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Protein aggregates can form in the cytoplasm of the cell and are accumulated at aggresomes localized to the microtubule organizing center (MTOC) where they are subsequently degraded by autophagy. In this process, aggregates are engulfed into autophagosomes which subsequently fuse with lysosomes for protein degradation. A member of the class II histone deacetylase family, histone deacetylase 6(HDAC6) has been shown to be involved in both aggresome formation and the fusion of autophagosomes with lysosomes making it an attractive target to regulate protein aggregation. The scaffolding protein sequestosome 1(SQSTM1)/p62 has also been shown to regulate accumulation and autophagic clearance of protein aggregates. Recent studies have revealed colocalization of HDAC6 and p62 to ubiquitinated mitochondria, as well as, ubiquitinated protein aggregates associated with the E3 ubiquitin ligase TRIM50. HDAC6 deacetylase activity is required for aggresome formation and can be regulated by protein interaction with HDAC6. Due to their colocalization at ubiquitinated protein aggregates, we sought to examine if p62 specifically interacted with HDAC6 and if so, if this interaction had any effect on HDAC6 activity and/or the physiological function of cortactin-F-actin assembly. We succeeded in identifying and mapping the direct interaction between HDAC6 and p62. We further show that this interaction regulates HDAC6 deacetylase activity. Data are presented demonstrating that the absence of p62 results in hyperactivation of HDAC6 and deacetylation of α-tubulin and cortactin. Further, upon induction of protein misfolding we show that p62 is required for perinuclear co-localization of cortactin-F-actin assemblies. Thus, our findings indicate that p62 plays a key role in regulating the recruitment of F-actin network assemblies to the MTOC, a critical cellular function that is required for successful autophagic clearance of protein aggregates.

Cytoplasmic localization and possession of two deacetylase domains and a ubiquitin-binding domain make histone deacetylase 6 (HDAC6) a unique histone deacetylase. HDAC6 interacts with a number of proteins in the cytoplasm. Some of these proteins can be deacetylated by HDAC6 deacetylase activity. Others can affect HDAC6 functions by modulating its catalytic activity or ubiquitin-binding capability. Over the last decade, HDAC6 has been shown to play important roles in the aggresome-autophagy pathway, which selectively targets on protein aggregates or damaged organelles for their accumulation and clearance in cells. HDAC6-interacting partners are integral components in this pathway with regard to their regulatory roles through interaction with HDAC6. The aggresome-autophagy pathway appears to be an attractive therapeutic target for the treatment of neurodegenerative diseases as accumulation of protein aggregates are hallmarks in these diseases. In the current review, I discuss the molecular details of how HDAC6 and its interacting partners regulate each individual step in the aggresome-autophagy pathway and also provide perspectives of how HDAC6 can be targeted in treating neurodegenerative diseases.

Background: Parkin is proposed to maintain mitochondrial QC through promoting mitophagy. Results: Under moderate mitochondrial stress conditions, parkin stimulates mitochondrial fusion instead of mitophagy by catalyzing K63-linked ubiquitination and inactivating ␣-synuclein. Conclusion: Parkin, PINK1, and ␣-synuclein form a regulatory circuit to regulate mitochondrial stress response. Significance: This study provides a physiological context to functionally connect key PARK genes in the pathogenesis of Parkinson disease.

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Highlights d Prefrontal CRF GABAergic interneurons are recruited during behavioral challenges d Manipulation of CRF neurons motivates selection of behavioral styles under challenges d Activation of CRF neurons promotes persistent stressresistant behaviors

Sodium salicylate (NaSal), an aspirin metabolite, can cause tinnitus in animals and human subjects. To explore neural mechanisms underlying salicylate-induced tinnitus, we examined effects of NaSal on neural activities of the medial geniculate body (MGB), an auditory thalamic nucleus that provides the primary and immediate inputs to the auditory cortex, by using the whole-cell patch-clamp recording technique in MGB slices. Rats treated with NaSal (350 mg/kg) showed tinnitus-like behavior as revealed by the gap prepulse inhibition of acoustic startle (GPIAS) paradigm. NaSal (1.4 mM) decreased the membrane input resistance, hyperpolarized the resting membrane potential, suppressed current-evoked firing, changed the action potential, and depressed rebound depolarization in MGB neurons. NaSal also reduced the excitatory and inhibitory postsynaptic response in the MGB evoked by stimulating the brachium of the inferior colliculus. Our results demonstrate that NaSal alters neuronal intrinsic properties and reduces the synaptic transmission of the MGB, which may cause abnormal thalamic outputs to the auditory cortex and contribute to NaSal-induced tinnitus.