Tau Clearance Mechanisms.

Efficient quality control mechanisms are essential for a healthy, functional neuron. Recognition and degradation of misfolded, damaged, or potentially toxic proteins, is a crucial aspect of protein quality control. Tau is a protein that is highly expressed in neurons, and plays an important role in modulating a number of physiological processes. Maintaining appropriate levels of tau is key for neuronal health; hence perturbations in tau clearance mechanisms are likely significant contributors to neurodegenerative diseases such as Alzheimer's disease and frontotemporal lobar degeneration. In this chapter we will first briefly review the two primary degradative mechanisms that mediate tau clearance: the proteasome system and the autophagy-lysosome pathway. This will be followed by a discussion about what is known about the contribution of each of these pathways to tau clearance. We will also present recent findings on tau degradation through the endolysosomal system. Further, how deficits in these degradative systems may contribute to the accumulation of dysfunctional or toxic forms of tau in neurodegenerative conditions is considered.

Nuclear transglutaminase 2 directly regulates expression of cathepsin S in rat cortical neurons.

Transglutaminase 2 (TG2) is a protein that modulates neuronal survival processes. Although TG2 is primarily cytosolic, data have suggested the nuclear localization of TG2 is strongly associated with neuronal viability. Depletion of TG2 in neurons results in neurite retraction and loss of viability, which is likely due to a dysregulation in gene expression. To begin to understand how TG2 regulates neuronal gene expression, chromatin immunoprecipitation was performed in neurons with TG2 overexpression. The resulting genomic DNA was recovered and sequenced. Bioinformatics analyses revealed that a signature DNA motif was enriched in the TG2 immunoprecipitated genomic DNA. In particular, this motif strongly mapped to a region proximate to the gene Ctss (cathepsin S). Knockdown of TG2 resulted in a significant increase in cathepsin S expression, which preceded the loss of neuronal viability. This is the first demonstration that TG2 directly associates with genomic DNA and regulates gene expression in neurons. Given that expression of cathepsin S is increased in neurological disease states, our data suggest that TG2 may play a role in promoting neuron health in part by repressing the expression of cathepsin S. Overall these data provide new insights into the function of nuclear TG2 in neurons.

The Presence of Histamine and a Histamine Receptor in the Bivalve Mollusc, Crassostrea virginica.

Histamine, a biogenic amine, is a neurotransmitter in neurons and sensory receptors in invertebrates. Histamine has rarely been reported in bivalves. We used HPLC with pre-column derivatization using 2,3-naphthalenedicarboxaldehyde (NDA) as a fluorescent labeling agent to measure histamine in ganglia, and peripheral tissues of the oyster Crassostrea virginica. We also used Western Blot technique to look for the presence of a histamine receptor in the mantle rim. HPLC results found histamine present in ng amounts in both the cerebral and visceral ganglia, as well as the mantle rim and other peripheral tissues of C. virginica. The study confirms and quantifies histamine as an endogenous biogenic amine in C. virginica in the nervous system and innervated organs. Western Blot technique also identified a histamine H2-like receptor present in sensory tissue of the oyster's mantle rim.