Contact

  • Academic
    kwu2@stanford.edu
    University - Student Department: School of Medicine Position: Graduate, Medicine
    University - Student Department: School of Medicine - IDP's - Neurosciences Position: Graduate

Additional Info

  • Mail Code: 5404

All Publications

  • CNS myelination requires VAMP2/3-mediated membrane expansion in oligodendrocytes. Nature communications Lam, M., Takeo, K., Almeida, R. G., Cooper, M. H., Wu, K., Iyer, M., Kantarci, H., Zuchero, J. B. 2022; 13 (1): 5583

    Abstract

    Myelin is required for rapid nerve signaling and is emerging as a key driver of CNS plasticity and disease. How myelin is built and remodeled remains a fundamental question of neurobiology. Central to myelination is the ability of oligodendrocytes to add vast amounts of new cell membrane, expanding their surface areas by many thousand-fold. However, how oligodendrocytes add new membrane to build or remodel myelin is not fully understood. Here, we show that CNS myelin membrane addition requires exocytosis mediated by the vesicular SNARE proteins VAMP2/3. Genetic inactivation of VAMP2/3 in myelinating oligodendrocytes caused severe hypomyelination and premature death without overt loss of oligodendrocytes. Through live imaging, we discovered that VAMP2/3-mediated exocytosis drives membrane expansion within myelin sheaths to initiate wrapping and power sheath elongation. In conjunction with membrane expansion, mass spectrometry of oligodendrocyte surface proteins revealed that VAMP2/3 incorporates axon-myelin adhesion proteins that are collectively required to form nodes of Ranvier. Together, our results demonstrate that VAMP2/3-mediated membrane expansion in oligodendrocytes is indispensable for myelin formation, uncovering a cellular pathway that could sculpt myelination patterns in response to activity-dependent signals or be therapeutically targeted to promote regeneration in disease.

    View details for DOI 10.1038/s41467-022-33200-4

    View details for PubMedID 36151203

  • Genome-wide synthetic lethal CRISPR screen identifies FIS1 as a genetic interactor of ALS-linked C9ORF72. Brain research Chai, N., Haney, M. S., Couthouis, J., Morgens, D. W., Benjamin, A., Wu, K., Ousey, J., Fang, S., Finer, S., Bassik, M. C., Gitler, A. D. 2019: 146601

    Abstract

    Mutations in the C9ORF72 gene are the most common cause of amyotrophic lateral sclerosis (ALS). Both toxic gain of function and loss of function pathogenic mechanisms have been proposed. Accruing evidence from mouse knockout studies point to a role for C9ORF72 as a regulator of immune function. To provide further insight into its cellular function, we performed a genome-wide synthetic lethal CRISPR screen in human myeloid cells lacking C9ORF72. We discovered a strong synthetic lethal genetic interaction between C9ORF72 and FIS1, which encodes a mitochondrial membrane protein involved in mitochondrial fission and mitophagy. Mass spectrometry experiments revealed that in C9ORF72 knockout cells, FIS1 strongly bound to a class of immune regulators that activate the receptor for advanced glycation end (RAGE) products and trigger inflammatory cascades. These findings present a novel genetic interactor for C9ORF72 and suggest a compensatory role for FIS1 in suppressing inflammatory signaling in the absence of C9ORF72.

    View details for DOI 10.1016/j.brainres.2019.146601

    View details for PubMedID 31843624