Molecular Bases of Disease
RNA induces unique tau strains and stabilizes Alzheimer’s disease seeds
Tau aggregation underlies neurodegenerative tauopathies, and transcellular propagation of tau assemblies of unique structure, i.e., strains, may underlie the diversity of these disorders. Polyanions have been reported to induce tau aggregation in vitro, but the precise trigger to convert tau from an inert to a seed-competent form in disease states is unknown. RNA triggers tau fibril formation in vitro and has been observed to associate with neurofibrillary tangles in human brain. Here, we have tested whether RNA exerts sequence-specific effects on tau assembly and strain formation.Parkinson’s disease and multiple system atrophy have distinct α-synuclein seed characteristics
Parkinson’s disease (PD) and multiple system atrophy (MSA) are distinct clinical syndromes characterized by the pathological accumulation of α-synuclein (α-syn) protein fibrils in neurons and glial cells. These disorders and other neurodegenerative diseases may progress via prion-like mechanisms. The prion model of propagation predicts the existence of “strains” that link pathological aggregate structure and neuropathology. Prion strains are aggregated conformers that stably propagate in vivo and cause disease with defined incubation times and patterns of neuropathology.Distinct Therapeutic Mechanisms of Tau Antibodies: PROMOTING MICROGLIAL CLEARANCE VERSUS BLOCKING NEURONAL UPTAKE
Background: Vaccination against Tau reduces pathology in vivo; however, the mechanism of action remains unclear.Results: Antibodies promote uptake of Tau fibrils in microglia or block uptake in neurons in a size- and epitope-dependent manner.Conclusion: Antibodies have multiple potential mechanisms.Significance: Establishing specific mechanisms of antibody activity may help in design and optimization of more effective agents.Tau Trimers Are the Minimal Propagation Unit Spontaneously Internalized to Seed Intracellular Aggregation
Background: It is unknown what the minimum assembly of Tau is that can trigger cell uptake and seeding of intracellular aggregation.Results: Recombinant and AD-derived Tau assemblies were fractionated, and uptake and intracellular seeding activities were determined.Conclusion: Only Tau assemblies of n ≥ 3 units trigger uptake and seeding.Significance: Definition of the minimal Tau propagation unit elucidates disease mechanisms for diagnosis and therapy.Subcellular Localization and Ser-137 Phosphorylation Regulate Tumor-suppressive Activity of Profilin-1
Background: The actin-binding protein profilin-1 is a eukaryotic protein essential for growth, with poorly understood antitumor function.Results: Profilin-1 antitumor activity requires nuclear localization and is inhibited by Ser-137 phosphorylation.Conclusion: Profilin-1 has spatially defined functions and is post-translationally regulated.Significance: Our data support a model to reconcile the seemingly oppositional functions of profilin-1 and may have implications for novel anticancer therapies.
