- Email: [email protected]
NOMINATION OF JAK-STAT SIGNALLING AS A TARGET FOR AD THERAPY THROUGH CLINICAL AND MOLECULAR INFORMATICS
P604
O2-18-05
Podium Presentations: Monday, July 17, 2017
PREVENTING TAUOPATHY BY TARGETING MSUT2
Brian C. Kraemer1,2, Gerard D. Schellenberg3, Jeanna Wheeler4, C. Dirk Keene5, Pamela McMillan1, Timothy C. Strovas2, 1 University of Washington, Seattle, WA, USA; 2GRECC VA PSHCS, Seattle, WA, USA; 3University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; 4GRECC VA Puget Sound, Seattle, WA, USA; 5University of Washington School of Medicine, Seattle, WA, USA. Contact e-mail: [email protected] Background: In Alzheimer’s disease, tau neuropathology correlates with severity of dementia. Interventions for Alzheimer’s disease and related dementias are limited to treatment of symptoms without directly altering tau pathology or the resultant neurodegeneration, underscoring the need for tau-targeted disease modifying therapeutics. Methods: To study tauopathy disorders in a genetically tractable model system, we developed a transgenic C. elegans model. This model recapitulates several hallmarks of human tauopathies including altered behavior, accumulation of abnormal tau protein, and neurodegeneration. To identify genes required for tau pathology, we conducted a genetic screen for mutations suppressing pathological tau phenotypes in C. elegans. We ultimately cloned the sut-2 gene, mutations in which alleviate tauopathy phenotypes in C. elegans. The sut-2 gene encodes distinct sub-type of RNA binding CCCH zinc finger protein conserved across animal phyla. C. elegans SUT-2 shares significant identity with the mammalian SUT-2 (MSUT2) homolog in both humans and mice. To study the translational relevance of MSUT2 to tauopathy, we knocked out the MSUT2 encoding gene in mice and crossed these knockout mice to the PS19 transgenic mouse model of tauopathy. Results: Knockout of MSUT2 in the PS19 mouse model of tauopathy ameliorates tau related neurodegenerative changes including decreased accumulation of abnormal tau, reduced neuronal loss, and reduced cognitive dysfunction. The CCCH type zinc finger domains of SUT-2 and MSUT2 have been implicated in RNA binding. Human MSUT2 CCCH domains bind to poly adenosine {poly(A)} stretches in mRNA as well as the nuclear poly(A) binding protein PABPN1. MSUT2 and PABPN1 have been previously reported to have reciprocal effects on poly(A) tail length (PMID 4671764). We have shown depletion of MSUT2 ameliorates tau oligomer and aggregate formation in a human cellular model of tau aggregation while depletion of PABPN1 has the reciprocal effect driving increased tau oligomerization or aggregation. Furthermore, decreasing poly(A) tail length exacerbates tauopathy in human cells. Taken together these findings suggest MSUT2 modulates tau toxicity through binding to and/or regulation of RNA poly(A) tails. Conclusions: Ablating MSUT2 activity decreases pathological tau accumulation in multiple model systems supporting further translational studies of human MSUT2 as a
candidate target for therapeutic intervention in diseases with tau pathology. O2-18-06
NOMINATION OF JAK-STAT SIGNALLING AS A TARGET FOR AD THERAPY THROUGH CLINICAL AND MOLECULAR INFORMATICS
Alejo J. Nevado-Holgado1, Elena M. Ribe1, Chi-Hun Kim1, Laura Furlong2, Miguel-Angel Mayer3, Simon Lovestone4, 1University of Oxford, Oxford, United Kingdom; 2Hospital del Mar Medical Research Institute, Barcelona, Spain; 3Hospital del Mar Medical Research Institute (IMIM) – Universitat Pompeu Fabra, Barcelona, Spain; 4King’s College London, Institute of Psychiatry and National Institute of Health Research (NIHR) Biomedical Research Centre for Mental Health, Oxford, United Kingdom. Contact e-mail: [email protected] Background: Epidemiological studies find that both users of
non-steroid anti-inflammatory drugs (Etminan 2003; Szekely et al. 2008; in ’t Veld et al. 2001; Wang et al. 2015) and patients with inflammatory diseases (McGeer et al. 1996; Myllykangas-Luosuj€aRvi & Isom€aKi 1994) have lower probability of developing AD later in life. In this study we combine real world clinical data with genetic data to understand the mechanism underlying this seemingly protective effect, together with confirmation using empirical studies in vitro and in vivo. Methods: Firstly, we analyse whether genetic variants identified as susceptibility factors for multiple diseases by GWAS overlap at the pathway level. Secondly, we investigate whether the proportion of GWAS variants on any given pathway correlate with the inflammatory epidemiology of AD. Thirdly we test whether expression of this pathway is anomalous in a number AD cohorts. Fourthly and finally, we validate alteration of the pathway with empirical experiments using a model of neuron-microglial interaction in vitro and acute Abeta challenge in vivo (one acute injection animal model and one neuron-microglia in-vitro model). Results: Using this workflow we find 1) that risk variants place AD in a cluster with inflammatory diseases and that it is the JAK-STAT pathway that accounts for this cluster; 2) that the degree of association between multiple diseases and variants of JAK-STAT pathway as risk factors correlates with the degree of association between that disease and AD; 3) in multiple cohorts, gene expression studies in peripheral fluids confirmed alteration of JAK-STAT pathway in AD; 4) challenge of models in vitro and in vivo with Abeta and interferon induced increase of markers of JAK-STAT activity. Conclusions: Using both clinical informatics from large real-word datasets together with open source GWAS data we identify JAKSTAT signalling as a pathway altered in AD and possibly underlying the know association between inflammation and risk of AD. We confirm the association through observational studies in man and empirical studies in vitro and in vivo demonstrating the power of target nomination driven by informatics.
O2-18-05
Podium Presentations: Monday, July 17, 2017
PREVENTING TAUOPATHY BY TARGETING MSUT2
Brian C. Kraemer1,2, Gerard D. Schellenberg3, Jeanna Wheeler4, C. Dirk Keene5, Pamela McMillan1, Timothy C. Strovas2, 1 University of Washington, Seattle, WA, USA; 2GRECC VA PSHCS, Seattle, WA, USA; 3University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; 4GRECC VA Puget Sound, Seattle, WA, USA; 5University of Washington School of Medicine, Seattle, WA, USA. Contact e-mail: [email protected] Background: In Alzheimer’s disease, tau neuropathology correlates with severity of dementia. Interventions for Alzheimer’s disease and related dementias are limited to treatment of symptoms without directly altering tau pathology or the resultant neurodegeneration, underscoring the need for tau-targeted disease modifying therapeutics. Methods: To study tauopathy disorders in a genetically tractable model system, we developed a transgenic C. elegans model. This model recapitulates several hallmarks of human tauopathies including altered behavior, accumulation of abnormal tau protein, and neurodegeneration. To identify genes required for tau pathology, we conducted a genetic screen for mutations suppressing pathological tau phenotypes in C. elegans. We ultimately cloned the sut-2 gene, mutations in which alleviate tauopathy phenotypes in C. elegans. The sut-2 gene encodes distinct sub-type of RNA binding CCCH zinc finger protein conserved across animal phyla. C. elegans SUT-2 shares significant identity with the mammalian SUT-2 (MSUT2) homolog in both humans and mice. To study the translational relevance of MSUT2 to tauopathy, we knocked out the MSUT2 encoding gene in mice and crossed these knockout mice to the PS19 transgenic mouse model of tauopathy. Results: Knockout of MSUT2 in the PS19 mouse model of tauopathy ameliorates tau related neurodegenerative changes including decreased accumulation of abnormal tau, reduced neuronal loss, and reduced cognitive dysfunction. The CCCH type zinc finger domains of SUT-2 and MSUT2 have been implicated in RNA binding. Human MSUT2 CCCH domains bind to poly adenosine {poly(A)} stretches in mRNA as well as the nuclear poly(A) binding protein PABPN1. MSUT2 and PABPN1 have been previously reported to have reciprocal effects on poly(A) tail length (PMID 4671764). We have shown depletion of MSUT2 ameliorates tau oligomer and aggregate formation in a human cellular model of tau aggregation while depletion of PABPN1 has the reciprocal effect driving increased tau oligomerization or aggregation. Furthermore, decreasing poly(A) tail length exacerbates tauopathy in human cells. Taken together these findings suggest MSUT2 modulates tau toxicity through binding to and/or regulation of RNA poly(A) tails. Conclusions: Ablating MSUT2 activity decreases pathological tau accumulation in multiple model systems supporting further translational studies of human MSUT2 as a
candidate target for therapeutic intervention in diseases with tau pathology. O2-18-06
NOMINATION OF JAK-STAT SIGNALLING AS A TARGET FOR AD THERAPY THROUGH CLINICAL AND MOLECULAR INFORMATICS
Alejo J. Nevado-Holgado1, Elena M. Ribe1, Chi-Hun Kim1, Laura Furlong2, Miguel-Angel Mayer3, Simon Lovestone4, 1University of Oxford, Oxford, United Kingdom; 2Hospital del Mar Medical Research Institute, Barcelona, Spain; 3Hospital del Mar Medical Research Institute (IMIM) – Universitat Pompeu Fabra, Barcelona, Spain; 4King’s College London, Institute of Psychiatry and National Institute of Health Research (NIHR) Biomedical Research Centre for Mental Health, Oxford, United Kingdom. Contact e-mail: [email protected] Background: Epidemiological studies find that both users of
non-steroid anti-inflammatory drugs (Etminan 2003; Szekely et al. 2008; in ’t Veld et al. 2001; Wang et al. 2015) and patients with inflammatory diseases (McGeer et al. 1996; Myllykangas-Luosuj€aRvi & Isom€aKi 1994) have lower probability of developing AD later in life. In this study we combine real world clinical data with genetic data to understand the mechanism underlying this seemingly protective effect, together with confirmation using empirical studies in vitro and in vivo. Methods: Firstly, we analyse whether genetic variants identified as susceptibility factors for multiple diseases by GWAS overlap at the pathway level. Secondly, we investigate whether the proportion of GWAS variants on any given pathway correlate with the inflammatory epidemiology of AD. Thirdly we test whether expression of this pathway is anomalous in a number AD cohorts. Fourthly and finally, we validate alteration of the pathway with empirical experiments using a model of neuron-microglial interaction in vitro and acute Abeta challenge in vivo (one acute injection animal model and one neuron-microglia in-vitro model). Results: Using this workflow we find 1) that risk variants place AD in a cluster with inflammatory diseases and that it is the JAK-STAT pathway that accounts for this cluster; 2) that the degree of association between multiple diseases and variants of JAK-STAT pathway as risk factors correlates with the degree of association between that disease and AD; 3) in multiple cohorts, gene expression studies in peripheral fluids confirmed alteration of JAK-STAT pathway in AD; 4) challenge of models in vitro and in vivo with Abeta and interferon induced increase of markers of JAK-STAT activity. Conclusions: Using both clinical informatics from large real-word datasets together with open source GWAS data we identify JAKSTAT signalling as a pathway altered in AD and possibly underlying the know association between inflammation and risk of AD. We confirm the association through observational studies in man and empirical studies in vitro and in vivo demonstrating the power of target nomination driven by informatics.