Tuesday
May312016

Girls with Autism Spectrum Disorder

According to the CDC, 4.5 times more boys are diagnosed with Autism Spectrum Disorder (ASD) than girls [1].

It is currently unknown if this is the result of a biological protection for the female sex or a diagnostic bias created by tools developed mostly by studying boys with ASD.

What is known is that girls need to have more severe symptoms in addition to their autistic traits in order to be diagnosed compared to boys with same level of autistic traits. [2] Genetic research has shown that compared to boys they need to have higher genetic burden (more mutations) before being diagnosed [2]. Girls may also be getting other diagnoses, such as attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD) or even anorexia instead of an ASD diagnosis. It has been proposed that the clinical phenotype may be different, with girls for example being better able to camouflage their symptoms. [3] 

Brain activation observed in socio-cognitive tasks may be different in girls and boys with ASD. Indeed, a candidate social cognition biomarker (assessed with fMRI) showed promising results in boys but not in girls. [4] Gender may need to be taken into consideration when searching for individual-level neuroimaging-based ASD biomarkers.

 N.Z.

[1] CDC. “Prevalence of autism spectrum disorders among children aged 8 years: autism and developmental disabilities monitoring network, 11 sites, United States, 2010.” MMWR Surveillance Summaries 63(2): 1–22. (2014)

[2] Dworzynski, Katharina, et al. "How different are girls and boys above and below the diagnostic threshold for autism spectrum disorders?." Journal of the American Academy of Child & Adolescent Psychiatry 51.8: 788-797. (2012)

[2] Jacquemont, Sébastien, et al. "A higher mutational burden in females supports a “female protective model” in neurodevelopmental disorders." The American Journal of Human Genetics 94.3: 415-425. (2014)

[3] Szalavitz Maia. “Autism – It’s different in girls.” Scientific American (2016).

[4] Björnsdotter, Malin, et al. "Evaluation of Quantified Social Perception Circuit Activity as a Neurobiological Marker of Autism Spectrum Disorder." JAMA psychiatry (2016).

 

Thursday
May052016

Prion-like proteins help guide plants to know when to bloom

With flowers blooming and plants finally producing their first leaves of the season, it can make one ask the following: how do plants know when to bloom? Scientists at the Whitehead Institute of Biomedical Research may have a lead on this question.  While studying Arabidopsis thaliana, they identified over 500 proteins in the species that have potential prion-like domains (PrDs). Of all of these proteins, Luminidependens PrD was one of the proteins that had traits similar to prions and could play a role in the plant’s response and memory with regards to seasonal environmental changes.

Prion proteins are thought to give a unique ability of biochemical memory, which has been studied in both mammals and fungi. Before the researchers at Whitehead discovered the Luminidependens PrD, there had been no known prions that existed in a plant model. When this protein was tested in a yeast model, it displayed all the functions of the yeast prion Sup35, which has been extensively studied. This PrD formed higher-order oligomers, which is similar to the function of prions in the yeast model.

 

The conformational switches that prions catalyze can lead to a variety of different outcomes. These scientists believe that in plants, the prions can aide in the response to seasonal changes and events, such as flowering every spring. The ability for plants to have a “memory,” from year to year is thought to be possible through the use of prions.  From season to season, plants will respond and regulate themselves differently based on their past experiences. Based on the researchers’ findings, these conformational changes in the proteins seem to be evolutionarily conserved and according to the researchers, could extend beyond the flowering and into different biological processes as well.

 

Chakrabortee, Sohini, et al. "Luminidependens (LD) is an Arabidopsis protein with prion behavior." Proceedings of the National Academy of Sciences (2016): 201604478.

Friday
Apr222016

The Emergence of Patient-centered outcomes in guiding clinical care

Last week, I had the opportunity to attend an educational forum offered by MassBio entitled “Communicating Clinical Benefit: The Role of Patient-Centered Measures” that opened my eyes to the importance of patient-reported outcomes (PRO) in improving clinical care. For those who are unfamiliar, PRO research aims to develop assessment tools that can be used to capture a patient’s self-reporting of health and quality of life. The assessment tools are often in the form of a questionnaire or interview asking patients directly about their symptoms, functioning, and overall mental state as they pertain to disease and/or treatment. These data are different from physiological measurements and investigator-reported measurements, which objectively measure and observe the patient’s biology. By creating standardized, reproducible methods to record reports from patients, these tools permit a more objective way to characterize the patients’ experience. Patient-centered tests obviously require thorough validation before FDA approval for use, as potential primary or secondary endpoints in clinical trials.

The compiled outcome data from these studies provides relevant guidance for patients in evaluating their care options and understanding the treatment-associated risks. In addition, these data offer insight for payers as to which clinical benefits are most meaningful to the patient, which in turn can help assign a monetary value to a particular therapy. The information generated in such studies may also be used to support labeling on the drug package insert and marketing indications for a product. Additionally, drug companies can use these data to confirm their product is fulfilling their patients’ needs early on in clinical development.

Growing interest in measuring patient-centered outcomes reflects a shift away from medicine’s former disease-centric approach. As the field of genomics uncovers an array of genetic and epigenetic influencers, diseases have become increasingly complex, easing the path for personalized medicine to emerge as a more direct way to help individuals solve health problems. While the need for research to identify biological mechanisms and markers of disease and therapeutic efficacy remains critical, it is exciting to learn about the research that helps to connect the biology to clinical outcomes important to the patient.

MMR

Thursday
Apr212016

Epigenetics and our sense of smell

The olfactory sensory neurons (OSNs) are a unique population of neurons that allow us to detect and identify specific odorants. The odorants are detected when they bind to specific olfactory receptors (ORs) expressed by the OSNs. Once an odorant is bound, a signaling cascade is initiated to notify neurons in the adjacent olfactory bulb and the rest of the olfactory pathway that the odorant is present.  

Usually, OSNs express a single olfactory receptor, and the axons of all OSNs that express the same OR meet at the same location within the olfactory bulb. It’s a great system – all inputs for a particular odor meet up in the same region of the olfactory bulb, presumably to consolidate and simplify the odor signals received by the brain.

But this system is also complex. It relies on each and every OSN expressing a single OR. In mice, this requires a selection of one OR out of a possible 1,400. Once chosen, the OR selection needs to be maintained throughout the life of the neuron, or bananas might start to smell like garbage.

On the surface, it makes sense that epigenetic regulation would be involved in the OR selection process – as one gene must be expressed in the face of a multitude of options. But how does this actually happen?

A recent study by Lyons, DB et al (1), used an army of mouse models to parse out important protein expression patterns necessary for the installment of a single OR in a single OSN. To begin, they found that the epigenetic protein lysine-specific demethylase 1 (LSD1) is involved in de-silencing individual ORs through histone H3 lysine K9 (H3K9) demethylase activity.  This initial process allows the next step to occur, transcriptional activation through histone H3 lysine K4 (H3K4) trimethylation, which initiates production of the OR.

So how is the selective expression of a single OR maintained? This is achieved through induction of adenylate cyclase 3 expression by the OR. Adenylate cyclase 3 expression downregulates LSD1 expression, and prevents the transcriptional activation of other ORs. Thus, once Adenylate cyclase 3 is expressed, the neuron becomes “trapped” through a feedback loop into making a single OR. And there you have it – bananas continue to smell like bananas.

 ~GV

1)     Lyons DB, Allen WE, Goh T, Tsai L, Barnea G, Lomvardas S. An epigenetic trap stabilizes singular olfactory receptor expression. Cell, 2013, 154, 325-336.

Tuesday
Apr192016

Complement Proteins May Provide a Gateway to Early Alzheimer’s Disease Therapeutics

Complement Proteins May Provide a Gateway to Early Alzheimer’s Disease Therapeutics

The classical complement pathway recognizes pathogens and uses macrophage-mediated phagocytosis to fight infection (1). In the brain, the complement pathway prunes synapses through microglia-mediated phagocytosis to fine-tune neuronal development (1). However, this process can go awry if it is activated later in life. Recently, the complement pathway has garnered a lot of attention for its connection to schizophrenia.  Specifically, a landmark study by Sekar et al showed that the very highly associated schizophrenia risk allele, complement component 4A (C4A), resulted in more C4A protein production in schizophrenic brain tissue (2). Importantly, the authors found that C4 deficiency reduces synaptic pruning in mice (2). This result provided mechanistic rationale for the pronounced synaptic loss experienced by schizophrenic patients. Moving forward, it will be very interesting to determine whether overexpression of C4 increases synaptic pruning in rodent models, as too much pruning is the expected phenotype in schizophrenia.

Beyond schizophrenia, the complement pathway was further tied to synaptic pruning in early Alzheimer’s disease (AD) through elegant work by Hong et al (3). Using super-resolution structured illumination microscopy (SIM, ~150-300nm resolution) in a mouse model of AD, the authors showed that complement component 1q (C1q) expression was increased in the dentate gyrus and frontal cortex (3). Increased C1q expression was localized to synapses and dependent on Aβ expression (3). In wildtype mice, administration of soluble oligomeric Aβ reduced synapse number via the complement pathway, as Aβ had no effect in C1q knockout mice (3). This result indicated that the complement pathway may propagate early AD pathology, as the effects of C1q on synapse loss were mediated before Aβ plaque deposition (a hallmark of late-stage AD). Perhaps the most exciting result from this study was demonstrated by biologic and genetic targeting of complement proteins. In wild type mice, administration of a C1q antibody rescued synapse loss and neuronal function (as determined by LTP) in the presence of oligomeric Aβ (3) (Figure, taken from Hong et al). Further, in an AD mouse model, genetic knockout of downstream complement component 3 (C3) rescued synapse loss (3). These results highlight the therapeutic potential of complement inhibitors for early-stage AD treatment.

Together these studies illuminate an entry point to prevent aberrant synaptic pruning. I look forward to future studies investigating the effects of complement inhibition on memory and learning behaviors in schizophrenia and AD models.

-TMG

1) Stephan AH, Barres BA, and Stevens B, Annu Rev Neurosci, 2012.

2) Sekar A et al., Nature, 2016.

3)Hong S et al., Science, 2016.

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