The shell of the amyloid fibrils: new insight on fuzzy coat polymorphs and function in proteinopathies

Protein aggregation is a hallmark of many neurodegenerative diseases, exemplified by amyloid plaques and neurofibrillary tangles in Alzheimer’s disease (AD) and Lewy bodies in Parkinson’s disease (PD). Increasing evidence indicates that these misfolded proteins can propagate between cells and brain regions as the diseases progress. The major components of these pathological deposits, such as Aβ and tau in AD, and α-synuclein in PD, are intrinsically disordered proteins whose pathological burden and distribution closely correlate with clinical decline. Under disease conditions, these proteins assemble into filaments containing rigid core regions that adopt disease-specific conformations, which are thought to underlie the clinical and pathological heterogeneity among disorders. Surrounding these cores are less-ordered, flexible regions known as the fuzzy coats, which encapsulate the filament core and often comprise substantial portions of the full-length protein, as seen in tau filaments. Despite their prevalence, the structural and functional properties of the fuzzy coat remain poorly understood. Recent studies, however, have begun to reveal its critical role in regulating fibril dynamics, intercellular transmission, and pathogenicity. In this review, we summarize current findings on the composition, structure, function and studying methodologies of the amyloid fibril fuzzy coat, and discuss its emerging significance in neurodegenerative disease pathogenesis.