Altered Trafficking of Mutant Connexin32

We examined the cellular localization of nine different connexin32 (Cx32) mutants associated with X-linked Charcot–Marie–Tooth disease (CMTX) in communication-incompetent mammalian cells. Cx32 mRNA was made, but little or no protein was detected in one class of mutants. In another class of mutants, Cx32 protein was detectable in the cytoplasm and at the cell surface, where it appeared as plaques and punctate staining. Cx32 immunoreactivity in a third class of mutants was restricted to the cytoplasm, where it often colocalized with the Golgi apparatus. Our studies suggest that CMTX mutations have a predominant effect on the trafficking of Cx32 protein, resulting in a potentially toxic cytoplasmic accumulation of Cx32 in these cells. These results and evidence of cytoplasmic accumulation of other mutated myelin proteins suggest that diseases affecting myelinating cells may share a common pathophysiology

Pain self-management in HIV-infected individuals with chronic pain: a qualitative study

OBJECTIVE: Chronic pain in individuals with HIV is a common, impairing condition. Behavioral interventions for chronic pain specifically tailored to this population have yet to be developed. We assert that understanding self-management strategies already used by persons living with these conditions is an essential first step, and is the objective of this investigation. DESIGN: We conducted a thematic analysis of qualitative data from 25 in-depth interviews with individuals with HIV and chronic pain. RESULTS: The primary pain self-management strategies articulated by participants were: physical activity; cognitive and spiritual strategies; spending time with family and friends and social support; avoidance of physical/social activity; medication-centric pain management; and substance use. CONCLUSIONS: Some of these strategies may be viewed as beneficial and overlap with known HIV self-management strategies (cognitive strategies), whereas others may have negative health consequences (substance use). Interventions that incorporate healthy self-management strategies may be particularly effective in improving both HIV and pain outcomes

Characterization of cellular and transgenic models of spinal and bulbar muscular atrophy

X-linked Spinal and Bulbar Muscular Atrophy (SBMA, Kennedy\u27s disease) is a slowly progressive neuromuscular disorder caused by an expanded polyglutamine repeat in the androgen receptor (AR) and characterized by a loss of motor neurons in the spinal cord and brainstem. SBMA is one of a group of progressive neurodegenerative diseases resulting from a polyglutamine repeat expansion. The disease is marked by the presence of AR-containing ubiquitinated neuronal intranuclear inclusions (NII) in motor neurons of the anterior horn of the spinal cord. We have developed cells and transgenic mice modeling aspects of SBMA to study the pathogenesis of the disease. Transgenic mice expressing a truncated form of the androgen receptor containing a highly expanded polyglutamine repeat developed gait abnormalities accompanied by the formation of ubiquitinated NII. NII sequestered molecular chaperones and CREB-binding protein. The lack of muscle and neuronal degeneration indicated that symptoms resulted from neuronal dysfunction rather than loss. This was the first mouse model expressing mutant AR to develop signs of neurological disease. We also created cellular models of SBMA using the entire AR protein. Transient expression of full-length AR was accompanied by the formation of an aberrant protein species containing portions of the amino- and carboxyl-termini of the androgen receptor. Further characterization of this AR species indicated that it forms independently of the full-length protein and is not likely a proteolytic fragment associated with SBMA pathogenesis. We went on to develop an inducible cell model of SBMA that reproduced the formation of intranuclear inclusions in the absence of the fragment species detected in transient transfection studies. PC12 cells expressing highly expanded AR formed ubiquitinated granular intranuclear inclusions containing only amino-terminal epitopes of the AR. Dihydrotestosterone treatment of mutant AR-expressing cells resulted in increased inclusion load. This cell model is the first to mimic the formation of ubiquitinated intranuclear inclusions containing the amino-terminal portion of AR observed in patient tissue and reveals a role for ligand in the pathogenesis of SBMA. This cell model system will be analyzed further to determine pathways of cellular dysfunction and to test potential therapeutics for the treatment of SBMA and other polyglutamine diseases

Characterization of cellular and transgenic models of spinal and bulbar muscular atrophy

X-linked Spinal and Bulbar Muscular Atrophy (SBMA, Kennedy\u27s disease) is a slowly progressive neuromuscular disorder caused by an expanded polyglutamine repeat in the androgen receptor (AR) and characterized by a loss of motor neurons in the spinal cord and brainstem. SBMA is one of a group of progressive neurodegenerative diseases resulting from a polyglutamine repeat expansion. The disease is marked by the presence of AR-containing ubiquitinated neuronal intranuclear inclusions (NII) in motor neurons of the anterior horn of the spinal cord. We have developed cells and transgenic mice modeling aspects of SBMA to study the pathogenesis of the disease. Transgenic mice expressing a truncated form of the androgen receptor containing a highly expanded polyglutamine repeat developed gait abnormalities accompanied by the formation of ubiquitinated NII. NII sequestered molecular chaperones and CREB-binding protein. The lack of muscle and neuronal degeneration indicated that symptoms resulted from neuronal dysfunction rather than loss. This was the first mouse model expressing mutant AR to develop signs of neurological disease. We also created cellular models of SBMA using the entire AR protein. Transient expression of full-length AR was accompanied by the formation of an aberrant protein species containing portions of the amino- and carboxyl-termini of the androgen receptor. Further characterization of this AR species indicated that it forms independently of the full-length protein and is not likely a proteolytic fragment associated with SBMA pathogenesis. We went on to develop an inducible cell model of SBMA that reproduced the formation of intranuclear inclusions in the absence of the fragment species detected in transient transfection studies. PC12 cells expressing highly expanded AR formed ubiquitinated granular intranuclear inclusions containing only amino-terminal epitopes of the AR. Dihydrotestosterone treatment of mutant AR-expressing cells resulted in increased inclusion load. This cell model is the first to mimic the formation of ubiquitinated intranuclear inclusions containing the amino-terminal portion of AR observed in patient tissue and reveals a role for ligand in the pathogenesis of SBMA. This cell model system will be analyzed further to determine pathways of cellular dysfunction and to test potential therapeutics for the treatment of SBMA and other polyglutamine diseases

‘Two Pains Together’: Patient Perspectives on Psychological Aspects of Chronic Pain while Living with HIV

Chronic pain is common in HIV-infected individuals. Understanding HIV-infected patients' chronic pain experience not just from a biological, but also from a psychological perspective, is a critical first step toward improving care for this population. Our objective was to explore HIV-infected patients' perspectives on psychological aspects of chronic pain using in-depth qualitative interviews.Investigators engaged in an iterative process of independent and group coding until theme saturation was reached.Of the 25 patients with chronic pain interviewed, 20 were male, 15 were younger than age 50, and 15 were African-American. Key themes that emerged included the close relationship between mood and pain; mood and pain in the context of living with HIV; use of alcohol/drugs to self-medicate for pain; and the challenge of receiving prescription pain medications while dealing with substance use disorders.The results suggest that psychological approaches to chronic pain treatment may be well received by HIV-infected patients