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  • 1
    Online Resource
    Online Resource
    A Druggable Genome Screen Identifies Modifiers of α-Synuclein Levels via a Tiered Cross-Species Validation Approach
    Society for Neuroscience ; 2018
    In:  The Journal of Neuroscience Vol. 38, No. 43 ( 2018-10-24), p. 9286-9301
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 38, No. 43 ( 2018-10-24), p. 9286-9301
    Abstract: Accumulation of α-Synuclein (α-Syn) causes Parkinson's disease (PD) as well as other synucleopathies. α-Syn is the major component of Lewy bodies and Lewy neurites, the proteinaceous aggregates that are a hallmark of sporadic PD. In familial forms of PD, mutations or copy number variations in SNCA (the α-Syn gene) result in a net increase of its protein levels. Furthermore, common risk variants tied to PD are associated with small increases of wild-type α-Syn levels. These findings are further bolstered by animal studies which show that overexpression of α-Syn is sufficient to cause PD-like features. Thus, increased α-Syn levels are intrinsically tied to PD pathogenesis and underscore the importance of identifying the factors that regulate its levels. In this study, we establish a pooled RNAi screening approach and validation pipeline to probe the druggable genome for modifiers of α-Syn levels and identify 60 promising targets. Using a cross-species, tiered validation approach, we validate six strong candidates that modulate α-Syn levels and toxicity in cell lines, Drosophila , human neurons, and mouse brain of both sexes. More broadly, this genetic strategy and validation pipeline can be applied for the identification of therapeutic targets for disorders driven by dosage-sensitive proteins. SIGNIFICANCE STATEMENT We present a research strategy for the systematic identification and validation of genes modulating the levels of α-Synuclein, a protein involved in Parkinson's disease. A cell-based screen of the druggable genome ( 〉 7,500 genes that are potential therapeutic targets) yielded many modulators of α-Synuclein that were subsequently confirmed and validated in Drosophila , human neurons, and mouse brain. This approach has broad applicability to the multitude of neurological diseases that are caused by mutations in genes whose dosage is critical for brain function.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.1523/JNEUROSCI.0254-18.2018
    DOI: 10.1523/JNEUROSCI.0254-18.2018.f1-1
    DOI: 10.1523/JNEUROSCI.0254-18.2018.f2-1
    DOI: 10.1523/JNEUROSCI.0254-18.2018.f3-1
    DOI: 10.1523/JNEUROSCI.0254-18.2018.video.1
    DOI: 10.1523/JNEUROSCI.0254-18.2018.t1-1
    DOI: 10.1523/JNEUROSCI.0254-18.2018.t1-2
    DOI: 10.1523/JNEUROSCI.0254-18.2018.f4-1
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2018
    detail.hit.zdb_id: 1475274-8
    SSG: 12
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  • 2
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    Online Resource
    Tau polarizes an aging transcriptional signature to excitatory neurons and glia
    eLife Sciences Publications, Ltd ; 2023
    In:  eLife Vol. 12 ( 2023-05-23)
    Details
    In: eLife, eLife Sciences Publications, Ltd, Vol. 12 ( 2023-05-23)
    Abstract: Aging is a major risk factor for Alzheimer’s disease (AD), and cell-type vulnerability underlies its characteristic clinical manifestations. We have performed longitudinal, single-cell RNA-sequencing in Drosophila with pan-neuronal expression of human tau, which forms AD neurofibrillary tangle pathology. Whereas tau- and aging-induced gene expression strongly overlap (93%), they differ in the affected cell types. In contrast to the broad impact of aging, tau-triggered changes are strongly polarized to excitatory neurons and glia. Further, tau can either activate or suppress innate immune gene expression signatures in a cell-type-specific manner. Integration of cellular abundance and gene expression pinpoints nuclear factor kappa B signaling in neurons as a marker for cellular vulnerability. We also highlight the conservation of cell-type-specific transcriptional patterns between Drosophila and human postmortem brain tissue. Overall, our results create a resource for dissection of dynamic, age-dependent gene expression changes at cellular resolution in a genetically tractable model of tauopathy.
    Type of Medium: Online Resource
    ISSN: 2050-084X
    URL: Article
    DOI: 10.7554/eLife.85251
    Language: English
    Publisher: eLife Sciences Publications, Ltd
    Publication Date: 2023
    detail.hit.zdb_id: 2687154-3
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  • 3
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    Online Resource
    The interrelationship of proteasome impairment and oligomeric intermediates in neurodegeneration
    Wiley ; 2015
    In:  Aging Cell Vol. 14, No. 5 ( 2015-10), p. 715-724
    Details
    In: Aging Cell, Wiley, Vol. 14, No. 5 ( 2015-10), p. 715-724
    Abstract: Various neurodegenerative diseases are characterized by the accumulation of amyloidogenic proteins such as tau, α‐synuclein, and amyloid‐β. Prior to the formation of these stable aggregates, intermediate species of the respective proteins—oligomers—appear. Recently acquired data have shown that oligomers may be the most toxic and pathologically significant to neurodegenerative diseases such as Alzheimer's and Parkinson's. The covalent modification of these oligomers may be critically important for biological processes in disease. Ubiquitin and small ubiquitin‐like modifiers are the commonly used tags for degradation. While the modification of large amyloid aggregates by ubiquitination is well established, very little is known about the role ubiquitin may play in oligomer processing and the importance of the more recently discovered sumoylation. Many proteins involved in neurodegeneration have been found to be sumoylated, notably tau protein in brains afflicted with Alzheimer's. This evidence suggests that while the cell may not have difficulty recognizing dangerous proteins, in brains afflicted with neurodegenerative disease, the proteasome may be unable to properly digest the tagged proteins. This would allow toxic aggregates to develop, leading to even more proteasome impairment in a snowball effect that could explain the exponential progression in most neurodegenerative diseases. A better understanding of the covalent modifications of oligomers could have a huge impact on the development of therapeutics for neurodegenerative diseases. This review will focus on the proteolysis of tau and other amyloidogenic proteins induced by covalent modification, and recent findings suggesting a relationship between tau oligomers and sumoylation.
    Type of Medium: Online Resource
    ISSN: 1474-9718 , 1474-9726
    URL: Issue
    URL: Article
    DOI: 10.1111/acel.2015.14.issue-5
    DOI: 10.1111/acel.12359
    Language: English
    Publisher: Wiley
    Publication Date: 2015
    detail.hit.zdb_id: 2099130-7
    SSG: 12
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  • 4
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    Online Resource
    Tidal Interactions and Mergers in Intermediate-redshift EDisCS Clusters
    American Astronomical Society ; 2018
    In:  The Astrophysical Journal Vol. 869, No. 1 ( 2018-12-05), p. 6-
    Details
    In: The Astrophysical Journal, American Astronomical Society, Vol. 869, No. 1 ( 2018-12-05), p. 6-
    Type of Medium: Online Resource
    ISSN: 1538-4357
    URL: Article
    DOI: 10.3847/1538-4357/aaeb87
    Language: Unknown
    Publisher: American Astronomical Society
    Publication Date: 2018
    detail.hit.zdb_id: 2207648-7
    detail.hit.zdb_id: 1473835-1
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  • 5
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    Online Resource
    Genome Sequencing in the Parkinson Disease Clinic
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Neurology Genetics Vol. 8, No. 4 ( 2022-08), p. e200002-
    Details
    In: Neurology Genetics, Ovid Technologies (Wolters Kluwer Health), Vol. 8, No. 4 ( 2022-08), p. e200002-
    Abstract: Genetic variants affect both Parkinson disease (PD) risk and manifestations. Although genetic information is of potential interest to patients and clinicians, genetic testing is rarely performed during routine PD clinical care. The goal of this study was to examine interest in comprehensive genetic testing among patients with PD and document reactions to possible findings from genome sequencing in 2 academic movement disorder clinics. Methods In 203 subjects with PD (age = 63 years, 67% male), genome sequencing was performed and filtered using a custom panel, including 49 genes associated with PD, parkinsonism, or related disorders, as well as a 90-variant PD genetic risk score. Based on the results, 231 patients (age = 67 years, 63% male) were surveyed on interest in genetic testing and responses to vignettes covering (1) familial risk of PD ( LRRK2 ); (2) risk of PD dementia ( GBA ); (3) PD genetic risk score; and (4) secondary, medically actionable variants ( BRCA1 ). Results Genome sequencing revealed a LRRK2 variant in 3% and a GBA risk variant in 10% of our clinical sample. The genetic risk score was normally distributed, identifying 41 subjects with a high risk of PD. Medically actionable findings were discovered in 2 subjects (1%). In our survey, the majority (82%) responded that they would share a LRRK2 variant with relatives. Most registered unchanged or increased interest in testing when confronted with a potential risk for dementia or medically actionable findings, and most (75%) expressed interest in learning their PD genetic risk score. Discussion Our results highlight broad interest in comprehensive genetic testing among patients with PD and may facilitate integration of genome sequencing in clinical practice.
    Type of Medium: Online Resource
    ISSN: 2376-7839
    URL: Article
    DOI: 10.1212/NXG.0000000000200002
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 2818607-2
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  • 6
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    Online Resource
    Insulin resistance is a significant determinant of sarcopenia in advanced kidney disease
    American Physiological Society ; 2018
    In:  American Journal of Physiology-Endocrinology and Metabolism Vol. 315, No. 6 ( 2018-12-01), p. E1108-E1120
    Details
    In: American Journal of Physiology-Endocrinology and Metabolism, American Physiological Society, Vol. 315, No. 6 ( 2018-12-01), p. E1108-E1120
    Abstract: Maintenance hemodialysis (MHD) patients display significant nutritional abnormalities. Insulin is an anabolic hormone with direct effects on skeletal muscle (SM). We examined the anabolic actions of insulin, whole-body (WB), and SM protein turnover in 33 MHD patients and 17 participants without kidney disease using hyperinsulinemic-euglycemic-euaminoacidemic (dual) clamp. Gluteal muscle biopsies were obtained before and after the dual clamp. At baseline, WB protein synthesis and breakdown rates were similar in MHD patients. During dual clamp, controls had a higher increase in WB protein synthesis and a higher suppression of WB protein breakdown compared with MHD patients, resulting in statistically significantly more positive WB protein net balance [2.02 (interquartile range [IQR]: 1.79 and 2.36) vs. 1.68 (IQR: 1.46 and 1.91) mg·kg fat-free mass −1 ·min −1 for controls vs. for MHD patients, respectively, P 〈 0.001]. At baseline, SM protein synthesis and breakdown rates were higher in MHD patients versus controls, but SM net protein balance was similar between groups. During dual clamp, SM protein synthesis increased statistically significantly more in controls compared with MHD patients ( P = 0.03), whereas SM protein breakdown decreased comparably between groups. SM net protein balance was statistically significantly more positive in controls compared with MHD patients [67.3 (IQR: 46.4 and 97.1) vs. 15.4 (IQR: −83.7 and 64.7) μg·100 ml −1 ·min −1 for controls and MHD patients, respectively, P = 0.03]. Human SM biopsy showed a positive correlation between glucose and leucine disposal rates, phosphorylated AKT to AKT ratio, and muscle mitochondrial markers in controls but not in MHD patients. Diminished response to anabolic actions of insulin in the stimulated setting could lead to muscle wasting in MHD patients.
    Type of Medium: Online Resource
    ISSN: 0193-1849 , 1522-1555
    URL: Article
    DOI: 10.1152/ajpendo.00070.2018
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2018
    detail.hit.zdb_id: 1477331-4
    SSG: 12
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  • 7
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    Online Resource
    Cell‐specific responses to Tau pathology in the aging brain
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. S4 ( 2022-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S4 ( 2022-12)
    Abstract: Gene expression profiling has emerged as a promising unbiased approach to characterize putative mechanisms of Alzheimer’s disease (AD). We previously highlighted transcriptional signatures that are driven by Tau pathology or aging in a longitudinal Drosophila model of tauopathy and human RNA‐sequencing data. However, cellular heterogeneity confounds the interpretation of bulk‐tissue gene expression. Defining cell types and characterizing cell‐specific processes that precipitate neurodegeneration is crucial for elucidating AD pathogenesis. Method We use a highly tractable, longitudinal, Drosophila model of tauopathy and single cell transcriptomics (scRNA‐seq) to explore cell‐specific contributions to tau‐mediated gene expression while accounting for age‐related changes. Brains of adult Drosophila pan‐neuronally expressing a mutant variant of human Tau (R406W) and respective controls were dissociated for droplet‐based scRNA‐seq at 1‐, 10‐, and 20‐ days post‐eclosion. We computed differentially expressed genes (DEGs) for each cell subpopulation and profiled gene regulatory networks (regulons), highlighting cell‐specific Tau‐ and aging‐related changes. Tau‐induced changes were compared with previously published bulk RNA‐sequencing data and gene co‐expression networks. To address cross‐species conservation of single cell transcriptional signatures, we leverage published human single nuclei RNA‐sequencing (snRNA‐seq) data. Result We identified 96 cell subpopulations clustered by transcriptomic similarities in the adult Drosophila brain and annotated 59 with cell identities. We mapped half of all DEGs identified in our published bulk‐tissue RNA‐sequencing to cell subpopulations. We characterized 183 regulons in our dataset and demonstrated network‐level expression changes driven by Tau. Most Tau‐induced gene expression changes were observed in glutamatergic and cholinergic excitatory neurons while fewer changes were seen in GABAergic inhibitory neurons. Likewise, we observed Tau‐induced reductions in cholinergic and glutamatergic neuron numbers. Correlation of cluster‐specific transcriptional profiles between our data and mammalian snRNA‐seq demonstrate conservation of gene expression among inferred cell identities. Strikingly, we found abundant innate immune gene expression signatures among neuronal subpopulations, and pinpointed cell autonomous Nuclear Factor Kappa B (NFkB) signaling as a modifier in Tau‐induced neurodegeneration. Conclusion Our results comprise a powerful single cell transcriptomic resource for studying tau‐mediated disruption of gene expression and dynamic age‐dependent changes at cellular resolution in a tractable model system.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.S4
    DOI: 10.1002/alz.062729
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2201940-6
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