Taube Koret Center for Neurodegenerative Disease Research

San Francisco, CA, United States

Taube Koret Center for Neurodegenerative Disease Research

San Francisco, CA, United States
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Mason A.R.,Gladstone | Mason A.R.,Taube Koret Center for Neurodegenerative Disease Research | Mason A.R.,University of California at San Francisco | Elia L.P.,Gladstone | And 4 more authors.
Journal of Biological Chemistry | Year: 2017

Progranulin (PGRN), a secreted growth factor, is a key regulator of inflammation and is genetically linked to two common and devastating neurodegenerative diseases. Haploinsufficiency mutations in GRN, the gene encoding PGRN, cause frontotemporal dementia (FTD), and a GRN SNP confers significantly increased risk for Alzheimer's disease (AD). Because cellular and animal data indicate that increasing PGRN can reverse phenotypes of both FTD and AD, modulating PGRN level has been proposed as a therapeutic strategy for both diseases. However, little is known about the regulation of PGRN levels. In this study, we performed an siRNA-based screen of the kinome to identify genetic regulators of PGRN levels in a rodent cell-based model system. We found that knocking down receptor-interacting serine/threonine protein kinase 1 (Ripk1) increased both intracellular and extracellular PGRN protein levels by increasing the translation rate of PGRN without affecting mRNA levels. We observed this effect in Neuro2a cells, wildtype primary mouse neurons, and Grn-haploinsufficient primary neurons from an FTD mouse model. We found that the effect of RIPK1 on PGRN is independent of the kinase activity of RIPK1 and occurs through a novel signaling pathway. These data suggest that targeting RIPK1 may be a therapeutic strategy in both AD and FTD. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Toth G.,University of Cambridge | Toth G.,Elan Pharmaceuticals Inc. | Gardai S.J.,Elan Pharmaceuticals Inc. | Zago W.,Elan Pharmaceuticals Inc. | And 27 more authors.
PLoS ONE | Year: 2014

The misfolding of intrinsically disordered proteins such as α-synuclein, tau and the Aβ peptide has been associated with many highly debilitating neurodegenerative syndromes including Parkinson's and Alzheimer's diseases. Therapeutic targeting of the monomeric state of such intrinsically disordered proteins by small molecules has, however, been a major challenge because of their heterogeneous conformational properties. We show here that a combination of computational and experimental techniques has led to the identification of a drug-like phenyl-sulfonamide compound (ELN484228), that targets α-synuclein, a key protein in Parkinson's disease. We found that this compound has substantial biological activity in cellular models of α-synuclein-mediated dysfunction, including rescue of α-synuclein- induced disruption of vesicle trafficking and dopaminergic neuronal loss and neurite retraction most likely by reducing the amount of α-synuclein targeted to sites of vesicle mobilization such as the synapse in neurons or the site of bead engulfment in microglial cells. These results indicate that targeting α-synuclein by small molecules represents a promising approach to the development of therapeutic treatments of Parkinson's disease and related conditions. © 2014 Tóth et al.

Kaye J.A.,Gladstone | Finkbeiner S.,Gladstone | Finkbeiner S.,University of California at San Francisco | Finkbeiner S.,Taube Koret Center for Neurodegenerative Disease Research | Finkbeiner S.,Hellman Family Foundation Program in Alzheimers Disease Research
Molecular and Cellular Neuroscience | Year: 2013

Huntington's disease (HD) causes severe motor dysfunction, behavioral abnormalities, cognitive impairment and death. Investigations into its molecular pathology have primarily relied on murine tissues; however, the recent discovery of induced pluripotent stem cells (iPSCs) has opened new possibilities to model neurodegenerative disease using cells derived directly from patients, and therefore may provide a human-cell-based platform for unique insights into the pathogenesis of HD. Here, we will examine the practical implementation of iPSCs to study HD, such as approaches to differentiate embryonic stem cells (ESCs) or iPSCs into medium spiny neurons, the cell type most susceptible in HD. We will explore the HD-related phenotypes identified in iPSCs and ESCs and review how brain development and neurogenesis may actually be altered early, before the onset of HD symptoms, which could inform the search for drugs that delay disease onset. Finally, we will speculate on the exciting possibility that ESCs or iPSCs might be used as therapeutics to restore or replace dying neurons in HD brains. © 2013 Elsevier Inc.

Barmada S.J.,Gladstone | Barmada S.J.,University of California at San Francisco | Barmada S.J.,University of Michigan | Serio A.,University of Edinburgh | And 18 more authors.
Nature Chemical Biology | Year: 2014

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have distinct clinical features but a common pathology - cytoplasmic inclusions rich in transactive response element DNA-binding protein of 43 kDa (TDP43). Rare TDP43 mutations cause ALS or FTD, but abnormal TDP43 levels and localization may cause disease even if TDP43 lacks a mutation. Here we show that individual neurons vary in their ability to clear TDP43 and are exquisitely sensitive to TDP43 levels. To measure TDP43 clearance, we developed and validated a single-cell optical method that overcomes the confounding effects of aggregation and toxicity and discovered that pathogenic mutations shorten TDP43 half-life. New compounds that stimulate autophagy improved TDP43 clearance and localization and enhanced survival in primary murine neurons and in human stem cell-derived neurons and astrocytes harboring mutant TDP43. These findings indicate that the levels and localization of TDP43 critically determine neurotoxicity and show that autophagy induction mitigates neurodegeneration by acting directly on TDP43 clearance. © 2014 Nature America, Inc. All rights reserved.

Tsvetkov A.S.,Gladstone | Tsvetkov A.S.,Taube Koret Center for Neurodegenerative Disease Research | Arrasate M.,Gladstone | Arrasate M.,Taube Koret Center for Neurodegenerative Disease Research | And 9 more authors.
Nature Chemical Biology | Year: 2013

In polyglutamine (polyQ) diseases, only certain neurons die, despite widespread expression of the offending protein. PolyQ expansion may induce neurodegeneration by impairing proteostasis, but protein aggregation and toxicity tend to confound conventional measurements of protein stability. Here, we used optical pulse labeling to measure effects of polyQ expansions on the mean lifetime of a fragment of huntingtin, the protein that causes Huntington's disease, in living neurons. We show that polyQ expansion reduced the mean lifetime of mutant huntingtin within a given neuron and that the mean lifetime varied among neurons, indicating differences in their capacity to clear the polypeptide. We found that neuronal longevity is predicted by the mean lifetime of huntingtin, as cortical neurons cleared mutant huntingtin faster and lived longer than striatal neurons. Thus, cell type-specific differences in turnover capacity may contribute to cellular susceptibility to toxic proteins, and efforts to bolster proteostasis in Huntington's disease, such as protein clearance, could be neuroprotective. © 2013 Nature America, Inc. All rights reserved.

Skibinski G.,Gladstone | Skibinski G.,Taube Koret Center for Neurodegenerative Disease Research | Finkbeiner S.,Gladstone | Finkbeiner S.,Taube Koret Center for Neurodegenerative Disease Research | And 2 more authors.
FEBS Letters | Year: 2013

Protein misfolding and proteostasis decline is a common feature of many neurodegenerative diseases. However, modeling the complexity of proteostasis and the global cellular consequences of its disruption is a challenge, particularly in live neurons. Although conventional approaches, based on population measures and single "snapshots", can identify cellular changes during neurodegeneration, they fail to determine if these cellular events drive cell death or act as adaptive responses. Alternatively, a "systems" cell biology approach known as longitudinal survival analysis enables single neurons to be followed over the course of neurodegeneration. By capturing the dynamics of misfolded proteins and the multiple cellular events that occur along the way, the relationship of these events to each other and their importance and role during cell death can be determined. Quantitative models of proteostasis dysfunction may yield unique insight and novel therapeutic strategies for neurodegenerative disease. © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Vieira F.G.,ALS Therapy Development Institute | LaDow E.,Gladstone | Moreno A.,ALS Therapy Development Institute | Kidd J.D.,ALS Therapy Development Institute | And 7 more authors.
PLoS ONE | Year: 2014

Treatment options for people living with amyotrophic lateral sclerosis (ALS) are limited and ineffective. Recently, dexpramipexole (RPPX) was advanced into human ALS clinical trials. In the current studies, we investigated RPPX in two parallel screening systems: 1) appropriately powered, sibling-matched, gender-balanced survival efficacy screening in high-copy B6-SJL-SOD1G93A/Gur1 mice, and 2) high-content neuronal survival screening in primary rat cortical neurons transfected with wild-type human TDP43 or mutant human TDP43. In both cases, we exposed the test systems to RPPX levels approximating those achieved in human Phase II clinical investigations. In SOD1G93A mice, no effect was observed on neuromotor disease progression or survival. In primary cortical neurons transfected with either mutant or wild-type human TDP43, a marginally significant improvement in a single indicator of neuronal survival was observed, and only at the 10 μM RPPX treatment. These systems reflect both mutant SOD1- and TDP43-mediated forms of neurodegeneration. The systems also reflect both complex noncell autonomous and neuronal cell autonomous disease mechanisms. The results of these experiments, taken in context with results produced by other molecules tested in both screening systems, do not argue positively for further study of RPPX in ALS. © 2014 Vieira et al.

Oliveira A.O.,University of Lisbon | Oliveira A.O.,Gladstone | Osmand A.,University of Tennessee at Knoxville | Outeiro T.F.,University of Lisbon | And 6 more authors.
Human Molecular Genetics | Year: 2016

Huntington's disease (HD) is caused by an expanded polyglutamine (polyQ) tract in the huntingtin (htt) protein. The polyQ expansion increases the propensity of htt to aggregate and accumulate, and manipulations that mitigate protein misfolding or facilitate the clearance of misfolded proteins are predicted to slow disease progression in HD models. αB-crystallin (αBc) or HspB5 is a well-characterized member of the small heat shock protein (sHsp) family that reduces mutant htt (mhtt) aggregation and toxicity in vitro and in Drosophila models of HD. Here, we determined if overexpressing αBc in vivo modulates aggregation and delays the onset and progression of disease in a full-length model of HD, BACHD mice. Expression of sHsps in neurodegenerative disease predominantly occurs in non-neuronal cells, and in the brain, αBc is mainly found in astrocytes and oligodendrocytes. Here, we show that directed αBc overexpression in astrocytes improves motor performance in rotarod and balance beam tests and improves cognitive function in the BACHD mice. Improvement in behavioral deficits correlated with mitigation of neuropathological features commonly observed in HD. Interestingly, astrocytic αBc overexpression was neuroprotective against neuronal cell loss in BACHD brains, suggesting αBc might be acting in a non-cell-autonomous manner. At the protein level, αBc decreased the level of soluble mhtt and decreased the size of mhtt inclusions in BACHD brain. Our results support a model in which elevating astrocytic αBc confers neuroprotection through a potential non-cell-autonomous pathway that modulates mhtt aggregation and protein levels. © The Author 2016. Published by Oxford University Press. All rights reserved.

Barmada S.J.,University of Michigan | Ju S.,Wright State University | Arjun A.,Gladstone | Batarse A.,Gladstone | And 13 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

Over 30% of patients with amyotrophic lateral sclerosis (ALS) exhibit cognitive deficits indicative of frontotemporal dementia (FTD), suggesting a common pathogenesis for both diseases. Consistent with this hypothesis, neuronal and glial inclusions rich in TDP43, an essential RNA-binding protein, are found in the majority of those with ALS and FTD, and mutations in TDP43 and a related RNA-binding protein, FUS, cause familial ALS and FTD. TDP43 and FUS affect the splicing of thousands of transcripts, in some cases triggering nonsense-mediated mRNA decay (NMD), a highly conserved RNA degradation pathway. Here, we take advantage of a faithful primary neuronal model of ALS and FTD to investigate and characterize the role of human up-frameshift protein 1 (hUPF1), an RNA helicase and master regulator of NMD, in these disorders. We show that hUPF1 significantly protects mammalian neurons from both TDP43- and FUS-related toxicity. Expression of hUPF2, another essential component of NMD, also improves survival, whereas inhibiting NMD prevents rescue by hUPF1, suggesting that hUPF1 acts through NMD to enhance survival. These studies emphasize the importance of RNA metabolism in ALS and FTD, and identify a uniquely effective therapeutic strategy for these disorders. © 2015, National Academy of Sciences. All rights reserved.

Sun Y.,University of California at San Francisco | Dong Z.,University of California at San Francisco | Jin T.,University of California at San Francisco | Jin T.,Howard Hughes Medical Institute | And 14 more authors.
eLife | Year: 2013

Mammalian pluripotent stem cells (PSCs) represent an important venue for understanding basic principles regulating tissue-specific differentiation and discovering new tools that may facilitate clinical applications. Mechanisms that direct neural differentiation of PSCs involve growth factor signaling and transcription regulation. However, it is unknown whether and how electrical activity influences this process. Here we report a high throughput imaging-based screen, which uncovers that selamectin, an anti-helminthic therapeutic compound with reported activity on invertebrate glutamate-gated chloride channels, promotes neural differentiation of PSCs. We show that selamectin's pro-neurogenic activity is mediated by Γ2-containing GABAA receptors in subsets of neural rosette progenitors, accompanied by increased proneural and lineage-specific transcription factor expression and cell cycle exit. In vivo, selamectin promotes neurogenesis in developing zebrafish. Our results establish a chemical screening platform that reveals activity-dependent neural differentiation from PSCs. Compounds identified in this and future screening might prove therapeutically beneficial for treating neurodevelopmental or neurodegenerative disorders. © Sun et al.

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