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Skibinski G.,Gladstone | Skibinski G.,Taube Koret Center for Neurodegenerative Disease Research | Finkbeiner S.,Gladstone | Finkbeiner S.,Taube Koret Center for Neurodegenerative Disease Research | Finkbeiner S.,University of California at San Francisco
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.

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.

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.

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.

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.

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