Unraveling calcium dysregulation and autoimmunity in immune mediated rippling muscle disease.

Rippling Muscle Disease (RMD) is a rare skeletal myopathy characterized by abnormal muscular excitability manifesting with wave-like muscle contractions and percussion-induced muscle mounding. Hereditary RMD is associated with caveolin-3 or cavin-1 mutations. Recently, we identified cavin 4 autoantibodies as a biomarker of immune-mediated RMD (iRMD), though the underlying disease-mechanisms remain poorly understood.

Defective excitation-contraction coupling and mitochondrial respiration precede mitochondrial Ca accumulation in spinobulbar muscular atrophy skeletal muscle.

Polyglutamine expansion in the androgen receptor (AR) causes spinobulbar muscular atrophy (SBMA). Skeletal muscle is a primary site of toxicity; however, the current understanding of the early pathological processes that occur and how they unfold during disease progression remains limited. Using transgenic and knock-in mice and patient-derived muscle biopsies, we show that SBMA mice in the presymptomatic stage develop a respiratory defect matching defective expression of genes involved in excitation-contraction coupling (ECC), altered contraction dynamics, and increased fatigue.

Familial multiple sclerosis in patients with Von Hippel-Lindau disease.

Background: Multiple sclerosis (MS) is a progressive autoimmune demyelinating disorder. Recent studies suggest that a combination of genetic susceptibility and environmental insult contributes to its pathogenesis. Many candidate genes have been discovered to modulate susceptibility for developing MS by genome wide association studies (GWAS); these include major histocompatibility complex (MHC) genes and non-MHC genes.

MEF2 impairment underlies skeletal muscle atrophy in polyglutamine disease.

Polyglutamine (polyQ) tract expansion leads to proteotoxic misfolding and drives a family of nine diseases. We study spinal and bulbar muscular atrophy (SBMA), a progressive degenerative disorder of the neuromuscular system caused by the polyQ androgen receptor (AR). Using a knock-in mouse model of SBMA, AR113Q mice, we show that E3 ubiquitin ligases which are a hallmark of the canonical muscle atrophy machinery are not induced in AR113Q muscle.

Author Correction: Hsp70 and Hsp40 inhibit an inter-domain interaction necessary for transcriptional activity in the androgen receptor.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Hsp70 and Hsp40 inhibit an inter-domain interaction necessary for transcriptional activity in the androgen receptor.

Molecular chaperones such as Hsp40 and Hsp70 hold the androgen receptor (AR) in an inactive conformation. They are released in the presence of androgens, enabling transactivation and causing the receptor to become aggregation-prone. Here we show that these molecular chaperones recognize a region of the AR N-terminal domain (NTD), including a FQNLF motif, that interacts with the AR ligand-binding domain (LBD) upon activation.

Disease Affects Expression in Synaptic and Extrasynaptic Regions of Skeletal Muscle of Three SBMA Mouse Models.

Spinal bulbar muscular atrophy (SBMA) is a slowly progressive, androgen-dependent neuromuscular disease in men that is characterized by both muscle and synaptic dysfunction. Because gene expression in muscle is heterogeneous, with synaptic myonuclei expressing genes that regulate synaptic function and extrasynaptic myonuclei expressing genes to regulate contractile function, we used quantitative PCR to compare gene expression in these two domains of muscle from three different mouse models of SBMA: the "97Q" model that ubiquitously expresses mutant human androgen receptor (AR), the 113Q knock-in (KI) model that expresses humanized mouse AR with an expanded glutamine tract, and the "myogenic" model that overexpresses wild-type rat AR only in skeletal muscle. We were particularly interested in neurotrophic factors because of their role in maintaining neuromuscular function via effects on both muscle and synaptic function, and their implicated role in SBMA.

Androgen receptor polyglutamine expansion drives age-dependent quality control defects and muscle dysfunction.

Skeletal muscle has emerged as a critical, disease-relevant target tissue in spinal and bulbar muscular atrophy, a degenerative disorder of the neuromuscular system caused by a CAG/polyglutamine (polyQ) expansion in the androgen receptor (AR) gene. Here, we used RNA-sequencing (RNA-Seq) to identify pathways that are disrupted in diseased muscle using AR113Q knockin mice. This analysis unexpectedly identified substantially diminished expression of numerous ubiquitin/proteasome pathway genes in AR113Q muscle, encoding approximately 30% of proteasome subunits and 20% of E2 ubiquitin conjugases.

The Ubiquitination, Disaggregation and Proteasomal Degradation Machineries in Polyglutamine Disease.

Polyglutamine disorders are chronic, progressive neurodegenerative diseases caused by expansion of a glutamine tract in widely expressed genes. Despite excellent models of disease, a well-documented clinical history and progression, and established genetic causes, there are no FDA approved, disease modifying treatments for these disorders. Downstream of the mutant protein, several divergent pathways of toxicity have been identified over the last several decades, supporting the idea that targeting only one of these pathways of toxicity is unlikely to robustly alleviate disease progression.

Internalized HIV/AIDS-related stigma in a sample of HIV-positive people in Bangladesh.

Internalized stigma among people living with HIV/AIDS (PLHA) is prevalent in Bangladesh. A better understanding of the effects of stigma on PLHA is required to reduce this and to minimize its harmful effects. This study employed a quantitative approach by conducting a survey with an aim to know the prevalence of internalized stigma and to identify the factors associated with internalized stigma among a sample of 238 PLHA (male=152 and female=86) in Bangladesh.