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Masliah, E.

Publications and source records attributed to Masliah, E..

7 recordsLinked to original sources

PRISM-M: A Recurrent Framework for the Formation of Stable Internal Neural Models

How transient neural representations become integrated and stable enough to function as internal neural models remains incompletely understood. Grounded in efficient coding, Bayesian and predictive frameworks, recurrent and attractor dynamics, neural state-space models, and systems neuroscience, the Principle of Representation Integration for Stable Models (PRISM) proposes five operations: extraction, compression, integration, stabilization, and prediction/action. Here we developed PRISM-M, a minimal nine-equation recurrent dynamical realization with an explicit contraction condition (0 < J < 1), to examine whether these operations can generate persistent, context-sensitive, and prospectively informative model states. Seven simulation analyses showed persistent but revisable trajectories and a 0.209 context-dependent shift in the event-period model state. A 60 x 60 parameter sweep identified 719 rigid, 2,344 adaptive, and 537 high-gain trajectories within this structurally contractive parameter space, and the same regimes were recovered across 1,000 randomized environments. Perturbations of extraction, integration, and stabilization altered model trajectories, whereas the scalar compression perturbation had a small effect. The full PRISM state predicted the next model state more accurately than the model-state-only baseline (RMSE 0.0186 versus 0.0218), while performing similarly to an unconstrained ARX model. In the BART dataset, spatial fMRI states were distinguishable in 155 participants (69.7% accuracy; 33.3% chance), and inflation-related activity was modestly associated with pumping behavior in the 99 participants with matched behavioral data ({beta} = 0.198, P = 0.040). PRISM-M provides a constrained, testable framework centered on four operational signatures of model-like organization structured representation, contextual integration, persistence or reconstructability, and prospective relevance.

neuroscience↗

Single-cell spatial transcriptomics reveals molecular patterns of selective neuronal vulnerability to α-synuclein pathology in a transgenic mouse model of Lewy body disease

In Parkinsons disease and dementia with Lewy bodies, aggregated and phosphorylated -synuclein pathology appears in select neurons throughout cortical and subcortical regions, but little is currently known about why certain populations are selectively vulnerable. Here, using imaging spatial transcriptomics (IST) coupled with downstream immunofluorescence for -synuclein phosphorylated at Ser129 (pSyn) in the same tissue sections, we identified neuronal subtypes in the cortex and hippocampus of transgenic human -synuclein-overexpressing mice that preferentially developed pSyn pathology. Additionally, we investigated the transcriptional underpinnings of this vulnerability, pointing to expression of Plk2, which phosphorylates -synuclein at Ser129, and human SNCA (hSNCA), as key to pSyn pathology development. Finally, we performed differential expression analysis, revealing gene expression changes broadly downstream of hSNCA overexpression, as well as pSyn-dependent alterations in mitochondrial and endolysosomal genes. Overall, this study yields new insights into the formation of -synuclein pathology and its downstream effects in a synucleinopathy mouse model.

neuroscience↗

Characterization of altered molecular mechanisms in Parkinson disease through cell type-resolved multi-omics analyses

Parkinsons disease (PD) is a progressive neurodegenerative disorder. However, cell type-dependent transcriptional regulatory programs responsible for PD pathogenesis remain elusive. Here, we establish transcriptomic and epigenomic landscapes of the substantia nigra (SN) by profiling 87,733 nuclei obtained from healthy controls and PD patients. Our multi-omic data integration provides functional annotation of 128,724 cis-regulatory elements (cREs) and uncovers cell-type specific dysregulated cREs with a strong transcriptional influence on genes implicated in PD. The establishment of high-resolution three-dimensional chromatin contact maps identifies 656 target genes of dysregulated cREs and genetic risk loci, including both novel candidates and known PD risk genes. Notably, these new PD candidate genes exhibit modular gene expression patterns with unique molecular signatures in distinct cell types. Thus, our single-cell transcriptome and epigenome uncover cell type-specific disrupted transcriptional regulations in PD. TeaserSingle-cell transcriptome and epigenome uncover cell type-specific disrupted transcriptional regulations in Parkinsons disease.

genomics↗

Specific Detection of Endogenous S129 Phosphorylated α-Synuclein in Tissue Using Proximity Ligation Assay

BACKGROUNDSynucleinopathies are a group of neurodegenerative disorders that are pathologically characterized by the accumulation of protein aggregates called Lewy Bodies. Lewy bodies are primarily composed of -synuclein (asyn) protein, which is phosphorylated at serine 129 (pS129) when aggregated. Currently available commercial antibodies used to stain for pS129 asyn can cross react with other proteins, thus making it difficult to specifically detect endogenous pS129 asyn and to interpret pS129 asyn staining. OBJECTIVETo develop a staining procedure that detects pS129 asyn with high specificity and low background. METHODSWe use the fluorescent and brightfield in situ Proximity Ligation Assay (PLA) to specifically detect pS129 asyn in cell culture, mouse and human brain sections. RESULTSThe pS129 asyn PLA specifically stained for endogenous, soluble pS129 asyn in cell culture, mouse brain sections, and human brain tissue without significant cross-reactivity or background signal. CONCLUSIONSThis PLA method can be used to specifically detect pS129 asyn in order to further explore and understand its role in health and disease.

neuroscience↗

Novel Small Molecules Targeting the Intrinsically Disordered Structural Ensemble of α-Synuclein Protect Against Diverse α-Synuclein Mediated Dysfunctions

The over-expression and aggregation of -synuclein (Syn) are linked to the onset and pathology of Parkinsons disease. Native monomeric Syn exists in an intrinsically disordered ensemble of interconverting conformations, which has made its therapeutic targeting by small molecules highly challenging. Nonetheless, here we successfully target the monomeric structural ensemble of Syn and thereby identify novel drug-like small molecules that impact multiple pathogenic processes. Using a surface plasmon resonance high-throughput screen, in which monomeric Syn is incubated with microchips arrayed with tethered compounds, we identified novel Syn interacting drug-like compounds. Because these small molecules could impact a variety of Syn forms present in the ensemble, we tested representative hits for impact on multiple Syn malfunctions in vitro and in cells including aggregation and perturbation of vesicular dynamics. We thereby identified a compound that inhibits Syn misfolding and is neuroprotective, multiple compounds that restore phagocytosis impaired by Syn overexpression, and a compound blocking cellular transmission of Syn. Our studies demonstrate that drug-like small molecules that interact with native Syn can impact a variety of its pathological processes. Thus, targeting the intrinsically disordered ensemble of Syn offers a unique approach to the development of small molecule research tools and therapeutics for Parkinsons disease.

neuroscience↗

Amyloid accumulation drives proteome-wide alterations in mouse models of Alzheimers disease like pathology

Amyloid beta (A{beta}) peptides impair multiple cellular pathways in the brain and play a causative role in Alzheimers disease (AD) pathology, but how the brain proteome is remodeled during this process is unknown. To identify new protein networks associated with AD-like pathology, we performed global quantitative proteomic analysis in three mouse models at pre- and post-symptomatic ages. Our analysis revealed a robust and consistent increase in Apolipoprotein E (ApoE) levels in nearly all transgenic brain regions with increased A{beta} levels. Taken together with prior findings on ApoE driving A{beta} accumulation, this analysis points to a pathological dysregulation of the ApoE-A{beta} axis. We also found dysregulation of protein networks involved in excitatory synaptic transmission consistent with AD pathophysiology. Targeted analysis of the AMPA receptor complex revealed a specific loss of TARP{gamma}-2, a key AMPA receptor trafficking protein. Expression of TARP{gamma}-2 in vivo in hAPP transgenic mice led to a restoration of AMPA currents. This database of proteome alterations represents a unique resource for the identification of protein alterations responsible for AD.\n\nHighlightsO_LIProteomic analysis of mouse brains with AD-like pathology reveals stark remodeling\nC_LIO_LIProteomic evidence points to a dysregulation of ApoE levels associated with A{beta} clearance rather than production\nC_LIO_LICo-expression analysis found distinctly impaired synapse and mitochondria modules\nC_LIO_LIIn-depth analyses of AMPAR complex points to loss of TARP{gamma}-2, which may compromise synapses in AD\nC_LI\n\neTOC BlurbProteome-wide profiling of brain tissue from three mouse models of AD-like pathology reveals A{beta}, brain region, and age dependent alterations of protein levels. This resource provides a new global protein expression atlas for the Alzheimers disease research community.

neuroscience↗

Gene expression patterns associated with neurological disease in HIV infection

To provide new insight into the pathogenesis of neurocognitive impairments (NCI) in HIV infection, we used the Gene Set Enrichment Analysis (GSEA) algorithm to analyze pathway dysregulations in gene expression profiles of HIV-infected patients with or without NCI and HIV encephalitis (HIVE). While HIVE was characterized by widespread inflammation and tissue damage, gene expression evidence of induction of interferon (IFN), cytokines and tissue injury was apparent in all brain regions studied before the emergence of NCI. Various degrees of white matter changes were present in all HIV-infected subjects and were the primary manifestation in patients with NCI in the absence of HIVE. The latter showed a distinct pattern of immune activation with induction of chemokines, cytokines, {beta}-defensins, and limited IFN induction.\n\nAltogether results indicate that significant neuroinflammation and neuronal suffering precede NCI. Patients with NCI without HIVE showed a predominantly white matter dysfunction with a distinct pattern of immune activation.

neuroscience↗