Duchenne muscular dystrophy (DMD), which is a severe disorder characterized by rapid progression of muscle weakness that ultimately leads to death, is caused by genetic mutations that result in the absence of the protein dystrophin. Loss of localization of the muscle-related molecule nNOS at the muscle cell membrane (which is known as the sarcolemma) is also observed in DMD and has been linked to muscle damage. What determines the localization of nNOS in muscle cells is not well understood. However, in a new study, Dongsheng Duan and his colleagues, at the University of Missouri, Columbia, have determined that specific regions of dystrophin anchor nNOS to the sarcolemma, providing new avenues of research for the development of DMD therapies.
In the study, analysis of mutant forms of dystrophin lacking specific regions indicated that regions known as spectrin-like repeats 16 and 17 (R16/17) were necessary for localizing nNOS to the sarcolemma. Further, treatment of a mouse model of DMD with gene therapy to introduce the region R16/17 of dystrophin restored muscle strength and exercise performance. This targeting of nNOS to the sarcolemma enabled nNOS to improve blood flow through the muscles during exercise. In an accompanying commentary, Ahlke Heydemann and Elizabeth McNally, at the University of Chicago, Chicago, indicate that in addition to providing targets for DMD, these results also "advance our understanding of exercise-induced muscle fatigue and treatment".
TITLE: Dystrophins carrying spectrin-like repeats 16 and 17 anchor nNOS to the sarcolemma and enhance exercise performance in a mouse model of muscular dystrophy
University of Missouri, Columbia, Missouri, USA.
View the PDF of this article at: https://www.the-jci.org/article.php?id=36612
TITLE: NO more muscle fatigue
University of Chicago, Chicago, Illinois, USA.
View the PDF of this article at: https://www.the-jci.org/article.php?id=38618
ONCOLOGY: New approaches to delivering siRNA anticancer therapeutic
Many researchers are working on converting a Nobel prize-winning technology known as siRNA into a therapeutic approach for treating diseases such as cancer and viral infections. siRNAs are double-stranded RNA molecules designed to suppress the expression of a specific target gene. In the setting of cancer, although siRNAs targeting specific genes critical for the growth and/or survival of a tumor have proven effective in animal models, whether the effects are mediated directly by the drugs or are mediated by an immune response to the drugs has not been clearly determined. However, Ian MacLachlan and colleagues, at Tekmira Pharmaceuticals Corp., Canada, have now developed a way in which to deliver siRNA intravenously into mice with tumors such that it inhibited tumor growth and even led to tumor cell death without inducing an immune response. In an accompanying commentary, Gunther Hartmann, at the University of Bonn, Germany, discusses the importance of these data, noting that this technical advance holds immense importance for guiding the future clinical development of siRNA as a cancer therapeutic.
TITLE: Confirming the RNAi-mediated mechanism of action of siRNA-based cancer therapeutics in mice
Tekmira Pharmaceuticals Corp., Burnaby, British Columbia, Canada.
View the PDF of this article at: https://www.the-jci.org/article.php?id=37515
TITLE: Gene silencing below the immune radar
Institute of Clinical Chemistry and Pharmacology, University of Bonn, Bonn, Germany.
View the PDF of this article at: https://www.the-jci.org/article.php?id=38475
IMMUNOLOGY: New insight into how the immune system is finely balanced in the livers of individuals chronically infected with hepatitis C virus
One group of immune cells that help control viral infections are known as T cells. However, it is important to keep these cells under control, as overly vigorous T cell responses can lead to tissue damage, which has potentially serious health consequences. Vincenzo Barnaba and colleagues, at Sapienza Università di Roma, Italy, have now provided new insight into the regulation of cells known as Tregs, which control the balance between an adequate antiviral immune response and suppression of tissue damage, in the livers of patients chronically infected with hepatitis C virus (HCV). In an accompanying commentary, Arash Grakoui and colleagues, at Emory University School of Medicine, Atlanta, discuss the clinical importance of these data.
In the study, although Tregs were found to accumulate at sites of infection in the livers of patients chronically infected with HCV, they were substantially fewer in number and proliferated less than effector T cells (the cells that control the viral infection). The level of expression of the protein PD-1 on Tregs inversely correlated with both their ability to proliferate and clinical markers of immune suppression in vivo. In vitro analysis indicated that blocking the interaction between PD-1 and PD-L1 enhanced the proliferation and suppressive function of Tregs from the livers of patients chronically infected with HCV, indicating that PD-L1 negatively regulates Tregs at sites of chronic inflammation. Further analysis provided evidence of the mechanism underlying this: PD-L1 downregulates STAT-5 phosphorylation.
TITLE: PD-L1 negatively regulates CD4+CD25+Foxp3+ Tregs by limiting STAT-5 phosphorylation in patients chronically infected with HCV
Sapienza Università di Roma, Rome, Italy.
View the PDF of this article at: https://www.the-jci.org/article.php?id=36604
TITLE: PD-1 tempers Tregs in chronic HCV infection
Emory University School of Medicine, Atlanta, Georgia, USA.
View the PDF of this article at: https://www.the-jci.org/article.php?id=38661
NEUROBIOLOGY: Protein complex linked to Parkinson disease
Mutations in the genes PINK1, PARKIN, and DJ-1 have each been linked to early-onset inherited forms of Parkinson disease. However, the functional relationship between the proteins generated by these genes and how the mutations lead to Parkinson disease are not well understood. Now, Zhuohua Zhang and colleagues, at the Burnham Institute for Medical Research, La Jolla, have determined that the proteins generated by these genes form a complex in neuroblastoma cells and human brain lysates. Further analysis indicated the function of this complex and how this is impaired by mutant forms of the proteins associated with Parkinson disease.
In the study, the Parkin/PINK1/DJ-1 complex was shown to control the degradation of certain proteins (including Parkin itself) in neuroblastoma cells and human brain lysates. If the complex contained the mutant forms of either PINK1 or Parkin associated with Parkinson disease, its ability to degrade proteins was dramatically reduced. The authors therefore suggest that the proteins generated by the three Parkinson disease-associated genes PINK1, PARKIN, and DJ-1 function in a common pathway and that dysfunction in this pathway might underlie the development of Parkinson disease in individuals with mutations in these genes.
In an accompanying commentary, Han Li and Ming Guo, at the David Geffen School of Medicine and Molecular Biology Institute, Los Angeles, put these data in context with other studies indicating additional roles for PINK1 and PARKIN.
TITLE: Parkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex promoting unfolded protein degradation
Burnham Institute for Medical Research, La Jolla, California, USA.
View the PDF of this article at: https://www.the-jci.org/article.php?id=37617
TITLE: Protein degradation in Parkinson disease revisited: it's complex
David Geffen School of Medicine and Molecular Biology Institute, University of California, Los Angeles, Los Angeles, California, USA.
View the PDF of this article at: https://www.the-jci.org/article.php?id=38619
Source: Karen Honey
Journal of Clinical Investigation