Commonly used asthma medications appear to regulate epigenetic mechanisms and may be associated with decreased risk for Parkinson’s disease

Arrows indicate Lew bodies, arrowheads, Lewy neuritesIn an interesting new study, β2-adrenoreceptor ligands were found to regulate the α-synuclein gene (SNCA) via epigenetic mechanisms [1].  Further, prolonged use of the asmtha medication salbutamol, which is a β2-adrenoreceptor agonist, was linked to reduced risk associated with Parkinson’s disease [1]. Results from the study demonstrated that the β2-adrenoreceptor regulates histone H3 acetylation and DNA replication in the cell, controlling the amount of α-synuclein [1,2]. Lewy bodies, one of the neural hallmarks of Parkinson’s, are protein aggregates mainly formed from α-synuclein. Lewy bodies are connected to the death of neuronal cells as they are mainly found in brain areas where the most severe neuronal loss is seen [3]. Thus decreasing the amount of α-synuclein in neuronal cells is thought be one way to potentially prevent Parkinson's disease.

After a compound screen, the researchers identified four that reduced SNCA gene activity in human cells and further tests showed that β2-adrenoreceptor agonists led to reduced H3 acetylation, SNCA expression, and the amount of α-synuclein in both cell culture and in animal studies [1]. These results prompted researchers ask whether β2-adrenoreceptor agonist or antagonist medications might influence the prevalence of Parkinson’s disease. By studying the medical records of nearly 5 million Norwegians, they found that those with long term use of salbutamol for their asthma, had lower risk of Parkinson’s, whereas people using propranolol for heart conditions appeared to have increased risk [1]. These findings suggest that the β2-adrenoreceptor may play a role in Parkinson’s disease and opens new doors for Parkinson’s disease research. Perhaps in the future Parkinson’s could be treated, or even pre-treated using epigenetic drugs.




[1] Mittal S, Bjørnevik K, Im DS, Flierl A, Dong X, Locascio JJ, Abo KM, Long E, Jin M, Xu B, Xiang YK, Rochet JC, Engeland A, Rizzu P, Heutink P, Bartels T, Selkoe DJ, Caldarone BJ, Glicksman MA, Khurana V, Schüle B, Park DS, Riise T, Scherzer CR: β2-Adrenoreceptor is a regulator of the α-synuclein gene driving risk of Parkinson's disease. Science. 2017;357(6354):891-98

[2] Bannister AJ, Kouzarides T: Regulation of chromatin by histone modifications. Cell Res. 2011;21(3):381-95

[3] Michael J. Fox Foundation for Parkinson’s Research: Alpha-synuclein and Parkinson's Disease.

Image: Ingelsson M (2016) Alpha-Synuclein Oligomers—Neurotoxic Molecules in Parkinson's Disease and Other Lewy Body Disorders. Front. Neurosci. 10:408. doi: 10.3389/fnins.2016.00408


Not so fun facts about psychiatry...

Out of all the medical disciplines psychiatry may arguably have the worst reputation. Unfortunately, this view is not entirely undeserved; the first two Nobel Prizes awarded to psychiatrists were for the discovery that infecting patients with malaria - a form of pyrotherapy - could cure certain psychotic disorders (a consequence of syphilis, and the induced fevers either killed the pathogen - or the patient) and the invention of lobotomy, in which lesioning neural connections, or basically, scraping out pieces of the frontal lobes, made aggressive patients complacent. While much easier to manage afterwards, these patients also lacked any recognizable personality. In all fairness, while these approaches were both literal and metaphorical stabs into the dark, unknown realm of mental illness, terrible treatments such as pyrotherapy and lobotomy were the only alternatives to a lifetime shuttered away in an asylum.  Unfortunately, these institutions were often overcrowded, typically poorly maintained psychiatric hospitals with the main purpose of preventing patients from doing damage to themselves or society because no cures were available.

It is until the middle of the last century that Freud’s legacy firmly controlled the discipline of psychiatry in the United States. It was a widely held belief that all psychiatric illness stemmed from unresolved conflicts of the subconscious that simply needed to be uncovered and discussed to resolve the condition.  Though a neurologist by training, Freud’s approach was not based on biological data but rather on the interpretation of patient case studies fueled by theoretical considerations, many of which when judged by today’s standards appear to be based upon idiosyncratic convictions. For example, today we know that autism is not caused by “frigid mothers” and schizophrenia is not a consequence of obscure inner conflicts.

Initial attempts to classify neuropsychiatric illness in the United States grew out of the 1840 census.  The first Diagnostic and Statistical Manual (DSM) was a medical document which emerged from the assessment of soldiers during World War II. While some biological aspects of mental illness had been considered by this time, a major step forward was the development of the DSM-III, the first guidebook to facilitate the diagnosis of psychiatric illness in a systematic way, based on data rather than on purely Kraepelinian views or Freudian anecdotes. DSM-III was published in 1980(!) as a response to public frustration over inconsistent diagnoses and treatments in psychiatry. The practitioners realized that in order to maintain public trust in psychiatry, insurance coverage for psychiatric procedures, and to find actual cures for devastating illnesses such as depression, bipolar disorder and schizophrenia, a data-based approach was indispensable.

Now, almost 40 years and two DSM versions later, we have a variety of psychopharmacological treatment options. We have also realized that neither pharmacological treatment nor psychotherapy alone can solve the big problems in neuropsychiatric illness, and that combined, these approaches are only a small step towards actually understanding and curing the most devastating disorders. Even with our most advanced neuroimaging technology it is still painstakingly difficult to advance our knowledge. But, taking the history of treatment into perspective along with our evolving  understanding of mental illness, at least we no longer infect patients with malaria or blindly poke around in the frontal lobes of patients suffering from psychoses. We are still a long way from general, reliable solutions but psychiatric illness is no longer a life sentence to an asylum.



Sources/Further Reading:

Lieberman, J., Ogas, O., (2015). Shrinks: the Untold Story of Psychiatry. London: Weidenfeld and Nicolson.

Jamison, Kay Redfield, (1995). An Unquiet Mind. New York: Knopf.

Decker, Hannah, (2013). The making of DSM-III. Oxford: Oxford University Press.

Schematic of a transorbital lobotomy:



First-in-Human: the moment research turns to medicine

 If you have not been watching the recent three-part series on the Discovery channel entitled “First-in-human,” I highly recommend checking it out. As a medical researcher who works in a translational lab, it is both refreshing and inspiring to get a glimpse into the moment where all of the basic research and development translates into a treatment for human disease. The documentary, which is targeted for a wide audience, provides rare insight into this critical first stage of drug development when a drug is first put into a human body, and includes the point of view of clinicians, researchers, and patients.

Three patients are introduced in the first episode who each have been left with little to no treatment options for their incurable diseases, two of which are types of cancer. Each patient has traveled to the hospital in building 10 at the NIH, which houses labs and clinical treatment facilities to support bench-to-bedside, first-in-human clinical trials. While these patients are quite sick, their remarkable courage is apparent as they listen to the doctor explain the risks and unknowns associated with taking part in a first-in-human study. The episode then offers an intimate portrait of how dynamic and emotional this first drug treatment can be for both the clinicians and the family members present, with the patient’s desire to maximize the potential for treatment success battling with the clinician’s oath to keep the patient out of unnecessary harm. This humanization of the scientific process of drug development was eye opening. As researchers, it is easy to hyper focus on the data and the statistics of drug success, so it is important to see the other side of the development process.

In addition to portraying the patient/clinician experience in a first-in-human trial, the documentary highlighted two novel immuno-oncology treatments, CAR-T (chimeric antigen receptor) therapy and TILS (tumor infiltrating lymphocytes). Both of these new technologies utilize the patient’s own immune cells to fight their cancer using a true bench-to-bedside technique. In CAR-T therapy, blood cells are harvested from a patient (in the documentary, the patient has relapsing leukemia), engineered and grown in the lab to recognize a target specifically expressed on leukemia cells, CD22, and then reintroduced into the patient’s body to attack the leukemia. Similarly, TIL therapy works by extracting a tumor from a patient’s body, slicing up the tumor and amplifying the endogenous immune cells already working to fight the tumor (lymphocytes), and reintroducing the immune cells back into the body to fight the cancer. Both of these therapeutic mechanisms amplify the patients’ own immune system responses to tackle the malignancy in their bodies. There is a unique aspect compared to small molecule treatments as these therapeutics require a concerted effort between the lab and the clinicians to develop a patient-specific treatment that will be successful.

It is no small feat to drive these types of projects forward in medicine, and it takes the researchers, clinicians, families, and patients to succeed.



Watch full episodes of First in Human here


Gut Instinct

Anatomy of a pycnogonid: A: head; B: thorax; C: abdomen 1: proboscis; 2: chelifores; 3: palps; 4: ovigers; 5: egg sacs; 6a–6d: four pairs of legsWhen an animal is all legs and almost no body, questions abound - and one question in particular springs to mind - where do they keep all their essential biological parts? Most mammals have plenty of internal space for the heart, lungs, and gastrointestinal organs. Not so for sea spiders! Some species are as large as a dinner plate (i.e., Antarctic sea spiders), with legs-for-days, but others have a tiny “torso” that is basically an attachment site for legs. So, how do they manage to reproduce or circulate blood, not to mention, process their food?

Sea spiders manage these important functions with their long legs. Interestingly, females grow ovaries on their legs and release them through pores. During mating, the male climbs over the female to fertilize her eggs and then carries them until they hatch. Similar to seahorses, male sea spiders carry their offspring until birth –and while the male seahorse swims away soon after - male sea spider cares for the young after they are born!

Not only are sea spiders’ reproductive organs located in their legs, but so are their guts. The distance between the mouth and anus is so small that the intestines reach down each leg so that food can be adequately processed. The guts contract to move food along just like our intestines do.

Sea spiders do not have any respiratory organs, instead, they receive oxygen through passive diffusion across their 4-6 pairs of legs. But because these pycnogonids can become so large, scientists wondered how they get the amount of oxygen they need to survive. Larger animals need to get plenty of oxygen into their bloodstreams and need to be able to pump that blood around their bodies. Passive diffusion might be fine in a small body, but Atlantic sea spiders tip the scale for size. Drs. Amy Moran and Arthur Woods, of the University of Hawaii at Manoa, recently discovered that sea spider hearts are not large enough to efficiently pump blood throughout their whole body. Instead, they circulate blood using their guts!

Each leg contains blood vessels as well as intestines, so as food is processed, blood is also circulated through the legs and into the body. However, the legs of a sea spider are not expandable, so, when digestive fluid is pushed in one direction, it forces blood to flow in the opposite direction. After oxygen diffuses in the legs, it travels to the creature’s body cavity through contractions of the guts. Once the blood reaches the body cavity, the heart is then able to circulate it around the body and head.

Sea spiders are able to live without having a specialized system for pumping blood because they effectively use their legs as gills and their guts as hearts – a gut check for all of us – we are not the only complicated creatures on the planet!  




Woods, H. Arthur, Lane, Steven J., Shishido, Caitlin, Tobalske, Bret, Arango, Claudia P., Moran, Amy L. 2017. Respiratory gut peristalsis by sea spiders. Current Biology, Volume 27, Issue 13, R638 - R639

External anatomy of Nymphon sea spider. After G. O. Sars (1895).


Neural activity may differ between males and females with Adolescent Major Depressive Disorder

In a recent study, evidence of a sex difference in neural activation during a cognitive task was demonstrated in relation to adolescent major depressive disorder (MDD), with a novel focus on males [1]. There are differences between men and women in symptom presentation in MDD, and men are more likely to experience persistent, and women, recurrent, forms of depression [2]. By the age of 15, girls are two times as likely to experience depression compared to their male counterparts [3], whereas in adulthood, men are more likely to become suicidal [4].     

A recent study published in Frontiers in Psychiatry investigated depression in male and female adolescents between the ages of 11 and 17 [1]. Cognitive control of emotion, which also appears to differ between males and females, was tested using functional magnetic resonance imaging (fMRI) during an affective Go/No-Go task [1]. The participants’ responses to happy, sad or neutral words were measured during image acquisition. Neural activity in response to the sad words differed in the supramarginal gyrus in adolescent males compared to females [1]. Interestingly, depressed adolescent males showed decreased cerebellar activation and an age related decrease in its connectivity with the superior frontal gyrus compared to healthy adolescent males [1].

A number of brain regions found to be affected in adolescent males are involved in the default mode network, which is of interest as this network may be involved in the decline in cognition that occurs in MDD [5]. In light of sex differences related to MDD, the results of this study suggest that preventative and therapeutic interventions may be improved if neural differences are taken into consideration. It remains unknown whether developmental neural changes are involved in the etiology of this illness. As an important caveat, the study did encounter issues with enrollment, as fewer males participated compared to females, highlighting the need for matched sample sizes in future studies.



[1] Chuang J-Y, Hagan CC, Murray GK, Graham JME, Ooi C, Tait R, Holt RJ, Elliott R, van Nieuwenhuizen AO, Bullmore ET, Lennox BR, Sahakian BJ, Goodyer IM and Suckling J (2017) Adolescent Major Depressive Disorder: Neuroimaging Evidence of Sex Difference during an Affective Go/No-Go Task. Front. Psychiatry 8:119. doi: 10.3389/fpsyt.2017.00119


[2] Dunn V, Goodyer IM. Longitudinal investigation into childhood- and adolescence-onset depression: psychiatric outcome in early adulthood. Br J Psychiatry (2006) 188:216–22.


[3] Cyranowski JM, Frank E, Young E, Shear MK. Adolescent onset of the gender difference in lifetime rates of major depression: a theoretical model. Arch Gen Psychiatry (2000) 57(1):21–7.


[4] Blair-West GW, Cantor CH, Mellsop GW, Eveson-Annan ML. Lifetime suicide risk in major depression: sex and age determinants.  J Affect Disord. 1999 Oct: 55 (2-3): 171-8.