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News From The Journal Of Clinical Investigation: October 8, 2012

Synaptic protein linked to Levodopa-induced dyskinesia

Dopamine replacement is a standard treatment for Parkinson’s disease; however, one of the side effects is a movement disorder known as Levodopa-induced dyskinesia (LID). In a study published in the Journal of Clinical Investigation, Erwan Bezard and colleagues at the University of Bordeaux found that the protein PSD-95, which which organizes proteins at neuronal synapses, was overexpressed in monkeys with LID. PSD-95 determines the cellular localization of the D1 dopamine receptor (D1R) and excess PSD-95 altered dopamine signaling to induce LID symptoms . By disrupting the interaction between D1R and PSD-95, Bezard and colleauges were able to improve LID symptoms in rats and monkeys. Imaging studies revealed that loss of PSD-95 reduced the amount of D1R at the synapse. These studies suggest that PSD-95 may be a suitable therapeutic target to ameliorate a major side effect of Parkinson’s disease treatment.

TITLE: PSD-95 expression controls L-dopa dyskinesia through Dopamine D1 receptor trafficking


Researchers elucidate role of progranulin in frontotemporal dementia

Loss of one copy of the gene that codes for the protein progranulin (PGRN) is a major cause of frontotemporal dementia; however, the mechanism by which loss of PGRN causes neurodegeneration is unknown. In a study published in the Journal of Clinical Investigation, researchers led by Robert Farese at the University of California, San Francisco, demonstrated that loss of PGRN increased neuron loss in response to CNS injury in mice. PGRN was required to attenuate the post-injury inflammatory response that causes neuronal damage. These findings suggest that PGRN deficiency may contribute to increased neural inflammation and subsequent neurodegeneration.

TITLE: Progranulin deficiency promotes neuroinflammation and neuron loss following toxin-induced injury


Defining the pathogenesis of spinocerebellar ataxia

Spinocerebellar ataxia 28 (SCA28) is an inherited neuropathy characterized by a lack of muscle coordination affecting the limbs and the muscles that control the eyes. Mutations in the AFG3L2 gene have been linked to SCA28, but the pathogenic mechanism is undefined. In a study published in the Journal of Clinical Investigation, researchers led by Elena Rugarli at the University of Cologne found that AFG3L2 was required for the survival of Purkinje cells, which are involved in the coordination of movement. Using AFG3L2-mutant mice, Rugarli and colleagues demonstrated that Purkinje cells expressing mutant AFG3L2 had defects in mitochondrial protein synthesis that eventually killed the cells, leading to neurodegeneration and the movement disorder that characterizes SCA28.

TITLE: AFG3L2 supports mitochondrial protein synthesis and Purkinje cell survival


Hedgehog signaling is associated with poor clinical outcome in intermediate risk prostate cancer

Prostate cancer patients are classified into low, intermediate, and high-risk groups that reflect relative survival categories. While there are accepted treatment regimens for low and high-risk patients, intermediate risk patients pose a clinical dilemma, as treatment outcomes are highly variable for these individuals. In this issue of the Journal of Clinical Investigation, Ruth Muschel and colleagues at the University of Oxford identified the protein PN1 as a negative regulator of the oncogenic Hedgehog signaling pathway in prostate cancer. In a mouse model of prostate cancer, increased expression of PN1 inhibited tumor growth. Further, comparisons of tumor tissue from human prostate cancer patients showed that genetic alterations in Hedgehog pathway regulators correlated with worse clinical outcomes in intermediate risk patients.

TITLE: Protease Nexin 1 inhibits hedgehog signaling in prostate adenocarcinoma


MicroRNA-155 influences atherosclerotic plaque formation

Atherosclerosis causes the thickening and hardening of the arteries. Macrophages participate in the formation of atherosclerotic plaques by driving inflammatory responses, accumulating LDL, and releasing factors that influence the behavior of cells within the plaque. MicroRNAs (miRs) control the activity of macrophages by regulating gene expression, but the exact roles of different miRs remain undefined. In a study published in the Journal of Clinical Investigation, Andreas Schober and colleagues at Ludwig Maximilians University in Munich, Germany report that miR-155 is induced by LDL and inflammatory factors in macrophages. Expression of miR-155 in macrophages reduced atherosclerotic plaque formation in mice by repressing the transcription factor Bcl6, which attenuates inflammatory signaling pathways. This study demonstrates that miR-155 plays a key role in macrophage-mediated vascular inflammation in atherosclerosis.

TITLE: MicroRNA-155 promotes atherosclerosis by repressing Bcl6 in macrophages


A new model of Shiga toxin-producing E. coli infection

Shiga toxin-producing E. coli (STEC) have been implicated in multiple outbreaks of food-borne illness and can cause intestinal and systemic disease, including severe renal damage. Upon attachment to the intestine, STEC generate lesions that allow the shiga toxin to cross the intestinal wall and enter the blood stream. Current mouse models of STEC do not accurately reflect this aspect of the human disease and the molecular mechanisms that allow the Shiga toxin to enter the blood stream are undefined. In a study published in the Journal of Clinical Investigation, John Leong and colleagues at Tufts University developed a mouse model of STEC infection that replicated the intestinal damage seen in the human disease. This new model will serve as a platform to determine how STEC crosses the intestinal wall to cause systemic disease.

TITLE: A novel murine infection model for Shiga toxin-producing Escherichia coli


Viral antigen cross-presentation protects dendritic cells from infection

Dendritic cells (DC) are gatekeepers that patrol the body, looking for signs of infection. Once they find a virus, they sample a bit of the virus and present the viral antigens to T cells, which are responsible for finding and killing infected cells. The role of DC antigen cross-presentation in the induction of anti-viral cytotoxic T cells is not entirely clear. In a study published in the Journal of Clinical Investigation, researchers led by Miriam Merad at Mount Sinai Medical School used a recombinant, fluorescent influenza virus to visualize antigen presentation of DC cells in the lungs of mice infected with influenza. They found that a specific subset of DC cells (CD103+) carried fluorescent virus to the lymph nodes, where they induced virus-specific T cells. Additionally, cross-presenting DCs were protected from viral infection.

TITLE: Cross-presenting CD103+ dendritic cells are protected from influenza virus infection


Endotrophin links obesity to breast cancer progression

Fat cells (adipocytes) surround breast tumors and contribute to tumor growth by expressing factors that aid oncogenesis. Col6 is a protein that is highly expressed in adipocytes and its expression is further increased in both obesity and in breast cancer cells. In this issue of the Journal of Clinical Investigation, Phillip Scherer and Jiyoung Park of the University of Texas Southwestern Medical Center report that a portion of the Col6 protein, known as endotrophin, alters the tumor environment to promote tumor growth and metastasis in mice. Mice with reduced endotrophin expression had significantly less tumor burden and fewer metastases. These findings link obesity and cancer progression and suggest that endotrophin may serve as novel therapeutic target in the treatment of breast cancer.

TITLE: Endotrophin links obesity to breast cancer progression



Journal of Clinical Investigation