For the first project, in collaboration with Jennifer Lippincott Schwartz (HHMI) and Peter Hyslop (U. Cambridge), we made the surprising discovery that RNA granules are indirectly transported long distances in axons by hitchhiking on moving lysosomes. Using proteomics, imaging, and biophysics, we showed that this hitchhiking is mediated by a newly-discovered ALS protein, ANXA11, which serves as a regulatable molecular tether between RNA granules and lysosomes during transport. ALS-associated mutations in ANXA11 block RNA transport and local translation of RNA in distal neuronal processes, suggesting dysfunctional local translation as a new ALS mechanism. A manuscript describing these findings (Liao YCLippincott-Schwartz J & Ward ME) is currently in resubmission. For the second project, we developed a new method to perform large-scale, forward-genetic CRISPR-inhibition (CRISPR-i) screens in human iPSC-derived neurons. This technology merged a highly-scalable iPSC-neuron differentiation method developed by my lab with a highly-potent CRISPRi screening approach developed by Martin Kampmanns team at UCSF. In a paper in revision in Neuron, we describe the first large-scale CRISPR-based screens in differentiated-iPSC derived neurons, using readouts of survival, single-cell transcriptomics, and morphology (Ruilin TWard ME & Kampmann M, Neuron, In Press). In addition to identifying several new neuron-specific survival-related pathways, this tool will serve as the backbone for future projects in my lab to identify pathways in FTD/ALS pathogenesis.
| Fernandopulle, Michael S; Prestil, Ryan; Grunseich, Christopher et al. (2018) Transcription Factor-Mediated Differentiation of Human iPSCs into Neurons. Curr Protoc Cell Biol 79:e51 |
| Ward, Michael E; Gelfand, Jeffrey M; Lui, Li-Yung et al. (2018) Reduced contrast sensitivity among older women is associated with increased risk of cognitive impairment. Ann Neurol 83:730-738 |
| Ward, Michael E; Chen, Robert; Huang, Hsin-Yi et al. (2017) Individuals with progranulin haploinsufficiency exhibit features of neuronal ceroid lipofuscinosis. Sci Transl Med 9: |
| Wang, Chao; Ward, Michael E; Chen, Robert et al. (2017) Scalable Production of iPSC-Derived Human Neurons to Identify Tau-Lowering Compounds by High-Content Screening. Stem Cell Reports 9:1221-1233 |
| Krencik, Robert; Seo, Kyounghee; van Asperen, Jessy V et al. (2017) Systematic Three-Dimensional Coculture Rapidly Recapitulates Interactions between Human Neurons and Astrocytes. Stem Cell Reports 9:1745-1753 |
