonstrating utility and versatility of the GeoMx platform for individually characterized neurons and isolated cortical ribbons within postmortem FFPE human brain tissue for downstream analyses.
PMID: 40473120
ISSN: 1872-678x
CID: 5862732
Posterior cingulate cortex microRNA dysregulation differentiates cognitive resilience, mild cognitive impairment, and Alzheimer's disease
Counts, Scott E; Beck, John S; Maloney, Bryan; Malek-Ahmadi, Michael; Ginsberg, Stephen D; Mufson, Elliott J; Lahiri, Debomoy K
INTRODUCTION/BACKGROUND:MicroRNA (miRNA) activity is increasingly appreciated as a key regulator of pathophysiologic pathways in Alzheimer's disease (AD). However, the role of miRNAs during the progression of AD, including resilience and prodromal syndromes such as mild cognitive impairment (MCI), remains underexplored. METHODS:We performed miRNA-sequencing on samples of posterior cingulate cortex (PCC) obtained post mortem from Rush Religious Orders Study participants diagnosed ante mortem with no cognitive impairment (NCI), MCI, or AD. NCI subjects were subdivided as low pathology (Braak stage I/II) or high pathology (Braak stage III/IV), suggestive of resilience. Bioinformatics approaches included differential expression, messenger RNA (mRNA) target prediction, interactome modeling, functional enrichment, and AD risk modeling. RESULTS:We identified specific miRNA groups, mRNA targets, and signaling pathways distinguishing AD, MCI, resilience, ante mortem neuropsychological test performance, post mortem neuropathological burden, and AD risk. DISCUSSION/CONCLUSIONS:These findings highlight the potential of harnessing miRNA activity to manipulate disease-modifying pathways in AD, with implications for precision medicine. HIGHLIGHTS/CONCLUSIONS:MicroRNA (MiRNA) dysregulation is a well-established feature of Alzheimer's disease (AD). Novel miRNAs also distinguish subjects with mild cognitive impairment and putative resilience. MiRNAs correlate with cognitive performance and neuropathological burden. Select miRNAs are associated with AD risk with age as a significant covariate. MiRNA pathways include insulin, prolactin, kinases, and neurite plasticity.
PMCID:11863362
PMID: 40008917
ISSN: 1552-5279
CID: 5800972
Profiling hippocampal neuronal populations reveals unique gene expression mosaics reflective of connectivity-based degeneration in the Ts65Dn mouse model of Down syndrome and Alzheimer's disease
Alldred, Melissa J; Ibrahim, Kyrillos W; Pidikiti, Harshitha; Lee, Sang Han; Heguy, Adriana; Chiosis, Gabriela; Mufson, Elliott J; Stutzmann, Grace E; Ginsberg, Stephen D
INTRODUCTION/UNASSIGNED:Individuals with Down syndrome (DS) exhibit neurological deficits throughout life including the development of in Alzheimer's disease (AD) pathology and cognitive impairment. At the cellular level, dysregulation in neuronal gene expression is observed in postmortem human brain and mouse models of DS/AD. To date, RNA-sequencing (RNA-seq) analysis of hippocampal neuronal gene expression including the characterization of discrete circuit-based connectivity in DS remains a major knowledge gap. We postulate that spatially characterized hippocampal neurons display unique gene expression patterns due, in part, to dysfunction of the integrity of intrinsic circuitry. METHODS/UNASSIGNED:We combined laser capture microdissection to microisolate individual neuron populations with single population RNA-seq analysis to determine gene expression analysis of CA1 and CA3 pyramidal neurons and dentate gyrus granule cells located in the hippocampus, a region critical for learning, memory, and synaptic activity. RESULTS/UNASSIGNED:The hippocampus exhibits age-dependent neurodegeneration beginning at ~6 months of age in the Ts65Dn mouse model of DS/AD. Each population of excitatory hippocampal neurons exhibited unique gene expression alterations in Ts65Dn mice. Bioinformatic inquiry revealed unique vulnerabilities and differences with mechanistic implications coinciding with onset of degeneration in this model of DS/AD. CONCLUSIONS/UNASSIGNED:These cell-type specific vulnerabilities may underlie degenerative endophenotypes suggesting precision medicine targeting of individual populations of neurons for rational therapeutic development.
PMCID:11897496
PMID: 40078964
ISSN: 1662-5099
CID: 5808642
Evidence that cholinergic mechanisms contribute to hyperexcitability at early stages in Alzheimer's disease
Scharfman, Helen E; Kam, Korey; Duffy, Áine M; LaFrancois, John J; Leary, Paige; Chartampila, Elissavet; Ginsberg, Stephen D; Lisgaras, Christos Panagiotis
A long-standing theory for Alzheimer's disease (AD) has been that deterioration of synapses and depressed neuronal activity is a major contributing factor. We review the increasing evidence, in humans and in mouse models, that show that there is often neuronal hyperactivity at early stages rather than decreased activity. We discuss studies in mouse models showing that hyperexcitability can occur long before plaque deposition and memory impairment. In mouse models, a generator of the hyperactivity appears to be the dentate gyrus. We present evidence, based on mouse models, that inhibition of muscarinic cholinergic receptors or medial septal cholinergic neurons can prevent hyperactivity. Therefore, we hypothesize the novel idea that cholinergic neurons are overly active early in the disease, not depressed. In particular we suggest the medial septal cholinergic neurons are overly active and contribute to hyperexcitability. We further hypothesize that the high activity of cholinergic neurons at early ages ultimately leads to their decline in function later in the disease. We review the effects of a prenatal diet that increases choline, the precursor to acetylcholine and modulator of many other functions. In mouse models of AD, maternal choline supplementation (MCS) reduces medial septal cholinergic pathology, amyloid accumulation and hyperexcitability, especially in the dentate gyrus, and improves cognition.
PMCID:12209278
PMID: 40599392
ISSN: 2813-3919
CID: 5887932
Down syndrome frontal cortex layer III and layer V pyramidal neurons exhibit lamina specific degeneration in aged individuals
Alldred, Melissa J; Ibrahim, Kyrillos W; Pidikiti, Harshitha; Chiosis, Gabriela; Mufson, Elliott J; Stutzmann, Grace E; Ginsberg, Stephen D
Selective vulnerability of neuronal populations occurs in both Down syndrome (DS) and Alzheimer's disease (AD), resulting in disproportional degeneration of pyramidal neurons (PNs) affecting memory and executive function. Elucidating the cellular mechanisms underlying the selective vulnerability of these populations will provide pivotal insights for disease progression in DS and AD. Single population RNA-sequencing analysis was performed on neurons critical for executive function, prefrontal cortex Brodmann area 9 (BA9) layer III (L3) and layer V (L5) excitatory PNs in postmortem human DS and age- and sex-matched control (CTR) brains. Data mining was performed on differentially expressed genes (DEGs) from PNs in each lamina with DEGs divergent between lamina identified and interrogated. Bioinformatic inquiry of L3 PNs revealed more unique/differentially expressed DEGs (uDEGs) than in L5 PNs in DS compared to CTR subjects, indicating gene dysregulation shows both spatial and cortical laminar projection neuron dependent dysregulation. DS triplicated human chromosome 21 (HSA21) comprised a subset of DEGs only dysregulated in L3 or L5 neurons, demonstrating partial cellular specificity in HSA21 expression. These HSA21 uDEGs had a disproportionally high number of noncoding RNAs, suggesting lamina specific dysfunctional gene regulation. L3 uDEGs revealed overall more dysregulation of cellular pathways and processes, many relevant to early AD pathogenesis, while L5 revealed processes suggestive of frank AD pathology. These findings indicate that trisomy differentially affects a subpopulation of uDEGs in L3 and L5 BA9 projection neurons in aged individuals with DS, which may inform circuit specific pathogenesis underlying DS and AD.
PMCID:11603868
PMID: 39605035
ISSN: 2051-5960
CID: 5763552
Single-cell transcriptomic and proteomic analysis of Parkinson's disease brains
Zhu, Biqing; Park, Jae-Min; Coffey, Sarah R; Russo, Anthony; Hsu, I-Uen; Wang, Jiawei; Su, Chang; Chang, Rui; Lam, TuKiet T; Gopal, Pallavi P; Ginsberg, Stephen D; Zhao, Hongyu; Hafler, David A; Chandra, Sreeganga S; Zhang, Le
Parkinson's disease (PD) is a prevalent neurodegenerative disorder, and recent evidence suggests that pathogenesis may be in part mediated by inflammatory processes, the molecular and cellular architectures of which are largely unknown. To identify and characterize selectively vulnerable brain cell populations in PD, we performed single-nucleus transcriptomics and unbiased proteomics to profile the prefrontal cortex from postmortem human brains of six individuals with late-stage PD and six age-matched controls. Analysis of nearly 80,000 nuclei led to the identification of eight major brain cell types, including elevated brain-resident T cells in PD, each with distinct transcriptional changes in agreement with the known genetics of PD. By analyzing Lewy body pathology in the same postmortem brain tissues, we found that α-synuclein pathology was inversely correlated with chaperone expression in excitatory neurons. Examining cell-cell interactions, we found a selective abatement of neuron-astrocyte interactions and enhanced neuroinflammation. Proteomic analyses of the same brains identified synaptic proteins in the prefrontal cortex that were preferentially down-regulated in PD. By comparing this single-cell PD dataset with a published analysis of similar brain regions in Alzheimer's disease (AD), we found no common differentially expressed genes in neurons but identified many shared differentially expressed genes in glial cells, suggesting that the disease etiologies, especially in the context of neuronal vulnerability, in PD and AD are likely distinct.
PMID: 39475571
ISSN: 1946-6242
CID: 5747032
Phosphorylation-driven epichaperome assembly is a regulator of cellular adaptability and proliferation
Roychowdhury, Tanaya; McNutt, Seth W; Pasala, Chiranjeevi; Nguyen, Hieu T; Thornton, Daniel T; Sharma, Sahil; Botticelli, Luke; Digwal, Chander S; Joshi, Suhasini; Yang, Nan; Panchal, Palak; Chakrabarty, Souparna; Bay, Sadik; Markov, Vladimir; Kwong, Charlene; Lisanti, Jeanine; Chung, Sun Young; Ginsberg, Stephen D; Yan, Pengrong; De Stanchina, Elisa; Corben, Adriana; Modi, Shanu; Alpaugh, Mary L; Colombo, Giorgio; Erdjument-Bromage, Hediye; Neubert, Thomas A; Chalkley, Robert J; Baker, Peter R; Burlingame, Alma L; Rodina, Anna; Chiosis, Gabriela; Chu, Feixia
The intricate network of protein-chaperone interactions is crucial for maintaining cellular function. Recent discoveries have unveiled the existence of specialized chaperone assemblies, known as epichaperomes, which serve as scaffolding platforms that orchestrate the reconfiguration of protein-protein interaction networks, thereby enhancing cellular adaptability and proliferation. This study explores the structural and regulatory aspects of epichaperomes, with a particular focus on the role of post-translational modifications (PTMs) in their formation and function. A key finding is the identification of specific PTMs on HSP90, particularly at residues Ser226 and Ser255 within an intrinsically disordered region, as critical determinants of epichaperome assembly. Our data demonstrate that phosphorylation of these serine residues enhances HSP90's interactions with other chaperones and co-chaperones, creating a microenvironment conducive to epichaperome formation. Moreover, we establish a direct link between epichaperome function and cellular physiology, particularly in contexts where robust proliferation and adaptive behavior are essential, such as in cancer and pluripotent stem cell maintenance. These findings not only provide mechanistic insights but also hold promise for the development of novel therapeutic strategies targeting chaperone assemblies in diseases characterized by epichaperome dysregulation, thereby bridging the gap between fundamental research and precision medicine.
PMID: 39414766
ISSN: 2041-1723
CID: 5711702