Mark Zylka, PhD



Professor and Director

Research Description

Unsilencing Angelman Syndrome

Angelman syndrome is a severe disorder with symptoms that include speech impairment, intellectual disability and seizures. This lifelong disorder profoundly impacts patients and their families, yet no effective treatment currently exists. It is well established that this disorder is caused by genetic alterations in the maternally-inherited copy of a gene called Ube3a.

In collaboration with Drs. Ben Philpot and Bryan Roth, we found that topoisomerase inhibitors unsilence a dormant but functional copy of Ube3a in mice. We aim to advance our understanding of how these drugs work, with the ultimate goal of developing treatments for this debilitating, lifelong disorder.

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Molecules and Mechanisms for Pain

Chronic pain is a major medical issue, affecting more Americans than heart disease, diabetes and cancer combined (American Pain Foundation). In our laboratory, we are developing new approaches to treat chronic pain. In addition, we study the neural circuits that transmit pain-producing stimuli using molecular, genetic, electrophysiological and behavioral approaches.

Ectonucleotidases in nociceptive circuits.

We recently found that Prostatic Acid Phosphatase (PAP, also know as ACPP) is expressed in nociceptive (pain-sensing) neurons and functions as an ectonucleotidase, converting adenosine monophosphate (AMP) to adenosine. The released adenosine potently suppresses inflammatory pain and neuropathic pain by acting through A1 adenosine receptors.

Our studies suggest it might be possible to treat chronic pain using recombinant PAP protein or small-molecules that mimic the effects of PAP.

Neural circuit-based approaches.

In mammals, pain signals are transmitted from the periphery to the CNS by two neural circuits; the so called peptidergic and non-peptidergic circuits (Fig. 1). Peptidergic neurons contain neuropeptides, like CGRP, while non-peptidergic neurons bind the lectin IB4.

We recently found a G protein-coupled receptor (GPCR) called Mrgprd which is expressed in a majority of all non-peptidergic neurons. Mrgprd is not expressed in CGRP+ neurons, nor is it expressed anywhere else in the brain or body.

To identify the tissues that Mrgprd-expressing neurons innervate, we engineered knock-in mice that express a membrane-tethered version of enhanced Green Fluorescent Protein (EGFPf) from the Mrgprd locus (MrgprdΔEGFPf). Surprisingly, we found that Mrgprd-expressing neurons only innervate the epidermis of the skin (Fig. 2). Joints and internal organs were not innervated, suggesting pain signals are transmitted from these tissues by molecularly-distinct circuits.

In addition to molecular differences, Mrgprd-expressing axons and CGRP+ axons terminate within different zones of the epidermis (Fig. 2). Mrgprd-expressing axons (green) also terminate beneath the red-labeled CGRP lamina in the dorsal spinal cord (Fig. 3). Taken together, these findings suggest peptidergic and non-peptidergic neurons might have unique functions and connectivity.

Although studied for over 20 years, it is still not known why mammals have peptidergic and non-peptidergic circuits, both of which respond to noxious stimuli. Do these two molecularly different circuits have redundant or non-redundant functions in nociception? In our laboratory, we are trying to answer this fundamental question using a variety of approaches. As an example, we are making and studying circuit knockout mice. These mice are specifically missing either peptidergic or non-peptidergic neurons. We are studying the consequences of these ablations using molecular, electrophysiological and behavioral methodologies. We are also using Channelrhodopsin-2 (ChR2), a light-gated ion channel, to better understand how these circuits interface with pain-related regions of the central nervous system.

Selected Publications

McCoy ES, Taylor-Blake B, Street SE, Pribisko AL, Zheng J, Zylka MJ. Peptidergic CGRPα Primary Sensory Neurons Encode Heat and Itch and Tonically Suppress Sensitivity to Cold. Neuron. 2013 Apr 10;78(1):138-51. doi: 10.1016/j.neuron.2013.01.030. Epub 2013 Mar 21. PMID:23523592 . [cover]

Hurt JK, Zylka MJ. PAPupuncture has localized and long-lasting antinociceptive effects in mouse models of acute and chronic pain. Mol Pain. 2012 Apr 23;8(1):28. [Epub ahead of print] PMID:22524543

Huang HS, Allen JA, Mabb AM, King IF, Miriyala J, Taylor-Blake B, Sciaky N, Dutton JW Jr, Lee HM, Chen X, Jin J, Bridges AS, Zylka MJ, Roth BL, Philpot BD. Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons. Nature. 2011 Dec 21;481(7380):185-9. doi: 10.1038/nature10726. PMID: 22190039

Mabb AM, Judson MC, Zylka MJ, Philpot BD. Angelman syndrome: insights into genomic imprinting and neurodevelopmental phenotypes. Trends Neurosci. 2011 Jun;34(6):293-303. PMID: 21592595. [cover]

Contact Information

Office: (919) 966-2540
Lab: (919) 966-2541