CONTACT

Across neurodegenerative diseases, the shape and spatial organization of pathology carry rich mechanistic information. Vacuoles, spongiosis, oligodendroglial coiled bodies, dendritic dystrophic neurites, amyloid plaque compactness, and phase-separated droplets each reflect distinct cellular identities, subcellular compartments, trafficking pathways, and biophysical material states. Here, I synthesize morphological signatures across neurodegenerative diseases to propose a framework that links morphology to mechanism. Morphology is neither incidental nor merely descriptive. Rather, it is a readout of the basic mechanisms that govern self-assembly of proteins into aggregates, the cell’s attempts at proteostasis (clearance, sequestration, and transport), and the failure that ensues.

This meditation with apologies by a psychiatrist who is not a neuropathologist but attends CPCs of movement disorder patients speculates about how microscopic mechanical processes produce the variety of cellular neuropathological forms, which differ with diagnoses, and wonders what may be revealed by the shapes of these traces by future neuropathologists. New discoveries about tiny machines, nanotubules and the like only increase the intrigue and possibilities of revelations, likened to a crime scene investigation.