Purpose:To investigate whether the variable forms of putative iron deposition seen with susceptibility weighted imaging (SWI) will lead to a set of multiple sclerosis (MS) lesion characteristics different than that seen in conventional MR imaging. Materials and Methods:Twenty-seven clinically definite MS patients underwent brain scans using magnetic resonance imaging including: pre-and postcontrast T1-weighted imaging, T2-weighted imaging, FLAIR, and SWI at 1.5 T, 3 T, and 4 T. MS lesions were identified separately in each imaging sequence. Lesions identified in SWI were reevaluated for their iron content using the SWI filtered phase images. Results:There were a variety of new lesion characteristics identified by SWI, and these were classified into six types. A total of 75 lesions were seen only with conventional imaging, 143 only with SWI, and 204 by both. From the iron quantification measurements, a moderate linear correlation between signal intensity and iron content (phase) was established. Conclusion:The amount of iron deposition in the brain may serve as a surrogate biomarker for different MS lesion characteristics. SWI showed many lesions missed by conventional methods and six different lesion characteristics. SWI was particularly effective at recognizing the presence of iron in MS lesions and in the basal ganglia and pulvinar thalamus. MULTIPLE SCLEROSIS (MS) is an inflammatory demyelinating and neurodegenerative disease of the central nervous system (1,2). Most patients start with a relapsing-remitting course, which has a clearly defined episode of neurologic disability and recovery. The pathologic hallmark of multiple sclerosis is the demyelinated plaque, a well-demarcated hypocellular area characterized by the loss of myelin, along with axonal loss due to (3,4), and the formation of astrocytic scars. The etiologic mechanism underlying MS is generally believed to be autoimmune inflammation (5). Nevertheless, what initiates the disease and the sequence of events underlying the development of MS is not yet well established (6).Conventional magnetic resonance imaging (MRI) has been used routinely to diagnose and monitor the disease spatially and temporally. The use of conventional MRI to measure disease activity and assess effects of therapy is now standard in clinical practice and drug trials (7). T2-weighted imaging (T2WI) is highly sensitive in the detection of hyperintensities in white matter. However, hyperintensities on T2WI can correspond to a wide spectrum of pathology, ranging from edema and mild demyelination to lesions in which the neurons and supporting glial cells are replaced by glial scars or liquid necrosis (8 -14). In addition to T2WI, Gadolinium enhancement on T1-weighted imaging (T1WI) can suggest acute inflammation, which is a marker of disease It is becoming a consensus among many studies that iron is enriched within oligodendrocytes and myelin in both normal and diseased tissue (20 -23). One explanation for such findings proposes that iron is associated with the biosynthetic enzymes ...

Cells are equipped with an efficient quality control system to selectively eliminate abnormally folded and damaged proteins. Initially the cell tries to refold the unfolded proteins with the help of molecular chaperones, and failure to refold leads to their degradation by the ubiquitin proteasome system. But how this proteolytic machinery recognizes the abnormally folded proteins is poorly understood. Here, we report that E6-AP, a HECT domain family ubiquitin ligase implicated in Angelman syndrome, interacts with the substrate binding domain of Hsp70/ Hsc70 chaperones and promotes the degradation of chaperone bound substrates. The expression of E6-AP was dramatically induced under a variety of stresses, and overexpression of E6-AP was found to protect against endoplasmic reticulum stress-induced cell death. The inhibition of proteasome function not only increases the expression of E6-AP but also causes its redistribution around microtubule-organizing center, a subcellular structure for the degradation of the cytoplasmic misfolded proteins. E6-AP is also recruited to aggresomes containing the cystic fibrosis transmembrane conductance regulator or expanded polyglutamine proteins. Finally, we demonstrate that E6-AP ubiquitinates misfolded luciferase that is bound by Hsp70. Our results suggest that E6-AP functions as a cellular quality control ubiquitin ligase and, therefore, can be implicated not only in the pathogenesis of Angelman syndrome but also in the biology of neurodegenerative disorders involving protein aggregation.In the living cell both existing and newly synthesized proteins are at constant risk of misfolding and aggregation. However, cells have a surveillance system that maintains a delicate balance between protecting misfolded proteins with the help of molecular chaperones and promoting rapid and efficient clearance of the misfolded and damaged proteins by ubiquitin proteasome system (UPS) 3 (1-4). Any alteration of this homeostatic balance affects normal cellular function and cell viability. Environmental factors such as increased temperature or exposure of various chemical agents can lead to rapid build up of unfolded and damaged proteins inside the cells. Abnormally folded proteins also can be produced in cells resulting from various genetic mutations (5-9). The failure of clearance of misfolded and damaged proteins by UPS can result in the formation of potentially toxic aggregates. Once the aggregation process begins, it further disrupts the function of UPS by overloading its capacity (10). Degradation of a protein by UPS involves two distinct and successive steps; they are (a) covalent attachment of multiple molecules of ubiquitin to the target protein and (b) degradation of the targeted protein by 26 S proteasome (11). Ubiquitination is a multistep process consisting of activating (E1), conjugating (E2), and ligating (E3) enzymes. The E3 ubiquitin ligase plays a critical role in the substrate selectivity and exists with large diversity (12). However, the molecular mechanisms through which UPS s...

Angelman syndrome (AS) is a neurodevelopmental disorder caused due to deletions or loss-of-function mutations in maternally inherited UBE3A. Ube3a functions as an ubiquitin ligase as well as a transcriptional coactivator of steroid hormone receptors. However, the mechanisms by which maternal Ube3a deficiency gives rise to phenotypic features of AS are not clear. We report here that Ube3a regulates glucocorticoid receptor (GR) transactivation and GR signaling pathway is disrupted in Ube3a-maternal-deficient mice brain. The expression of several GR-dependent genes is down-regulated in multiple brain regions of Ube3a-maternal-deficient mice. AS mice show significantly higher level of blood corticosterone, selective loss of GR and reduced number of parvalbumin-positive inhibitory interneurons in their hippocampus that could ultimately lead to increased stress. These mice also exhibit increased anxiety-like behavior, which could be due to chronic stress. Altogether, our findings suggest that chronic stress due to altered GR signaling might lead to anxiety-like behavior in a mouse of model of AS.

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by abnormal expansion of glutamine repeats in the protein huntingtin. In HD brain, mutant huntingtin undergoes proteolytic processing, and its N-terminal fragment containing poly-glutamine repeats accumulate as insoluble aggregates leading to the defect in cellular protein quality control system and heat shock response (HSR). Here we demonstrate that the defective HSR in the brain is due to the down-regulation of heat shock factor 1 (HSF1) in both mice and fly models of HD. Interestingly, treatment of dexamethasone (a synthetic glucocorticoid) to HD mice or flies significantly increased the expression and transactivation of HSF1 and induction of HSR and these effects are mediated through the down-regulation of HSP90. Dexamethasone treatment also significantly decreased the aggregate load and transient recovery of HD-related behavioural phenotypes in both disease models. These results suggest that dexamethasone could be a potential therapeutic molecule for the treatment of HD and related poly-glutamine disorders.

Reversing and arresting the epidemic of HIV are a challenge for any country. Early diagnosis and rapid initiation of treatment remain a key strategy in the control of HIV. Technological advances in the form of low-cost rapid point-of-care tests have completely transformed the diagnosis and management of HIV, especially in resource limited settings, where health infrastructure is poor and timely access to medical care is a challenge. Point-of-care devices have proven to be easy to transport, operate, and maintain, and also lower-skilled staff is equally able to perform these tests as compared to trained laboratory technicians. Point-of-care tests allow rapid detection of HIV allowing for rapid initiation of therapy, monitoring of antiretroviral therapy and drug toxicity, and detection of opportunistic infections and associated illnesses.