HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS.

A prominent feature of late-onset neurodegenerative diseases is accumulation of misfolded protein in vulnerable neurons. When levels of misfolded protein overwhelm degradative pathways, the result is cellular toxicity and neurodegeneration. Cellular mechanisms for degrading misfolded protein include the ubiquitin-proteasome system (UPS), the main non-lysosomal degradative pathway for ubiquitinated proteins, and autophagy, a lysosome-mediated degradative pathway. The UPS and autophagy have long been viewed as complementary degradation systems with no point of intersection. This view has been challenged by two observations suggesting an apparent interaction: impairment of the UPS induces autophagy in vitro, and conditional knockout of autophagy in the mouse brain leads to neurodegeneration with ubiquitin-positive pathology. It is not known whether autophagy is strictly a parallel degradation system, or whether it is a compensatory degradation system when the UPS is impaired; furthermore, if there is a compensatory interaction between these systems, the molecular link is not known. Here we show that autophagy acts as a compensatory degradation system when the UPS is impaired in Drosophila melanogaster, and that histone deacetylase 6 (HDAC6), a microtubule-associated deacetylase that interacts with polyubiquitinated proteins, is an essential mechanistic link in this compensatory interaction. We found that compensatory autophagy was induced in response to mutations affecting the proteasome and in response to UPS impairment in a fly model of the neurodegenerative disease spinobulbar muscular atrophy. Autophagy compensated for impaired UPS function in an HDAC6-dependent manner. Furthermore, expression of HDAC6 was sufficient to rescue degeneration associated with UPS dysfunction in vivo in an autophagy-dependent manner. This study suggests that impairment of autophagy (for example, associated with ageing or genetic variation) might predispose to neurodegeneration. Morover, these findings suggest that it may be possible to intervene in neurodegeneration by augmenting HDAC6 to enhance autophagy.

"Quadripolar" Transcranial Electrical Stimulation for Motor Evoked Potentials.

PURPOSE: To determine if transcranial electrical stimulation (TES)-induced motor evoked potentials (MEPs) are of higher amplitude when using two electrodes as anodes and two as cathodes, known as "quadripolar stimulation." METHODS: Patients who underwent TES MEP monitoring in which control, bipolar stimulation and four variations of quadripolar stimulation were used were evaluated. The bipolar stimulation montage was C3-C4 (C3 was used as anode for stimulation first, then the polarity was switched to stimulate the contralateral side). Four quadripolar montages were used: C3/C1-C4/C2 (step 1), M3/M1-M4/M2 (step 2), C3/M1-C4/M2 (step 3), and M3/C1-M4/C2 (step 4). The area under the curve for the right foot TES MEP was compared for the various montages using descriptive statistics and Fisher exact test for proportions. RESULTS: Sixteen patients were retrospectively evaluated. The mean age as 51.6 years, range 4 to 80 years; 11 were female. The transcranial electrical stimulation MEP area under the curve for the right foot MEP was highest in the bipolar montage in 1 of 16 patients (6.3%). Meanwhile, it was highest in step 4 (M3/C1-M4/C2) in 9 of 16 patients (56.3%; P = 0.027). The highest right foot MEP area under the curve with one of the quadripolar montages was seen in 15 of 16 patients (93.8%; P = 0.0001). CONCLUSIONS: Quadripolar stimulation resulted in higher area under the curve for right foot MEP compared with conventional bipolar stimulation.

Lower Extremity Somatosensory Evoked Potential P37 Waveform Optimization.

Somatosensory evoked potentials (SEPs) using tibial nerve stimulation are used during neurophysiologic intraoperative monitoring (NIOM). These SEPs produce a P37 waveform that is recorded from scalp electrodes. In this study, we attempted to determine the best derivation for recording the P37 waveform. Surgical cases using tibial nerve SEP NIOM were reviewed. Only cases in which the P37 was recorded using all of the following derivations were analyzed: centroparietal ipsilateral-centroparietal contralateral (CPi-CPc), centroparietal midline-frontopolar midline (CPz-Fpz), and CPz-CPc. The amplitude of the P37 waveform was measured in each derivation. Descriptive statistics were obtained for the P37 waveform amplitude. The mean amplitude in each of the derivations was compared using a chi-square test. Data from 39 patients (78 lower limbs) were available for analysis. The mean age of the patients was 49.64 years (range: 4-87 years); 18 were female. The highest amplitude P37 waveform was recorded from the CPz-Fpz derivation in 29 (35.4%) limbs, whereas the CPz-CPc and CPi-CPc derivations showed the highest amplitude in 29 (35.4%) and 20 (24.4%) limbs, respectively. The mean amplitudes were not significantly different between the various derivations. In only 10 (24.4%) of patients was the best derivation the same for both left and right limbs. A single best derivation was not found for recording the P37 waveform. Multiple derivations should be used to record cortical channels whenever possible. If the number of available channels is limited, using at least the CPz-Fpz and CPz-CPc derivations is recommended.

Endocytic trafficking of Wingless and its receptors, Arrow and DFrizzled-2, in the Drosophila wing.

During animal development, Wnt/Wingless (Wg) signaling is required for the patterning of multiple tissues. While insufficient signal transduction is detrimental to normal development, ectopic activation of the pathway can be just as devastating. Thus, numerous controls exist to precisely regulate Wg signaling levels. Endocytic trafficking of pathway components has recently been proposed as one such control mechanism. Here, we characterize the vesicular trafficking of Wg and its receptors, Arrow and DFrizzled-2 (DFz2), and investigate whether trafficking is important to regulate Wg signaling during dorsoventral patterning of the larval wing. We demonstrate a role for Arrow and DFz2 in Wg internalization. Subsequently, Wg, Arrow and DFz2 are trafficked through the endocytic pathway to the lysosome, where they are degraded in a hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs)-dependent manner. Surprisingly, we find that Wg signaling is not attenuated by lysosomal targeting in the wing disc. Rather, we suggest that signaling is dampened intracellularly at an earlier trafficking step. This is in contrast to patterning of the embryonic epidermis, where lysosomal targeting is required to restrict the range of Wg signaling. Thus, signal modulation by endocytic routing will depend on the tissue to be patterned and the goals during that patterning event.