Numerous pathological amyloid proteins spread from cell to cell during neurodegenerative disease, facilitating the propagation of cellular pathology and disease progression. Understanding the mechanism by which disease-associated amyloid protein assemblies enter target cells and induce cellular dysfunction is, therefore, key to understanding the progressive nature of such neurodegenerative diseases. In this study, we utilized an imaging-based assay to monitor the ability of disease-associated amyloid assemblies to rupture intracellular vesicles following endocytosis. We observe that the ability to induce vesicle rupture is a common feature of α-synuclein (α-syn) assemblies, as assemblies derived from WT or familial disease-associated mutant α-syn all exhibited the ability to induce vesicle rupture. Similarly, different conformational strains of WT α-syn assemblies, but not monomeric or oligomeric forms, efficiently induced vesicle rupture following endocytosis. The ability to induce vesicle rupture was not specific to α-syn, as amyloid assemblies of tau and huntingtin Exon1 with pathologic polyglutamine repeats also exhibited the ability to induce vesicle rupture. We also observe that vesicles ruptured by α-syn are positive for the autophagic marker LC3 and can accumulate and fuse into large, intracellular structures resembling Lewy bodies in vitro. Finally, we show that the same markers of vesicle rupture surround Lewy bodies in brain sections from PD patients. These data underscore the importance of this conserved endocytic vesicle rupture event as a damaging mechanism of cellular invasion by amyloid assemblies of multiple neurodegenerative disease-associated proteins, and suggest that proteinaceous inclusions such as Lewy bodies form as a consequence of continued fusion of autophagic vesicles in cells unable to degrade ruptured vesicles and their amyloid contents.

Tau pathology propagates within synaptically connected neuronal circuits, but the underlying mechanisms are unclear. BIN1-amphiphysin2 is the second most prevalent genetic risk factor for late-onset Alzheimer's disease. In diseased brains, the BIN1-amphiphysin2 neuronal isoform is downregulated. Here, we show that lowering BIN1-amphiphysin2 levels in neurons promotes Tau pathology propagation whereas overexpression of neuronal BIN1-amphiphysin2 inhibits the process in two in vitro models. Increased Tau propagation is caused by increased endocytosis, given our finding that BIN1-amphiphysin2 negatively regulates endocytic flux. Furthermore, blocking endocytosis by inhibiting dynamin also reduces Tau pathology propagation. Using a galectin-3-binding assay, we show that internalized Tau aggregates damage the endosomal membrane, allowing internalized aggregates to leak into the cytoplasm to propagate pathology. Our work indicates that lower BIN1 levels promote the propagation of Tau pathology by efficiently increasing aggregate internalization by endocytosis and endosomal trafficking.

Although trace levels of phosphorylated ␣-synuclein (␣-syn) are detectable in normal brains, nearly all ␣-syn accumulated within Lewy bodies in Parkinson disease brains is phosphorylated on serine 129 (Ser-129). The role of the phosphoserine residue and its effects on ␣-syn structure, function, and intracellular accumulation are poorly understood. Here, co-expression of ␣-syn and polo-like kinase 2 (PLK2), a kinase that targets Ser-129, was used to generate phosphorylated ␣-syn for biophysical and biological characterization. Misfolding and fibril formation of phosphorylated ␣-syn isoforms were detected earlier, although the fibrils remained phosphatase-and protease-sensitive. Membrane binding of ␣-syn monomers was differentially affected by phosphorylation depending on the Parkinson disease-linked mutation. WT ␣-syn binding to presynaptic membranes was not affected by phosphorylation, whereas A30P ␣-syn binding was greatly increased, and A53T ␣-syn was slightly lower, implicating distal effects of the carboxyl-on amino-terminal membrane binding. Endocytic vesicle-mediated internalization of pre-formed fibrils into non-neuronal cells and dopaminergic neurons matched the efficacy of ␣-syn membrane binding. Finally, the disruption of internalized vesicle membranes was enhanced by the phosphorylated ␣-syn isoforms, a potential means for misfolded extracellular or lumenal ␣-syn to access cytosolic ␣-syn. Our results suggest that the threshold for vesicle permeabilization is evident even at low levels of ␣-syn internalization and are relevant to therapeutic strategies to reduce intercellular propagation of ␣-syn misfolding.

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Tau is a protein that has received national mainstream recognition for its potential negative impact to the brain. This review succinctly provides information on the structure of tau and its normal physiological functions, including in hibernation and changes throughout the estrus cycle. There are many pathways involved in phosphorylating tau including diabetes, stroke, Alzheimer’s disease (AD), brain injury, aging, and drug use. The common mechanisms for these processes are put into context with changes observed in mild and repetitive mild traumatic brain injury (TBI). The phosphorylation of tau is a part of the progression to pathology, but the ability for tau to aggregate and propagate is also addressed. Summarizing both the functional and dysfunctional roles of tau can help advance our understanding of this complex protein, improve our care for individuals with a history of TBI, and lead to development of therapeutic interventions to prevent or reverse tau-mediated neurodegeneration.