, 2010, Kawajiri et al., 2010, Lee et al., 2010b, Matsuda et al., 2010, Michiorri et al.,

2010, Narendra et al., 2008, Narendra et al., Ion Channel Ligand Library nmr 2010 and Vives-Bauza and Przedborski, 2010). PD may also be associated with a general defect in lysosomal degradation. In PD postmortem brains, there is a reduction in lysosomes and an accumulation of autophagosomes (Dehay et al., 2010). α-synuclein is a substrate of chaperone-mediated autophagy (Vogiatzi et al., 2008) and PD-linked mutants or dopamine-modified forms of α-synuclein act as lysosomal uptake blockers, impairing its own degradation and that of other lysosome substrates (Cuervo et al., 2004 and Martinez-Vicente et al., 2008). This review highlights the diversity and importance of proteolytic pathways in synapse development, synaptic plasticity, and the maintenance of neuronal health (Figure 2). The destruction of proteins—which can result in either loss- or gain-of-signaling pathway functions—has generally received less attention than the production of proteins in the control of neural plasticity. In most cases of proteolytic control, the details of the regulation (when and how proteolysis is activated) and the molecular mechanisms (for instance, which particular substrates are important and which specific

E3s are responsible) have yet to unfold. Of special interest is how protein degradation events are confined to specific VX-770 manufacturer compartments such as synapses, dendrite branches, and axon growth cones. It would not be surprising if different proteolytic pathways regulate each other to achieve spatial and temporal specificity of protein turnover. Another major question is how the destruction of existing proteins is coordinated with the synthesis and delivery of new proteins to achieve remodeling of neurons and their connections. Recent studies suggest a protective role of autophagy in neurons, but we know very little about the physiological roles of this process in mature neurons and whether it is involved in plasticity to remodel

neurites and synapses. How autophagy interacts functionally with the UPS and other proteolytic systems in neurons is also unclear. Understanding the roles and mechanisms of regulated protein turnover in the health and plasticity of neurons promises to bring ADAMTS5 valuable insights into the pathogenesis of common neurodegenerative diseases. B.B. and M.S. are employees of Genentech Inc., a member of the Roche Group. “
“Tinnitus is a common hearing disorder characterized by a “phantom sensation” of ringing or buzzing in one’s ear in the absence of an external sound source. Although many people experience transient tinnitus-like symptoms as a result of brief loud-noise exposure (e.g., a rock concert) or stress, for an estimated 5%–15% of the population tinnitus can become chronic and detrimental to quality of life (Eggermont and Roberts, 2004, Heller, 2003 and Henry et al., 2005).