The association of transcription corepressors SMRT and N-CoR with retinoid and thyroid receptors results in suppression of basal transcriptional activity. A key event in nuclear receptor signaling is the hormone-dependent release of corepressor and the recruitment of coactivator. Biochemical and structural studies have identified a universal motif in coactivator proteins that mediates association with receptor LBDs. We report here the identity of complementary acting signature motifs in SMRT and N-CoR that are sufficient for receptor binding and ligand-induced release. Interestingly, the motif contains a hydrophobic core (⌽xx⌽⌽) similar to that found in NR coactivators. Surprisingly, mutations in the amino acids that directly participate in coactivator binding disrupt the corepressor association. These results indicate a direct mechanistic link between activation and repression via competition for a common or at least partially overlapping binding site. Members of the steroid hormone receptor superfamily are hormone-activated transcription factors that control vertebrate development, differentiation, and homeostasis through regulating complex gene networks . Receptors for thyroid hormone and retinoid acid function as potent repressors in the absence of ligand and as activators upon ligand binding. Intensive studies on the mechanisms underlying this regulation led to the identification of different families of proteins that bind to the receptors in the absence and presence of hormone. SMRT (for silencing mediator for retinoid and thyroid hormone receptors) and N-CoR (for nuclear receptor corepressor) are homologous proteins that mediate the repressive effect of unliganded nuclear receptors through the recruitment of histone deacetylase complexes (Alland et al. 1997;Hassig et al. 1997;Heinzel et al. 1997;Laherty et al. 1997;Nagy et al. 1997;Zhang et al. 1997). In contrast, CBP/p300, p300/CBP-associated factor (PCAF), and members of the p160 family (SRC-1; GRIP1/ TIF2; activator for thyroid hormones and retinoid receptor (ACTR)/RAC3/P/CIP) (Onate et al. 1995;Hong et al. 1996;Kamei et al. 1996;Yao et al. 1996;Chen et al. 1997;Torchia et al. 1997;Blanco et al. 1998) possess intrinsic histone acetyl transferase activity and potentiate the transcriptional activity of ligand bound receptors.Nuclear receptors contain two evolutionarily conserved modules, the DNA binding domain (DBD) and the ligand binding domain (LBD). LBDs are required for nuclear localization, homo-and/or heterodimerization, and most importantly ligand binding and ligand-induced switch of the transcriptional activity. Molecular studies established that the LXXLL signature motif within coactivators confers stereospecific interaction with ligandactivated nuclear receptors (Heery et al. 1997). Biochemical and crystallographic analyses revealed that an LXXLL motif-containing ␣-helix from coactivators interacts with a hydrophobic groove within the ligand-bound LBDs (Darimont et al. 1998;Nolte et al. 1998;Shiau et al. 1998). Importantly, the residues that co...

Depletion of peroxisome proliferator-activated receptor ␥ (PPAR␥) accompanies myofibroblastic transdifferentiation of hepatic stellate cells (HSC), the primary cellular event underlying liver fibrogenesis. The treatment of activated HSC in vitro or in vivo with synthetic PPAR␥ ligands suppresses the fibrogenic activity of HSC. However, it is uncertain whether PPAR␥ is indeed a molecular target of this effect, because the ligands are also known to have receptor-independent actions. To test this question, the present study examined the effects of forced expression of PPAR␥ via an adenoviral vector on morphologic and biochemical features of culture-activated HSC. The vector-mediated expression of PPAR␥ itself is sufficient to reverse the morphology of activated HSC to the quiescent phenotype with retracted cytoplasm, prominent dendritic processes, reduced stress fibers, and accumulation of retinyl palmitate. These effects are abrogated by concomitant expression of a dominant negative mutant of PPAR␥ that prevents transactivation of but not binding to the PPAR response element. PPAR␥ expression also inhibits the activation markers such as the expression of ␣-smooth muscle actin, type I collagen, and transforming growth factor ␤1; DNA synthesis; and JunD binding to the activator protein-1 (AP-1) site and AP-1 promoter activity. Inhibited JunD activity by PPAR␥ is not due to reduced JunD expression or JNK activity or to a competition for p300. But it is due to a JunD-PPAR␥ interaction as demonstrated by co-immunoprecipitation and glutathione S-transferase pull-down analysis. Further, the use of deletion constructs reveals that the DNA binding region of PPAR␥ is the JunD interaction domain. In summary, our results demonstrate that the restoration of PPAR␥ reverses the activated HSC to the quiescent phenotype and suppresses AP-1 activity via a physical interaction between PPAR␥ and JunD.

Freezing of gait (FOG) is a common and debilitating, but largely mysterious, symptom of Parkinson disease. In this review, we will discuss the cerebral substrate of FOG focusing on brain physiology and animal models. Walking is a combination of automatic movement processes, afferent information processing, and intentional adjustments. Thus, normal gait requires a delicate balance between various interacting neuronal systems. To further understand gait control and specifically FOG, we will discuss the basic physiology of gait, animal models of gait disturbance including FOG, alternative etiologies of FOG, and functional magnetic resonance studies investigating FOG. The outcomes of these studies point to a dynamic network of cortical areas such as the supplementary motor area, as well as subcortical areas such as the striatum and the mesencephalic locomotor region including the pedunculopontine nucleus (PPN). Additionally, we will review PPN (area) stimulation as a possible treatment for FOG, and ponder whether PPN stimulation truly is the right step forward. Ann Neurol 2016;80:644-659.

right-handed woman in her 90s presented with essential tremor involving bilateral arms, head, and voice. The tremors started 15 years ago and progressively became disabling. She had failed propranolol hydrochloride, primidone, and gabapentin, but she had an unremarkable medical history otherwise. Her examination revealed considerable symmetric tremor, with a Clinical Rating Scale for Tremor (score range: 0-132, with the highest score indicating severe tremor) score of 88 and scores of 38 in subscale A (at rest, posture, and action), 26 in subscale B (drawing spiral, handwriting), 24 in subscale C (quality-of-life), and 26 in subscales A and B (right-side tremor). The remainder of the neurological examina-tion results were unremarkable. Preoperative magnetic resonance imaging (MRI) revealed periventricular white-matter changes and mild age-related diffuse atrophy.After a multidisciplinary evaluation, she was not recommended for ventral intermediate nucleus (VIM) deep brain stimulation (DBS) due to her advanced age. Instead, she was offered focused ultrasound (FUS) thalamotomy. Computed tomography imaging determined that her skull was suitable for ultrasonographic treatment; her skull homogeneity was greater than 0.4, as calculated by skull density ratio (SDR, which is the median ratio of skull density between cortical and trabecular bone; higher SDR IMPORTANCE Magnetic resonance imaging-guided focused ultrasound ablation has been approved for the treatment of refractory essential tremor and is being studied for other neurological indications, including dyskinesias and tremor in Parkinson disease, dystonia, neuropathic pain, obsessive-compulsive disorder, epilepsy, and brain tumors. OBJECTIVE To review the scientific foundations of FUS technology, existing neurological applications, and future advances.EVIDENCE REVIEW PubMed was searched for the past 10 years using the terms "transcranial ultrasound," "focused ultrasound," and "neurological applications." Relevant references were selected from the author's reference collection. From the 2855 unique records, 243 publications were screened. After excluding abstracts detailing in vitro studies or non-neurological applications, 86 full texts were retrieved for qualitative review.FINDINGS Advances in the transducer design and electronic phase correction have allowed efficient focusing of ultrasounds for transcranial treatment. The mid-frequency (650 kHz) transducer can make small (4-6 mm in diameter) and precise (accuracy of <2 mm) brain lesions. The treatment monitoring is achieved via "live" anatomical thermography imaging and clinical feedback. The initial results from its clinical application in movement disorders are encouraging. Emerging applications in epilepsy and neurobehavioral and cognitive disorders are being explored. The low-frequency (220 kHz) transducer coupled with microbubbles can potentially enable targeted drug delivery for novel applications, such as Alzheimer disease and brain tumors. Finally, neuromodulation with subthreshold sonications may allow...