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Mok, Woon Jong Joanie

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Mok

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Woon Jong Joanie

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Mok, Woon Jong Joanie

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2016 - 20202

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Author's Publications: search.filters.isAuthorOfPublication.e8404bce-614c-4aa8-85e8-56b95004748c

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    Monitoring peripheral nerve degeneration in ALS by label-free stimulated Raman scattering imaging
    (Nature Publishing Group, 2016) Tian, Feng; Yang, Wenlong; Mordes, Daniel; Wang, Jin-Yuan; Salameh, Johnny S.; Mok, Woon Jong Joanie; Chew, Jeannie; Sharma, Aarti; Leno-Duran, Ester; Suzuki-Uematsu, Satomi; Suzuki, Naoki; Han, Steve S.; Lu, Fa-Ke; Ji, Minbiao; Zhang, Rosanna; Liu, Yue; Strominger, Jack; Shneider, Neil A.; Petrucelli, Leonard; Xie, X. Sunney; Eggan, Kevin
    The study of amyotrophic lateral sclerosis (ALS) and potential interventions would be facilitated if motor axon degeneration could be more readily visualized. Here we demonstrate that stimulated Raman scattering (SRS) microscopy could be used to sensitively monitor peripheral nerve degeneration in ALS mouse models and ALS autopsy materials. Three-dimensional imaging of pre-symptomatic SOD1 mouse models and data processing by a correlation-based algorithm revealed that significant degeneration of peripheral nerves could be detected coincidentally with the earliest detectable signs of muscle denervation and preceded physiologically measurable motor function decline. We also found that peripheral degeneration was an early event in FUS as well as C9ORF72 repeat expansion models of ALS, and that serial imaging allowed long-term observation of disease progression and drug effects in living animals. Our study demonstrates that SRS imaging is a sensitive and quantitative means of measuring disease progression, greatly facilitating future studies of disease mechanisms and candidate therapeutics.
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    C9orf72 suppresses systemic and neural inflammation induced by gut bacteria
    (Springer Science and Business Media LLC, 2020-05-13) Burberry, Aaron; Wells, Michael; Limone, Francesco; Couto, Alexander; Smith, Kevin; Van Gastel, Nick; Wang, Jin-Yuan; Pietilainen, Olli; Qian, Menglu; Cantrell, Chris; Mok, Woon Jong Joanie; Scadden, David; Eggan, Kevin
    A hexanucleotide repeat expansion in C9ORF72 is the most common genetic variant contributing to Amyotrophic lateral sclerosis (ALS) and Frontotemporal dementia (FTD)1,2. The C9ORF72 mutation acts through gain and loss of function mechanisms to induce pathways implicated in neural degeneration3–9. The expansion is transcribed into a long repetitive RNA, which may negatively sequester RNA binding proteins4 prior to its non-canonical translation into neural-toxic di-peptide proteins3,5. Failure of RNA-polymerase to read through the mutation also reduces abundance of the endogenous C9ORF72 gene product, which functions in endo-lysosomal pathways and suppresses systemic and neural inflammation6–9. Notably, effects of the repeat expansion act with incomplete penetrance in ALS/FTD families, indicating that either genetic or environmental factors modify each individual’s risk of disease. Identifying disease modifiers is of significant translational interest, as it could suggest strategies that diminish the risk of developing ALS/FTD, or that slow progression. Here, we report that an environment with reduced abundance of immune-stimulating bacteria10,11 protects C9orf72 mutant mice from premature mortality and significantly ameliorates their underlying systemic inflammation and autoimmunity. Consistent with C9orf72 functioning to prevent microbiota from inducing a pathological inflammatory response, we found that reducing microbial burden in mutants with broad spectrum antibiotics, as well as transplanting gut microflora from a protective environment attenuated inflammatory phenotypes, even after their onset. Our studies provide further evidence that the microbial constituency of our gut plays an important role in brain health and can interact in surprising ways with well-known genetic risk factors for nervous system disorders.