Histone deacetylase inhibitors reduce polyglutamine toxicity.

Polyglutamine diseases include at least nine neurodegenerative disorders, each caused by a CAG repeat expansion in a different gene. Accumulation of mutant polyglutamine-containing proteins occurs in patients, and evidence from cell culture and animal experiments suggests the nucleus as a site of pathogenesis. To understand the consequences of nuclear accumulation, we created a cell culture system with nuclear-targeted polyglutamine. In our system, cell death can be mitigated by overexpression of full-length cAMP response element binding protein (CREB)-binding protein (CBP) or its amino-terminal portion alone. CBP is one of several histone acetyltransferases sequestered by polyglutamine inclusions. We found histone acetylation to be reduced in cells expressing mutant polyglutamine. Reversal of this hypoacetylation, which can be achieved either by overexpression of CBP or its amino terminus or by treatment with deacetylase inhibitors, reduced cell loss. These findings suggest that nuclear accumulation of polyglutamine can lead to altered protein acetylation in neurons and indicate a novel therapeutic strategy for polyglutamine disease.

CREB-binding protein sequestration by expanded polyglutamine.

Spinal and bulbar muscular atrophy (SBMA) is one of eight inherited neurodegenerative diseases known to be caused by CAG repeat expansion. The expansion results in an expanded polyglutamine tract, which likely confers a novel, toxic function to the affected protein. Cell culture and transgenic mouse studies have implicated the nucleus as a site for pathogenesis, suggesting that a critical nuclear factor or process is disrupted by the polyglutamine expansion. In this report we present evidence that CREB-binding protein (CBP), a transcriptional co-activator that orchestrates nuclear response to a variety of cell signaling cascades, is incorporated into nuclear inclusions formed by polyglutamine-containing proteins in cultured cells, transgenic mice and tissue from patients with SBMA. We also show CBP incorporation into nuclear inclusions formed in a cell culture model of another polyglutamine disease, spinocerebellar ataxia type 3. We present evidence that soluble levels of CBP are reduced in cells expressing expanded polyglutamine despite increased levels of CBP mRNA. Finally, we demonstrate that over-expression of CBP rescues cells from polyglutamine-mediated toxicity in neuronal cell culture. These data support a CBP-sequestration model of polyglutamine expansion disease.

Cleavage, aggregation and toxicity of the expanded androgen receptor in spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disease caused by the expansion of a polyglutamine repeat within the androgen receptor (AR). We have studied the mutant AR in an in vitro system, and find both aggregation and proteolytic processing of the AR protein to occur in a polyglutamine repeat length-dependent manner. In addition, we find the aberrant metabolism of expanded repeat AR to be coupled to cellular toxicity, indicating a likely molecular basis for the toxic gain of AR function that produces neuronal degeneration in SBMA.

Fine needle aspiration cytology of breast lesions: a clinicocytologic review of 1211 cases.

Fine needle aspiration (FNA) is a widely accepted cytologic technique for the early diagnosis of palpable breast lesions. Early diagnosis and treatment of benign and malignant breast lesions in turn are associated with increased chance of long term survival. Clinical data and results of fine needle aspiration done at the Department of Pathology in Tikur Anbessa Hospital between January 1991 to December 1994 were reviewed to study the cytologic features of breast lesions and to elucidate the clinical use of fine needle aspiration. A total of 9,946 fine needle aspirations were done in the department, out of which 1,211 (12.2%) were from breast lesions. Results from breast lesions were reported as: malignant, benign suspicious and unsatisfactory. Repeat aspiration was performed for all unsatisfactory cases. Fine needle aspiration of the 1,211 breast lesions in the four year period revealed 255 (21%) malignant, 901 (74%) benign, 15 (1.2%) suspicious and 40 (3.3%) unsatisfactory cases. The malignant lesions ranged from small, mobile, firm nodules measuring 4 cm to fixed ulcerated and fungating mass, measuring 20 cm or more. The benign lesions were small and mobile, measuring from 2 cm to 6 cm, mostly fibroadenoma (38%). Biopsy result was found for 20 patients. Out of these 14 were benign lesions and 6 were malignant lesions, confirmed by surgical biopsy. The mean age of patients with malignant lesions was 43 years (range: 24 to 80 years), while it was 27 years (range: 15 to 50 years) for those with benign lesion. There were 1132 (93.5%) females and 79 (6.5%) males. Fine needle aspiration diagnostic technique is recommended to be widely introduced into the health system of Ethiopia in order to ensure timely diagnosis of benign and malignant breast lesions. Furthermore a properly designed study will be beneficial to elucidate the cytologic and clinical characteristics of breast lesions in Ethiopian setting.