My work seeks to see cell biology in action. I study how cells remodel membranes and organize internal compartments in space and time. My work has linked molecular structure to cellular dynamics by combining structural biology, single-molecule biophysics, cryo-EM, live-cell lattice light-sheet microscopy, adaptive-optics imaging, and large-scale 3D FIB-SEM. This progression from molecular snapshots to quantitative 4D imaging has allowed us to build “molecular movies” of membrane traffic, organelle biogenesis, ER remodeling, nuclear pore assembly, cell–cell communication, and virus–host interactions. Over the past three decades, our studies established key structural and mechanistic principles of clathrin-mediated endocytosis, a central pathway for receptor uptake, synaptic vesicle recycling, and pathogen entry. We helped define the atomic structure of the clathrin triskelion and its adaptors, the architecture of the triskelion lattice within the coat, and the ATP-dependent uncoating mechanism driven by auxilin and Hsc70. More recent work has extended these approaches to disease-relevant problems, revealing endolysosomal membrane perforations in neurons that permit endosome escape and promote amyloid-seeded aggregation, with implications for Parkinson’s and Alzheimer’s diseases. The common thread is a simple one: to make important cellular events visible, mechanistically precise, and biologically meaningful.

In my lecture, I will focus on cytosolic delivery by endosomes gone wrong: endosome escape. Our recent work has identified distinctive perforations in the endolysosomal membranes of neurons. These openings allow cytosolic α-synuclein or tau to contact internalized preformed fibrils, whether assembled from recombinant proteins or derived from patients, and thus to nucleate toxic aggregation within endosomes. This mechanism does not occur in non-neuronal cells, defining a neuron-specific route for pathogenic seeding with direct relevance to synucleinopathies such as Parkinson’s disease and to related tauopathies. We find, moreover, that PIKfyve inhibitors block seeded aggregation and prevent neuronal cell death without preventing endocytic uptake of the fibrils themselves. Although the basis of this protection remains unknown, the result illustrates how cell-biological imaging can expose unsuspected mechanisms and open paths toward clinically important questions, particularly for devastating disorders such as Parkinson’s and Alzheimer’s diseases, for which effective solutions remain elusive.

東京大学大学院理学系研究科・生物科学専攻・濡木理

 

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