Disturbances in RNA metabolism have emerged as an important contributor to several related neurological diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and inclusion body myopathy (IBM). The familial and sporadic forms of these degenerative diseases are typically characterized pathologically by cytoplasmic inclusions composed of fibrillar deposits of RNA-binding proteins (RBPs). Moreover, mutations in RBPs or other proteins that regulate RNA metabolism frequently cause the familial forms of these diseases. Over the past 7 years my lab has been at the forefront of illuminating the molecular basis for these diseases, including identifying new diseases genes, elucidating the normal function of these and other disease-related genes, and determining the consequences of disease mutations. Based on these studies we have advanced the hypothesis that disturbance in the assembly, disassembly and function of diverse RNA-protein assemblies, including cytoplasmic RNA granules, underlies the pathogenesis of the aforementioned neurological diseases. We have developed a comprehensive research program that, over the next 8 years, will investigate the molecular bases of RNA granule assembly, elucidate in detail how RNA granule dynamics are regulated, determine the role of RNA granules in spatial and temporal control of gene expression, and most importantly elucidate the mechanism whereby defects in RNA granule dynamics contribute to neurological diseases.

Public Health Relevance

Disturbances in the assembly and disassembly of RNA granules has recently emerged as the key defect underlying common neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). This project seeks to understand the molecular basis of RNA granule assembly and how this process is disturbed in disease. These insights will be used to guide therapeutic intervention for ALS and related degenerative diseases.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Unknown (R35)
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Special Emphasis Panel (ZNS1)
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Gubitz, Amelie
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St. Jude Children's Research Hospital
United States
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Purice, Maria D; Taylor, J Paul (2018) Linking hnRNP Function to ALS and FTD Pathology. Front Neurosci 12:326
Guo, Lin; Kim, Hong Joo; Wang, Hejia et al. (2018) Nuclear-Import Receptors Reverse Aberrant Phase Transitions of RNA-Binding Proteins with Prion-like Domains. Cell 173:677-692.e20
Lee, YouJin; Jonson, Per Harald; Sarparanta, Jaakko et al. (2018) TIA1 variant drives myodegeneration in multisystem proteinopathy with SQSTM1 mutations. J Clin Invest 128:1164-1177
Wegmann, Susanne; Eftekharzadeh, Bahareh; Tepper, Katharina et al. (2018) Tau protein liquid-liquid phase separation can initiate tau aggregation. EMBO J 37:
Dao, Thuy P; Kolaitis, Regina-Maria; Kim, Hong Joo et al. (2018) Ubiquitin Modulates Liquid-Liquid Phase Separation of UBQLN2 via Disruption of Multivalent Interactions. Mol Cell 69:965-978.e6
Boeynaems, Steven; Bogaert, Elke; Kovacs, Denes et al. (2017) Phase Separation of C9orf72 Dipeptide Repeats Perturbs Stress Granule Dynamics. Mol Cell 65:1044-1055.e5
Taylor, J Paul (2017) A PR plug for the nuclear pore in amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A 114:1445-1447
Becker, Lindsay A; Huang, Brenda; Bieri, Gregor et al. (2017) Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice. Nature 544:367-371
Freibaum, Brian D; Taylor, J Paul (2017) The Role of Dipeptide Repeats in C9ORF72-Related ALS-FTD. Front Mol Neurosci 10:35
Kim, Hong Joo; Taylor, J Paul (2017) Lost in Transportation: Nucleocytoplasmic Transport Defects in ALS and Other Neurodegenerative Diseases. Neuron 96:285-297

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