Aggregation of scaffolding protein DISC1 dysregulates phosphodiesterase 4 in Huntington’s disease

Huntington’s disease (HD) is a polyglutamine (polyQ) disease caused by aberrant expansion of the polyQ tract in Huntingtin (HTT). While motor impairment mediated by polyQ-expanded HTT has been intensively studied, molecular mechanisms for nonmotor symptoms in HD, such as psychiatric manifestations, remain elusive. Here we have demonstrated that HTT forms a ternary protein complex with the scaffolding protein DISC1 and cAMP-degrading phosphodiesterase 4 (PDE4) to regulate PDE4 activity. We observed pathological cross-seeding between DISC1 and mutant HTT aggregates in the brains of HD patients as well as in a murine model that recapitulates the polyQ pathology of HD (R6/2 mice). In R6/2 mice, consequent reductions in soluble DISC1 led to dysregulation of DISC1-PDE4 complexes, aberrantly increasing the activity of PDE4. Importantly, exogenous expression of a modified DISC1, which binds to PDE4 but not mutant HTT, normalized PDE4 activity and ameliorated anhedonia in the R6/2 mice. We propose that cross-seeding of mutant HTT and DISC1 and the resultant changes in PDE4 activity may underlie the pathology of a specific subset of mental manifestations of HD, which may provide an insight into molecular signaling in mental illness in general

Development of a multialkali photocathode dc gun for a Smith-Purcell terahertz free-electron laser

We have developed a photocathode dc gun for a compact Smith-Purcell free-electron laser in the terahertz wavelength region. The gun system consists of an alkali antimonide photocathode preparation chamber, a dc gun with a 250 kV-50 mA Cockcroft-Walton high-voltage power supply, and a downstream beamline with a water-cooled beam dump to accommodate a beam power of 5 kW. We fabricated a Cs3Sb photocathode with quantum efficiency of 5.8% at a wavelength of 532 nm and generated a 150 keV beam with current of up to 4.3 mA with a 500 mW laser. A vacuum chamber for the Smith-Purcell free-electron laser has been installed in the downstream beamline. We describe the present status of our work

Development of a multialkali photocathode dc gun for a Smith-Purcell terahertz free-electron laser

We have developed a photocathode dc gun for a compact Smith-Purcell free-electron laser in the terahertz wavelength region. The gun system consists of an alkali antimonide photocathode preparation chamber, a dc gun with a 250 kV-50 mA Cockcroft-Walton high-voltage power supply, and a downstream beamline with a water-cooled beam dump to accommodate a beam power of 5 kW. We fabricated a Cs3Sb photocathode with quantum efficiency of 5.8% at a wavelength of 532 nm and generated a 150 keV beam with current of up to 4.3 mA with a 500 mW laser. A vacuum chamber for the Smith-Purcell free-electron laser has been installed in the downstream beamline. We describe the present status of our work