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STAT

An MUSC blog
Date: Mar 16, 2016

Photograph of veteran on tranIn an article published in the March 2016 issue of the Journal of Anxiety Disorders, investigators in the Department of Psychiatry and Behavioral Sciences at the Medical University of South Carolina (MUSC) report that veterans who fall just below the threshold for a diagnosis of post-traumatic stress disorder (PTSD) respond to a psychotherapy regimen better than those with full PTSD. The study highlights the need to recognize veterans suffering from an overlooked condition called subclinical PTSD. “The study shows not only that we can treat those experiencing subclinical presentations of PTSD, but also that those with subclinical PTSD may actually respond better to treatment than those with more severe forms of the disease,” says MUSC investigator Kristina Korte, Ph.D., who is the first author on the article. MUSC co-authors include Ron Acierno, Ph.D., Daniel F. Gros, Ph.D., and Nicholas P. Allan, MS.

Just like patients with full PTSD, those with subclinical PTSD have experienced a traumatic event and are regularly re-experiencing it, often in nightmares or flashbacks. Patients with full PTSD also experience hyperarousal (i.e., they are easily startled) and avoid reminders of the event, for example by withdrawing from social interaction or turning to substance abuse. In addition re-experiencing the event, patients with subclinical PTSD may exhibit either hyperarousal or avoidance, but not both.

Psychologists began noticing this pattern more frequently in the nineties in veterans returning from the first Iraq War, and even more frequently in veterans returning from Iraq and Afghanistan in the last decade. As researchers have learned more about these patients over time, varying and sometimes conflicting symptoms have provided an incomplete picture of the disorder and how to treat it. Further confounding the issue is that those with subclinical PTSD are often excluded from clinical trials testing treatments for PTSD—patients with only some symptoms of PTSD commonly aren’t included in the healthy control group or in the group with full PTSD. As a result, there is still no standard psychotherapy for treating subclinical PTSD as there is for full PTSD.

The researchers devised an intuitive approach—Why not treat subclinical PTSD patients with one of the standard evidence-based psychotherapy tools already being used in PTSD patients? They enrolled 200 patients with combat-related PTSD symptoms from the Ralph H. Johnson VA Medical Center located adjacent to MUSC, identifying those with either subclinical or full PTSD. For eight weeks, patients received intensive weekly sessions of behavioral activation and therapeutic exposure therapy, designed to lessen their PTSD symptoms by helping them safely re-experience and resolve elements of the original trauma. Psychologists rated the patients’ PTSD symptoms and had patients rate their own symptoms before, during, and after the eight weeks.

The results were encouraging. Those with subclinical or full PTSD each experienced a real drop in PTSD symptoms after treatment. The striking result was in how much those symptoms dropped: 29% in those with subclinical PTSD as compared to 14% with full PTSD.

It may seem obvious that patients with a less severe form of PTSD would respond better to standard psychotherapy, but the implications for treatment extend beyond that. PTSD symptoms often worsen over time; as they do, treatments become less effective at reducing symptoms. In this context, subclinical PTSD could be seen as “early-stage” PTSD, in that treatment might be more effective when the disorder is caught early.

Gros’ group hopes these early studies can move beyond men in combat to civilians of both sexes.

“It is our hope that providing treatment for subclinical PTSD could have a significant impact on the cost-effectiveness of treating this common disorder,” says Korte. “It could lead to the prevention of more intractable forms of PTSD that can occur when subclinical PTSD goes untreated.”

Image Caption:  Licensed from iStock. Copyright: Mie Ahmt.

Aberrant phenotypes in zebrafish after Tuba knockdown

Image Caption: Aberrant phenotypes resulting from Tuba knockdown in zebrafish. Image courtesy of Dr. Joshua Lipschutz.

Summary: Zebrafish help investigators at the Medical University of South Carolina shed light on the mechanisms underlying cilia dysfunction in polycystic kidney disease and other ciliopathies

In an article published online ahead of print on February 19, 2015 in the Journal of Biological Chemistry (JBC), investigators at the Medical University of South Carolina (MUSC) and the Ralph H. Johnson VA Medical Center report findings from in vitro and in vivo studies that elucidate the mechanisms underlying the impaired ciliogenesis and abnormal kidney development characteristic of polycystic kidney disease (PKD). Depletion of dynamin-binding protein or Tuba, a guanine nucleotide exchange factor, disrupted renal ciliogenesis in cell culture and led to abnormal kidney morphology in a Tuba knockdown zebrafish model of PKD.

Currently, no drug has been approved by the U.S. Food and Drug Administration to treat autosomal dominant PKD, which affects a half million Americans and more than 12 million people worldwide. The disease is characterized by the development of fluid-filled cysts in both kidneys, leading to end-stage renal disease, usually around age 50 to 60. In PKD, it is speculated that dysfunctional cilia are unable to detect the presence of urine flow, triggering reactivation of developmental pathways, which lead to the uncontrolled production of cysts that eventually destroy the kidney.

Cilia, the finger-like protrusions on most epithelial cells, were not so long ago thought to be as irrelevant to cell biology as the appendix is to physiology, a vestigial remnant of a long ago evolutionary past.  Today, they are recognized as essential chemo-mechanical sensors that monitor and regulate what crosses into and out of a cell. Dysfunctional cilia are now known to be implicated in not only PKD but a wide range of diseases affecting the eyes, ears, heart, and other organs. Understanding how cilia become dysfunctional in these diseases could provide insight into how to better treat or prevent them.  

“How are cilia made? If you know that, you can figure out what goes wrong in ciliopathies, including polycystic kidney disease,” says nephrologist Joshua H. Lipschutz, M.D., the senior author on the article, who holds a dual appointment at MUSC and the Ralph H. Johnson VA Medical Center. 

Much must go right for ciliogenesis to occur. Proteins necessary for ciliogenesis are manufactured in the endoplasmic reticulum before traveling to the trans-Golgi network to be sorted into “zip-coded packages” or vesicles for transport to the cilia. Lipschutz and others previously showed that the exocyst, a protein targeting complex, plays a crucial role in receiving these “zip-coded packages” containing ciliary proteins.  The GTPase Cdc42 regulates the exocyst, which is the mailbox where these “packages” are received in the kidney.  Renal ciliogenesis occurs only when the packaged proteins are delivered to the Cdc42-activated exocyst complex. Depleting either the exocyst or Cdc42 disrupts renal ciliogenesis.

In the JBC article, Lipschutz and his MUSC coauthors go a step further—showing in cell culture and a zebrafish model that depletion of Tuba, a guanine nucleotide exchange factor required for Cdc42 activation, also disrupts renal ciliogenesis. Tuba is thought to ensure that the Cdc42/exocyst mailbox is in place at the base of the cilia and ready to receive the packaged proteins. Without Tuba, Cdc42 is not appropriately activated, and the exocyst is mislocalized, so the undelivered packages continue to pile up, perhaps playing a role in the uncontrolled production of renal cysts in PKD.

When grown in a collagen gel, Madin-Darby canine kidney (MDCK) cells form into cysts, and the orientation of proteins, called polarity, are abnormal following Tuba knockdown.  Specifically, apical proteins that would normally face the urinary space are mislocalized throughout the cell. 

In zebrafish, injection of low doses of both Tuba and Cdc42 antisense morpholinos, which had no effect when administered separately, led to severe phenotypes similar to those seen following knockdown of other ciliary proteins. This is called genetic synergy and provides further evidence that both Tuba and Cdc42 are part of the same pathway. Because knockdown of Tuba in zebrafish affects cilia in a number of organs, including the brain, a variety of aberrant phenotypes were seen in the Tuba knockdown zebrafish model.

Lipschutz, who directs the zebrafish core at MUSC along with co-author Seok-Hyung Kim, Ph.D., is well aware of the advantages of the zebrafish for research—its genome is well characterized, it can be bred rapidly and inexpensively, and its transparent body enables easy visualization of aberrations under microscopy. However, the next step in this line of research will be to study the effects of Tuba depletion in the kidneys of mice, since murine kidneys are more like human kidneys than those of zebrafish.

Once the pathways underlying impaired ciliogenesis in PKD are more fully understood, therapeutic interventions can be designed to disrupt those pathways.  As Lipschutz notes, “We do this research to help our patients. Further elucidating the pathways that underlie impaired ciliogenesis is an essential step in beginning to develop treatment options for PKD and other ciliopathies.”

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