Tau-Independent Microtubule Stabilization via MAP6 Enhancement

Corticostriatal projections originate from the entire cerebral cortex and provide the major source of glutamatergic inputs to the basal ganglia. Despite the importance of corticostriatal connections in sensorimotor learning and cognitive functions, plasticity forms at these synapses remain strongly debated. Using a corticostriatal slice preserving the connections between the somatosensory cortex and the target striatal cells, we report the induction of both non-Hebbian and Hebbian forms of long-term potentiation (LTP) and long-term depression (LTD) on striatal output neurons (SONs). LTP and LTD can be induced selectively by different stimulation patterns (high-frequency trains vs low-frequency pulses) and were evoked with similar efficiency in non-Hebbian and Hebbian modes. Combination of LTP-LTD and LTD-LTP sequences revealed that bidirectional plasticity occurs at the same SONs and provides efficient homeostatic mechanisms leading to a resetting of corticostriatal synapses avoiding s

Ebselen [2-phenyl-1,2-benzisoselenazol-3(2H)-one], a seleno-organic compound with glutathione peroxidase-like activity is used in clinical trials against stroke. Human and bovine TrxR catalyzed the reduction of ebselen to ebselen selenol by NADPH with an apparent K(M)-value of 2.5 microM and a kcat of 588 min(-1). The addition of thioredoxin (Trx) stimulated the TrxR-catalyzed reduction of ebselen several-fold. This result was caused by a very fast oxidation of reduced Trx by ebselen with a rate constant in excess of 2 x 10(7) M(-1) s(-1). This rate is orders of magnitude faster than the reaction of dithiol Trx with insulin disulfides. Ebselen competed with disulfide substrates for reduction by Trx and, therefore, acted as an inhibitor of protein disulfide reduction by the Trx system. The inherent H2O2 reductase activity of mammalian TrxR dependent on its active-site selenocysteine residue was stimulated 10-fold by 2 microM ebselen and 25-fold in the additional presence of 5 microM Trx

Observable patterns of cultural variation are consistently intertwined with demic movements, cultural diffusion, and adaptation to different ecological contexts [Cavalli-Sforza and Feldman (1981) Cultural Transmission and Evolution: A Quantitative Approach; Boyd and Richerson (1985) Culture and the Evolutionary Process]. The quantitative study of gene-culture coevolution has focused in particular on the mechanisms responsible for change in frequency and attributes of cultural traits, the spread of cultural information through demic and cultural diffusion, and detecting relationships between genetic and cultural lineages. Here, we make use of worldwide whole-genome sequences [Pagani et al. (2016) Nature 538:238-242] to assess the impact of processes involving population movement and replacement on cultural diversity, focusing on the variability observed in folktale traditions (n = 596) [Uther (2004) The Types of International Folktales: A Classification and Bibliography. Based on the Sy

Major depression affects multiple physiologic systems. Therefore, analysis of signals that reflect integrated function may be useful in probing dynamical changes in this syndrome. Increasing evidence supports the conceptual framework that complex variability is a marker of healthy, adaptive control mechanisms and that dynamical complexity decreases with aging and disease. We tested the hypothesis that heart rate (HR) dynamics in non-medicated, young to middle-aged males during an acute major depressive episode would exhibit lower complexity compared with healthy counterparts. We analyzed HR time series, a neuroautonomically regulated signal, during sleep, using the multiscale entropy method. Our results show that the complexity of the HR dynamics is significantly lower for depressed than for non-depressed subjects for the entire night (P<0.02) and combined sleep stages 1 and 2 (P<0.02). These findings raise the possibility of using the complexity of physiologic signals as the basis of

The functional and molecular similarities and distinctions between human and murine astrocytes are poorly understood. Here, we report the development of an immunopanning method to acutely purify astrocytes from fetal, juvenile, and adult human brains and to maintain these cells in serum-free cultures. We found that human astrocytes have abilities similar to those of murine astrocytes in promoting neuronal survival, inducing functional synapse formation, and engulfing synaptosomes. In contrast to existing observations in mice, we found that mature human astrocytes respond robustly to glutamate. Next, we performed RNA sequencing of healthy human astrocytes along with astrocytes from epileptic and tumor foci and compared these to human neurons, oligodendrocytes, microglia, and endothelial cells (available at http://www.brainrnaseq.org). With these profiles, we identified novel human-specific astrocyte genes and discovered a transcriptome-wide transformation between astrocyte precursor cel

The development and function of the central nervous system rely on the microtubule (MT) and actin cytoskeletons and their respective effectors. Although the structural role of the cytoskeleton has long been acknowledged in neuronal morphology and activity, it was recently recognized to play the role of a signaling platform. Following this recognition, research into Microtubule Associated Proteins (MAPs) diversified. Indeed, historically, structural MAPs-including MAP1B, MAP2, Tau, and MAP6 (also known as STOP);-were identified and described as MT-binding and -stabilizing proteins. Extensive data obtained over the last 20 years indicated that these structural MAPs could also contribute to a variety of other molecular roles. Among multi-role MAPs, MAP6 provides a striking example illustrating the diverse molecular and cellular properties of MAPs and showing how their functional versatility contributes to the central nervous system. In this review, in addition to MAP6's effect on microtub

We previously documented that individual microtubules in the axons of cultured juvenile rodent neurons consist of a labile domain and a stable domain and that experimental depletion of tau results in selective shortening and partial stabilization of the labile domain. After first confirming these findings in adult axons, we sought to understand the mechanism that accounts for the formation and maintenance of these microtubule domains. We found that fluorescent tau and MAP6 ectopically expressed in RFL-6 fibroblasts predominantly segregate on different microtubules or different domains on the same microtubule, with the tau-rich ones becoming more labile than in control cells and the MAP6-rich ones being more stable than in control cells. These and other experimental findings, which we studied further using computational modeling with tunable parameters, indicate that these two MAPs do not merely bind to pre-existing stable and labile domains but actually create stable and labile domains

Association of tau (encoded by Mapt) with microtubules causes them to be labile, whereas association of MAP6 with microtubules causes them to be stable. As axons differentiate and grow, tau and MAP6 segregate from one another on individual microtubules, resulting in the formation of stable and labile domains. The functional significance of the yin-yang relationship between tau and MAP6 remains speculative, with one idea being that such a relationship assists in balancing morphological stability with plasticity. Here, using primary rodent neuronal cultures, we show that tau depletion has opposite effects compared to MAP6 depletion on the rate of neuronal development, the efficiency of growth cone turning, and the number of neuronal processes and axonal branches. Opposite effects to those seen with tau depletion were also observed on the rate of neuronal migration, in an in vivo assay, when MAP6 was depleted. When tau and MAP6 were depleted together from neuronal cultures, the morphologi

Microtubules assembled from purified tubulin in vitro are labile, rapidly disassembling when exposed to a variety of depolymerizing conditions such as cold temperature. In contrast, in many cell types, microtubules seem to be unaffected when the cell is exposed to the cold. This resistance of microtubules to the cold has been intriguing because the earliest and by far most studied microtubule-associated proteins such as MAP2 and tau are devoid of microtubule cold stabilizing activity. Over the past several years, it has been shown that resistance of microtubules to the cold is largely due to polymer association with a class of microtubule-associated proteins called STOPs. STOPs are calmodulin-binding and calmodulin-regulated proteins which, in mammals, are encoded by a single gene but exhibit substantial cell specific variability due to mRNA splicing and alternative promoter use. STOP microtubule stabilizing activity has been ascribed to two classes of new bifunctional calmodulin- and

Microtubules assembled from pure tubulin in vitro are labile, rapidly depolymerized upon exposure to the cold. In contrast, in a number of cell types, cytoplasmic microtubules are stable, resistant to prolonged cold exposure. During the past years, the molecular basis of this microtubule stabilization in cells has been elucidated. Cold stability is due to polymer association with different variants of a calmodulin-regulated protein, STOP protein. The dynamic and hence the physiological consequences of STOP association with microtubules vary in different tissues. In neurons, STOP seems almost permanently associated with microtubules. STOP is apparently a major determinant of microtubule turnover in such cells and is required for normal neuronal differentiation. In cycling cells, only minor amounts of STOP are associated with interphase microtubules and STOP does not measurably affects microtubule dynamics. However, STOP is associated with mitotic microtubules in the spindle. Recent resu

Microtubule-associated Protein 6 (MAP6) is critical for maintaining microtubule stability and synaptic plasticity, and its dysfunction is a key driver of cognitive impairment. However, the molecular mechanisms linking MAP6 deletion to cognitive deficits remain unclear. Here, we generated a novel Map6 knockout (KO, Map6-/-) mouse model using CRISPR/Cas9-mediated genome editing. Behavioral tests confirmed that Map6-/- mice exhibited prominent cognitive impairments, primarily in long-term memory and spatial learning. Hippocampal transcriptome profiling identified marked downregulation of neurotensin (Nts) in Map6-/- mice, which was validated at both mRNA and protein levels. Rescue experiments demonstrated that direct microinjection of neurotensin (NTS) peptide into the hippocampal CA1 subregion significantly improved cognitive deficits in Map6-/- mice. Electrophysiological recordings further confirmed that NTS restored impaired long-term potentiation (LTP)-a cellular substrate of learning

Tau is a multifunctional microtubule-associated protein in the neuron. For decades, tau's main function in neurons has been broadly accepted as stabilizing microtubules in the axon; however, this conclusion was reached mainly on the basis of studies performed in vitro and on ectopic expression of tau in non-neuronal cells. The idea has become so prevailing that some disease researchers are even seeking to use microtubule-stabilizing drugs to treat diseases in which tau dissociates from microtubules. Recent work suggests that tau is not a stabilizer of microtubules in the axon, but rather enables axonal microtubules to have long labile domains, in part by outcompeting genuine stabilizers. This new perspective on tau challenges long-standing dogma.

Neurons are terminally differentiated cells that use their microtubule arrays not for cell division but rather as architectural elements required for the elaboration of elongated axons and dendrites. In addition to acting as compression-bearing struts that provide for the shape of the neuron, microtubules also act as directional railways for organelle transport. The stability properties of neuronal microtubules are commonly discussed in the biomedical literature as crucial to the development and maintenance of the nervous system, and have recently gained attention as central to the etiology of neurodegenerative diseases. Drugs that affect microtubule stability are currently under investigation as potential therapies for disease and injury of the nervous system. There is often a lack of consistency, however, in how the issue of microtubule stability is discussed in the literature, and this can affect the design and interpretation of experiments as well as potential therapeutic regimens.

Recent advancements in gene expression modulation and RNA delivery systems have underscored the immense potential of nucleic acid-based therapies (NA-BTs) in biological research. However, the blood-brain barrier (BBB), a crucial regulatory structure that safeguards brain function, presents a significant obstacle to the delivery of drugs to glial cells and neurons. The BBB tightly regulates the movement of substances from the bloodstream into the brain, permitting only small molecules to pass through. This selective permeability poses a significant challenge for effective therapeutic delivery, especially in the case of NA-BTs. Extracellular vesicles, particularly exosomes, are recognized as valuable reservoirs of potential biomarkers and therapeutic targets. They are also gaining significant attention as innovative drug and nucleic acid delivery (NAD) carriers. Their unique ability to safeguard and transport genetic material, inherent biocompatibility, and capacity to traverse physiolog

This review focuses on the discovery of activity-dependent neuroprotective protein (ADNP) and the ensuing discovery of NAP (davunetide) toward clinical development with emphasis on microtubule protection. ADNP immunoreactivity was shown to occasionally decorate microtubules and ADNP silencing inhibited neurite outgrowth as measured by microtubule associated protein 2 (MAP2) labeling. ADNP knockout is lethal, while 50% reduction in ADNP (ADNP haploinsufficiency) resulted in the microtubule associated protein tau pathology coupled to cognitive dysfunction and neurodegeneration. NAP (davunetide), an eight amino acid peptide derived from ADNP partly ameliorated deficits associated with ADNP deficiency. NAP (davunetide) interacted with microtubules, protected against microtubule toxicity associated with zinc, nocodazole and oxidative stress in vitro and against tau pathology and MAP6 (stable tubuleonly polypeptide - STOP) pathology in vivo. NAP (davunetide) provided neurotrophic functions p