Ferroptosis Promotes Microtubule-Associated Protein Tau Aggregation via GSK-3β Activition and Proteasome Inhibition

Ferroptosis is a form of regulated cell death resulting from iron accumulation and lipid peroxidation. In some particular brain regions, iron dyshomeostasis and peroxidation damage of neurons are closely related to a wide range of neurodegenerative diseases known as “tauopathies”, in which intracellular aggregation of microtubule-associated protein tau is the common neuropathological feature. However, the relationship between ferroptosis and tau aggregation is not well understood. The current study demonstrates that erastin-induced ferroptosis can promote tau hyperphosphorylation and aggregation in mouse neuroblastoma cells (N2a cells). Moreover, ferroptosis inhibitor ferrostatin-1 can alleviate tau aggregation effectively. In-depth mechanism research indicates that activated Glycogen synthase kinase-3β (GSK-3β) is responsible for abnormal hyperphosphorylation and accumulation. More importantly, proteasome inhibition can exacerbate the tau degradation obstacle and accelerate tau aggregation in the process of ferroptosis. Our results indicate that ferroptosis can lead to abnormal aggregation of tau protein and might be a promising therapeutic target of tauopathies.

The Microtubule Associated Protein Tau Regulates KIF1A Pausing Behavior and Motility

Many neurodegenerative diseases result from dysfunction of axonal transport, a highly regulated cellular process responsible for site-specific neuronal cargo delivery. The kinesin-3 family member KIF1A is a key mediator of this process by facilitating long-distance cargo delivery in a spatiotemporally regulated manner. While misregulation of KIF1A cargo delivery is observed in many neurodegenerative diseases, the regulatory mechanisms responsible for KIF1A cargo transport are largely unexplored. Our lab has recently characterized a mechanism for a unique pausing behavior of KIF1A in between processive segments on the microtubule. This behavior, mediated through an interaction between the KIF1A K-loop and the polyglutamylated C-terminal tails of tubulin, helps us further understand how KIF1A conducts long-range cargo transport. However, how this pausing behavior is influenced by other regulatory factors on the microtubule is an unexplored concept. The microtubule associated protein Tau is one potential regulator, as altered Tau function is a pathological marker in many neurodegenerative diseases. However, while the effect of Tau on kinesin-1 and -2 has been extensively characterized, its role in regulating KIF1A transport is greatly unexplored at the behavioral level. Using single-molecule imaging, we have identified Tau-mediated regulation of KIF1A pausing behavior and motility. Specifically, our findings imply a competitive interaction between Tau and KIF1A for the C-terminal tails of tubulin. We introduce a new mechanism of Tau-mediated kinesin regulation by inhibiting the ability of KIF1A to use C-terminal tail reliant pauses to connect multiple processive segments into a longer run length. Moreover, we have correlated this regulatory mechanism to the behavioral dynamics of Tau, further elucidating the function of Tau diffusive and static behavioral state on the microtubule surface. In summary, we introduce a new mechanism of Tau-mediated motility regulation, providing insight on how disruptions in axonal transport can lead to disease state pathology.

Microglia become hypofunctional and release metalloproteases and tau seeds after phagocytosing live neurons with P301S tau aggregates

The microtubule-associated protein tau aggregates in multiple neurodegenerative diseases, causing inflammation and changing the inflammatory signature of microglia by unknown mechanisms. We have shown that microglia phagocytose live neurons containing tau aggregates cultured from P301S tau transgenic mice due to neuronal tau aggregate-induced exposure of the 'eat me' signal phosphatidylserine. Here we show that after phagocytosis, microglia become hypophagocytic while releasing seed-competent insoluble tau aggregates. These microglia activate acidic β-galactosidase, and release senescence-associated cytokines and matrix remodeling enzymes alongside tau, indicating a senescent phenotype. In particular, the marked NFκB-induced activation of matrix metalloprotease 3 (MMP3/stromelysin1) was replicated in the brains of P301S mutant tau transgenic mice, and in human brains from tauopathy patients. These data show that microglia that have been activated to ingest live neurons with tau aggregates behave hormetically, becoming hypofunctional while acting as vectors of tau aggregate spreading.

Age and Dose-dependent Effects of Alpha-lipoic Acid on Human Microtubule-associated Protein Tau-induced Endoplasmic Reticulum Unfolded Protein Response: Implications for Alzheimer’s Disease

Background: In human tauopathies, pathological aggregation of misfolded/unfolded proteins particularly microtubule-associated protein tau (MAPT, tau) is considered to be essential mechanisms that trigger the induction of endoplasmic reticulum (ER) stress. Objective: Here we assessed the molecular effects of natural antioxidant alpha-lipoic acid (ALA) in human tauR406W (htau)-induced ER unfolded protein response (ERUPR) in fruit flies. Methods: In order to reduce htau neurotoxicity during brain development, we used a transgenic model of tauopathy where the maximum toxicity was observed in adult flies. Then, the effects of ALA (0.001, 0.005, and 0.025% w/w of diet) in htau-induced ERUPR and behavioral dysfunctions in the ages 20 and 30 days were evaluated in Drosophila melanogaster. Results: Data from expression (mRNA and protein) patterns of htau, analysis of eyes external morphology as well as larvae olfactory memory were confirmed our tauopathy model. Moreover, expression of ERUPR-related proteins involving activating transcription factor 6 (ATF6), inositol regulating enzyme 1 (IRE1), and protein kinase RNA-like ER kinase (PERK) were upregulated and locomotor function decreased in both ages of the model flies. Remarkably, the lower dose of ALA modified ERUPR and supported the reduction of behavioral deficits in youngest adults through enhancement of GRP87/Bip, reduction of ATF6, downregulation of PERK-ATF4 pathway, and activation of the IRE1-XBP1 pathway. On the other hand, only a higher dose of ALA was able to affect the ERUPR via moderation of PERK-ATF4 signaling in the oldest adults. As ALA also exerts their higher protective effects on the locomotor function of younger adults when htauR406W expressed in all neurons (htau-elav) and mushroom body neurons (htau-ok), we proposed that ALA has age-dependent effects in this model. Conclusion: Taken together, based on our results we conclude that aging potentially influences the ALA effective dose and mechanism of action on tau-induced ERUPR. Further molecular studies will warrant possible therapeutic applications of ALA in age-related tauopathies.

Tau and DNA Damage in Neurodegeneration

Neurodegenerative disorders are a family of incurable conditions. Among them, Alzheimer’s disease and tauopathies are the most common. Pathological features of these two disorders are synaptic loss, neuronal cell death and increased DNA damage. A key pathological protein for the onset and progression of the conditions is the protein tau, a microtubule-binding protein highly expressed in neurons and encoded by the MAPT (microtubule-associated protein tau) gene. Tau is predominantly a cytosolic protein that interacts with numerous other proteins and molecules. Recent findings, however, have highlighted new and unexpected roles for tau in the nucleus of neuronal cells. This review summarizes the functions of tau in the metabolism of DNA, describing them in the context of the disorders.