Polyglutamine expansion causes Huntington disease (HD) and at least seven other neurodegenerative diseases. In HD, N-terminal fragments of huntingtin with an expanded glutamine tract are able to aggregate and accumulate in the nucleus. Although intranuclear huntingtin affects the expression of numerous genes, the mechanism of this nuclear effect is unknown. Here we report that huntingtin interacts with Sp1, a transcription factor that binds to GC-rich elements in certain promoters and activates transcription of the corresponding genes. In vitro binding and immunoprecipitation assays show that polyglutamine expansion enhances the interaction of N-terminal huntingtin with Sp1. In HD transgenic mice (R6/2) that express N-terminal-mutant huntingtin, Sp1 binds to the soluble form of mutant huntingtin but not to aggregated huntingtin. Mutant huntingtin inhibits the binding of nuclear Sp1 to the promoter of nerve growth factor receptor and suppresses its transcriptional activity in cultured cells. Overexpression of Sp1 reduces the cellular toxicity and neuritic extension defects caused by intranuclear mutant huntingtin. These findings suggest that the soluble form of mutant huntingtin in the nucleus may cause cellular dysfunction by binding to Sp1 and thus reducing the expression of Sp1-regulated genes.Huntington disease (HD) is an autosomally dominant degenerative disorder resulting from expansion (Ͼ37 units) of a polyglutamine repeat in huntingtin, a 350-kDa protein of unknown function (15). The polyglutamine repeat is localized in the N-terminal region of huntingtin and is encoded by exon1 of the HD gene. Full-length huntingtin is predominantly distributed in the cytoplasm, whereas N-terminal fragments of huntingtin with expanded polyglutamine tracts accumulate in the nucleus (7,8,10). N-terminal huntingtin fragments containing expanded polyglutamine tracts are also toxic to cells. For example, transgenic mice expressing N-terminal fragments of mutant huntingtin develop rapidly progressing neurological symptoms (7, 37) that are more severe than those of mice expressing full-length mutant huntingtin (13,34). Smaller Nterminal huntingtin fragments, when transfected into cultured cells, kill more cells than do larger huntingtin fragments (11,27).The mechanisms for the cellular pathology associated with N-terminal-mutant huntingtin are unknown. N-terminal fragments of mutant huntingtin also form intranuclear aggregates (7, 8, 10, 37), a pathological hallmark that is found in many other polyglutamine diseases (43). Recent studies suggest that nuclear polyglutamine inclusions recruit transcription factors and that this recruitment affects gene expression (29, 39). Indeed, intranuclear huntingtin alters the expression of a number of genes, both in HD cells (22) and in transgenic animals (3, 26). The nuclear effect of mutant huntingtin may stem from its interactions with a number of transcription factors, such as the nuclear receptor corepressor (N-CoR) (2), cyclic AMP-responsive element-binding protein (CREB)-binding prote...

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Expanded polyglutamine tracts cause huntingtin and other proteins to accumulate and aggregate in neuronal nuclei. Whether the intranuclear aggregation or localization of a polyglutamine protein initiates cellular pathology remains controversial. We established stably transfected pheochromocytoma PC12 cells that express the N-terminal fragment of huntingtin containing 20 (20Q) or 150 (150Q) glutamine residues. The 150Q protein is predominantly present in the nuclei, whereas the 20Q protein is distributed throughout the cytoplasm. Electron microscopic examination confirmed that most of the 150Q protein is diffuse in the nucleus with very few microscopic aggregates observed. Compared with parental PC12 cells and cells expressing 20Q, cells expressing 150Q display abnormal morphology, lack normal neurite development, die more rapidly, and are more susceptible to apoptotic stimulation. The extent of these cellular defects in 150Q cells is correlated with the expression level of the 150Q protein. Differential display PCR and expression studies show that cells expressing 150Q have altered expression of multiple genes, including those that are important for neurite outgrowth. Our study suggests that mutant huntingtin in the nucleus is able to induce multiple cellular defects by interfering with gene expression even in the absence of aggregation.

The model offers strategies to enhance health care in youths with diabetes. Findings support the importance of adherence to the medical regimen but emphasize the complexity of the relationship between adherence behaviors and GC. Self-regulatory behaviors, rather than compliance with fixed instructions, appear to have the most impact on GC.

PURPOSE Effective therapies are needed for the treatment of patients with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer (MBC) with brain metastases. A trastuzumab radioisotope has been shown to localize in brain metastases of patients with HER2-positive MBC, and intracranial xenograft models have demonstrated a dose-dependent response to trastuzumab. METHODS In the phase II PATRICIA study (ClinicalTrials.gov identifier: NCT02536339 ), patients with HER2-positive MBC with CNS metastases and CNS progression despite prior radiotherapy received pertuzumab plus high-dose trastuzumab (6 mg/kg weekly) until CNS or systemic disease progression or unacceptable toxicity. The primary end point was confirmed objective response rate (ORR) in the CNS per Response Assessment in Neuro-Oncology Brain Metastases criteria. Secondary end points included duration of response, clinical benefit rate (complete response plus partial response plus stable disease ≥ 4 or ≥ 6 months) in the CNS, and safety. RESULTS Thirty-nine patients were treated for a median (range) of 4.5 (0.3-37.3) months at clinical cutoff. Thirty-seven patients discontinued treatment, most commonly because of CNS progression (n = 27); two remained on treatment. CNS ORR was 11% (95% CI, 3 to 25), with four partial responses (median duration of response, 4.6 months). Clinical benefit rate at 4 months and 6 months was 68% and 51%, respectively. Two patients permanently discontinued study treatment because of adverse events (left ventricular dysfunction [treatment-related] and seizure, both grade 3). No grade 5 adverse events were reported. No new safety signals emerged with either agent. CONCLUSION Although the CNS ORR was modest, 68% of patients experienced clinical benefit, and two patients had ongoing stable intracranial and extracranial disease for > 2 years. High-dose trastuzumab for HER2-positive CNS metastases may warrant further study.