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While neurodegenerative diseases affect millions of patients worldwide, there are insufficient available therapeutics to halt or slow down the progression of these diseases. A key pathological feature of several neurodegenerative diseases is the oligomerization and aggregation of specific intrinsically disordered proteins (IDPs) creating neuronal deposits, such as Lewy bodies in Parkinson's disease. Clearance of these pathogenic, aggregation-prone IDPs is mediated by the 20S isoform of the human proteasome. Thus, enhancing the 20S proteasome-mediated proteolysis could be a very useful therapeutic pathway to prevent neurotoxicity. Here, we report the successful development of sub-microM 20S proteasome activators based on a phenothiazine scaffold. This class of compounds prevented the accumulation of pathologically relevant IDPs, such as the pathogenic A53T mutated α-synuclein

OBJECTIVE The objective of this article was to assess the impact on behavioral and socioemotional development, 2 to 6 years postintervention (depending on the curriculum), of Legacy for Children, a public health approach to improve child developmental outcomes among families living in poverty. METHODS Mothers who were recruited prenatally or at the time of childbirth participated in a set of Legacy parallel design randomized control trials between 2001 and 2009 in Miami, Florida, or Los Angeles, California. Of the initial 574 mother-child dyads, 364 completed at least 1 behavioral or socioemotional outcome measure at the third-grade follow-up. Intention-to-treat analyses compared Legacy and comparison groups on behavioral and socioemotional outcomes. RESULTS Children of Legacy mothers in Los Angeles were at lower risk for externalizing behaviors and poor adaptive skills than children whose mothers did not participate in the intervention. No significant outcome differences by group assignment were found in Miami. CONCLUSION Group-based positive parenting interventions such as Legacy may have a sustained impact on children's behavioral and socioemotional development several years after intervention completion.

The 20S proteasome is the main protease that directly targets intrinsically disordered proteins (IDPs) for proteolytic degradation. Mutations, oxidative stress, or aging can induce the buildup of IDPs resulting in incorrect signaling or aggregation, associated with the pathogenesis of many cancers and neurodegenerative diseases. Drugs that facilitate 20S-mediated proteolysis therefore have many potential therapeutic applications. We report herein the modulation of proteasome assembly by the small molecule TCH-165, resulting in an increase in 20S levels. The increase in the level of free 20S corresponds to enhanced proteolysis of IDPs, including α-synuclein, tau, ornithine decarboxylase, and c-Fos, but not structured proteins. Clearance of ubiquitinated protein was largely maintained by single capped proteasome complexes (19S–20S), but accumulation occurs when all 19S capped proteasome complexes are depleted. This study illustrates the first example of a small molecule capable of targeting disordered proteins for degradation by regulating the dynamic equilibrium between different proteasome complexes.

The 20S proteasome is the main protease for the degradation of oxidatively damaged and intrinsically disordered proteins. When accumulation of disordered or oxidatively damaged proteins exceeds proper clearance in neurons, imbalanced pathway signaling or aggregation occurs, which have been implicated in the pathogenesis of several neurological disorders. Screening of the NIH Clinical Collection and Prestwick libraries identified the neuroleptic agent chlorpromazine as a lead agent capable of enhancing 20S proteasome activity. Chemical manipulation of chlorpromazine abrogated its D2R receptor binding affinity while retaining its ability to enhance 20S mediated proteolysis at low micromolar concentrations. The resulting small molecule enhancers of 20S proteasome activity induced the degradation of intrinsically disordered proteins, α-synuclein, and tau but not structured proteins. These small molecule 20S agonists can serve as leads to explore the therapeutic potential of 20S activation or as new tools to provide insight into the yet unclear mechanics of 20S-gate regulation.

Loss of proteome fidelity leads to the accumulation of non-native protein aggregates and oxidatively damaged species: hallmarks of an aged cell. These misfolded and aggregated species are often found, and suggested to be the culpable party, in numerous neurodegenerative diseases including Huntington’s, Parkinson’s, Amyotrophic Lateral Sclerosis (ALS), and Alzheimer’s Diseases (AD). Many strategies for therapeutic intervention in proteotoxic pathologies have been put forth; one of the most promising is bolstering the efficacy of the proteasome to restore normal proteostasis. This strategy is ideal as monomeric precursors and oxidatively damaged proteins, so called “intrinsically disordered proteins” (IDPs), are targeted by the proteasome. This review will provide an overview of disorders in proteins, both intrinsic and acquired, with a focus on susceptibility to proteasomal degradation. We will then examine the proteasome with emphasis on newly published structural data and summarize current known small molecule proteasome activators.

The authors' clinical impression that homosexual gender-dysphoric males are physically smaller than nonhomosexual gender-dysphoric males was tested. Subjects were 176 homosexual and 246 nonhomosexual male outpatients, ages 16 to 65, who complained of discontent with their biological sex. Compared with the nonhomosexual male gender dysphorics, the homosexual gender dysphorics were shorter, lighter, and lighter in proportion to their height. The homosexual gender dysphorics were also shorter than men in the general population, whereas the nonhomosexual gender dysphorics were not. The smaller physiques of homosexual gender-dysphoric men may partly explain the clinical observation that these patients are somewhat more successful in passing as women.