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Williams, Luis

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Williams

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Luis

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Williams, Luis
Author's Publications: search.filters.isAuthorOfPublication.4f8ee83b-5b90-4ea4-a068-17622845271b

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    TDP-43 induces p53-mediated cell death of cortical progenitors and immature neurons
    (Nature Publishing Group UK, 2018) Vogt, Miriam A.; Ehsaei, Zahra; Knuckles, Philip; Higginbottom, Adrian; Helmbrecht, Michaela S.; Kunath, Tilo; Eggan, Kevin; Williams, Luis; Shaw, Pamela J.; Wurst, Wolfgang; Floss, Thomas; Huber, Andrea B.; Taylor, Verdon
    TAR DNA-binding protein 43 (TDP-43) is a key player in neurodegenerative diseases including frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Accumulation of TDP-43 is associated with neuronal death in the brain. How increased and disease-causing mutant forms of TDP-43 induce cell death remains unclear. Here we addressed the role of TDP-43 during neural development and show that reduced TDP-43 causes defects in neural stem/progenitor cell proliferation but not cell death. However, overexpression of wild type and TDP-43A315T proteins induce p53-dependent apoptosis of neural stem/progenitors and human induced pluripotent cell (iPS)-derived immature cortical neurons. We show that TDP-43 induces expression of the proapoptotic BH3-only genes Bbc3 and Bax, and that p53 inhibition rescues TDP-43 induced cell death of embryonic mouse, and human cortical neurons, including those derived from TDP-43G298S ALS patient iPS cells. Hence, an increase in wild type and mutant TDP-43 induces p53-dependent cell death in neural progenitors developing neurons and this can be rescued. These findings may have important implications for accumulated or mutant TDP-43 induced neurodegenerative diseases.
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    In Vitro Studies of Amyotrophic Lateral Sclerosis Using Human Pluripotent Stem Cell-Derived Motor Neurons
    (2015-05-14) Williams, Luis; Hochedlinger, Konrad; Young-Pearse, Tracy; Brown, Robert
    Among the disciplines of medicine, the study of neurological disorders such as amyotrophic lateral sclerosis (ALS) is particularly challenging. In ALS, both cortical and spinal motor neurons progressively degenerate, leading to paralysis and death. The fundamental inaccessibility and the postmitotic state of these cells prevent their isolation and culture for studies of degenerative mechanisms or for drug screening efforts. The studies presented here support the premise that human motor neurons (MNs) generated by directed differentiation of induced pluripotent (iPS) or embryonic stem cells (ES) represent a great research tool to address this challenge. We show that MNs derived from patient-specific iPS cells with known ALS-linked mutations can recapitulate molecular and functional phenotypes associated with the disease. The phenotypes observed included transcriptional and morphological changes in mitochondria, protein solubility, membrane hyperexcitability, and defects in cell survival and axonal transport. By utilizing gene-targeting technology we further validated the requirement, and in some cases the sufficiency, of the SOD1A4V mutant allele to drive some of these phenotypes. Additionally, by means of a human ES cell line with a stable MN-specific green fluorescence protein (GFP) reporter, we carried out transcriptome profiling of cultured GFP+ cells following dysregulation of the ALS-associated RNA-binding protein TDP-43. We uncovered novel molecular targets downstream of the activity of TDP-43, one of which is the gene encoding for the tubulin-binding protein STMN2, with functional roles in cytoskeletal dynamics and axonal regeneration. Furthermore, we confirmed STMN2 response to TDP-43 downregulation at the protein level and provide evidence supporting its altered expression in spinal cord tissues from ALS cases. We propose that depletion of this neuronal growth factor following TDP-43 dysregulation could be a molecular mechanism by which the loss of normal nuclear TDP-43, seen in most ALS cases, contributes to MN degeneration. Finally, we discuss how future experiments, by integrating our findings with recent technological breakthroughs in genome-editing, stem cell differentiation and single-cell analysis, will further our understanding of disease mechanisms and facilitate the identification of novel therapeutic interventions.
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    ALS-Implicated Protein TDP-43 Sustains Levels of STMN2, a Mediator of Motor Neuron Growth and Repair
    (Springer Nature, 2019-01-14) Limone, Francesco; Guerra San Juan, Irune; Burberry, Aaron; Kirchner, Rory; Chen, Kuchuan; Eggan, Kevin; Klim, Joseph; Williams, Luis; Davis-Dusenbery, Brandi N; Mordes, Daniel; Steinbaugh, Michael; Gamage, Kanchana; Moccia, Rob; Cassel, Seth; Wainger, Brian; Woolf, Clifford
    The discovery that TDP-43 mutations cause familial ALS and that many patients display pathological TDP-43 mislocalization has nominated altered RNA metabolism as a potential disease mechanism. Despite its importance, the identity of RNAs regulated by TDP-43 in motor neurons remains poorly understood. Here, we report transcripts whose abundances in human motor neurons are sensitive to TDP-43 depletion. Notably, we found STMN2, which encodes a microtubule regulator, declined after TDP-43 knockdown, in patient-specific motor neurons, following TDP-43 mislocalization, and in the postmortem patient spinal cords. Loss of STMN2 upon reduced TDP-43 function was due to the emergence of a cryptic exon, which is of substantial functional importance, as we further demonstrate that STMN2 is necessary for both axonal outgrowth and repair. Importantly, post-translational stabilization of STMN2 could rescue neurite outgrowth and axon regeneration deficits induced by TDP-43 depletion. We propose restoring STMN2 expression warrants future examination as an ALS therapeutic strategy.