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Paul Heppenstall

Physiology of somatosensation

Paul HeppenstallFull Professor

How do neurons in the skin detect and convey information about pain, itch and touch to the brain? The Heppenstall group develops molecular, imaging and electrophysiological techniques to address this question and understand how sensory neurons give rise to our sense of touch.


Paul Heppenstall

Paul Heppenstall trained as a physiologist at the University of Edinburgh for his PhD, before moving to the Max Delbrueck Centrum, Berlin for postdoctoral training. In 2002, he was awarded a Junior Professor position in the Department of Anaesthesiology, Charité, Berlin where he started his own research programme in molecular pain research. In 2008, he moved to EMBL Rome where he led a research group studying the molecular physiology of somatosensation. In 2011, this was supplemented by a joint group leader position at the Molecular Medicine Partnership Unit (MMPU) in Heidelberg. Since 2018 he has been a full professor at SISSA. Paul has been working in pain research for more than 25 years and has made contributions to spinal cord physiology and pharmacology, sensory mechanotransduction, and peripheral nervous system biology. A major focus of his laboratory is to now translate research findings into new treatments for pain and itch. 



Research lines

Dissecting sensory neuron cell diversity

The peripheral nervous system is made up of subpopulations of functionally diverse neuronal types that detect and encode different types of stimuli. In order to understand this functional organization, the Heppenstall laboratory has developed a number of molecular genetic tools with which to manipulate peripheral neurons. This includes Cre driver lines to target distinct populations of neuron, and Cre reporter lines that allow for the probing of function through imaging and chemogenetic ablation. These technologies have enabled the lab to understand how distinct sensations such as itch versus touch are generated, and to investigate how injury triggers reorganization of the system provoking chronic pain. 

Heppenstall Image 1

 Sensory neurons surrounding a blood vessel in the skin. Credit: Barenghi


Targeting sensory neurons using ligands

Based upon their work on sensory neuron diversity, the Heppenstall group has been developing pharmacological approaches with which to gain control of sensory neuron activityand inhibit pain or itch at its source. At the core of the technology, the group has engineered protein ligands which bind selectively to subtypes of neuron that provoke itchmechanical hypersensitivity or inflammatory pain. Using these ligands they have been able to direct photosensitizers to neurons in the skin and achieve long-term inhibition of itch and pain. The lab is now exploring how these ligands can be used to deliver small molecules, proteins or genes into neurons, thus allowing for precise control over neuronal function. 

Heppenstall Image 2

 Gene delivery in sensory neurons. Credit: Barenghi


Tubulin acetylation and touch

Acetylated microtubules play a critical role in regulating the sensitivity of sensory neurons to mechanical touch. The protein Atat1 is the enzyme responsible for acetylation of α-tubulin, and in its absence mice, flies and nematode worms display a profound loss of mechanical sensitivity but no other overt phenotype. The Heppenstall group generated the first mouse knockout of Atat1, and demonstrated that mice lacking α-tubulin acetylation display a profound loss of mechanical touch and pain. They are now exploiting this finding to develop small molecule inhibitors for tubulin acetylation as a novel class of analgesic

Heppenstall Image 3

  Acetylated microtubules in sensory neurons. Credit: Castaldi


Imaging sensory neurons

The Heppenstall group has a long-standing interest in developing methods for live imaging of neurons in the skin. They have focused on chemogenetic approaches that utilize genetic targeting to localize synthetic indicators to cells of interest. For example, the lab produced the first Cre dependent reporter mouse line expressing the SNAP-tag, and demonstrated that it allowed for bothmanipulation of behaviour and monitoring of cellular fluorescence in complex tissue. More recently, they have generated a semisynthetic tethered voltage indicator called STeVI1 that can be genetically targeted to neuronal membranes for optical monitoring of voltage. In ongoing work, the team are optimizing this technology to visualize how neuronal circuitry is activated by defined sensory inputs.   

Heppenstall Image 4

 Snap-tag labelling of sensory neurons. Credit: Castaldi


Genetic sensory diseases

The Heppenstall laboratory has a strong interest in developing technology to treat heritable sensory diseases which cause itch and pain. They have been working on a rare skin disease called familial primary localized cutaneous amyloidosis (FPLCA) that provokes severe itching and damage to the skin. The group generated a mouse model of FPLCA and found that by targeting a photosensitizer to itch sensing neurons they were able to reverse symptoms of the disease for several months. They are now exploring whether disease causing mutations in FPLCA and other genetic diseases can be corrected in the skin through cell-directed gene editing. 

Heppenstall Image 5

 Amyloid deposits in the skin of an FPLCA mouse. Credit: Nocchi

Selected publications

Cell Rep. 2022 Jan 18;38(3):110260. doi: 10.1016/j.celrep.2021.110260. PMID: 35045284.

TrkC-CreERT2-mediated recombination supports evidence that TrkC+/TH+ DRG neurons contribute to cardiovascular homeostasis.

Heppenstall PA, Castaldi L, Morelli C.

Cell Rep. 2021 Jun 1;35(9):109191. doi: 10.1016/j.celrep.2021.109191. PMID: 34077727; PMCID: PMC8187988.

Identification of a population of peripheral sensory neurons that regulates blood pressure.

Morelli C, Castaldi L, Brown SJ, Streich LL, Websdale A, Taberner FJ, Cerreti B, Barenghi A, Blum KM, Sawitzke J, Frank T, Steffens LK, Doleschall B, Serrao J, Ferrarini D, Lechner SG, Prevedel R, Heppenstall PA.

Pain. 2021 May 1;162(5):1334-1351. doi: 10.1097/j.pain.0000000000002159. PMID: 33492037.

A genome-wide screen reveals microRNAs in peripheral sensory neurons driving painful diabetic neuropathy.

Bali KK, Gandla J, Rangel DR, Castaldi L, Mouritzen P, Agarwal N, Schmelz M, Heppenstall P, Kuner R.

Arthritis Rheumatol. 2020 Oct;72(10):1749-1758. doi: 10.1002/art.41314. Epub 2020 Aug 11. PMID: 32418284.

Intraarticular Adeno-Associated Virus Serotype AAV-PHP.S-Mediated Chemogenetic Targeting of Knee-Innervating Dorsal Root Ganglion Neurons Alleviates Inflammatory Pain in Mice.

Chakrabarti S, Pattison LA, Doleschall B, Rickman RH, Blake H, Callejo G, Heppenstall PA, Smith ESJ.

2019, Nat Biomed Eng. 3(2):114-125.

Interleukin-31-mediated photoablation of pruritogenic epidermal neurons reduces itch-associated behaviours in mice

Nocchi L, Roy N, D'Attilia M, Dhandapani R, Maffei M, Traista A, Castaldi L, Perlas E, Chadick CH, Heppenstall PA. 

2019, Angew Chem Int Ed Engl. 18;58(8):2341-2344.

A Chemogenetic Approach for the Optical Monitoring of Voltage in Neurons

Sundukova M, Prifti E, Bucci A, Kirillova K, Serrao J, Reymond L, Umebayashi M, Hovius R, Riezman H, Johnsson K, Heppenstall PA.  

2018, Nat Commun. 24;9(1):1640.

Control of mechanical pain hypersensitivity in mice through ligand-targeted photoablation of TrkB-positive sensory neurons

Dhandapani R, Arokiaraj CM, Taberner FJ, Pacifico P, Raja S, Nocchi L, Portulano C, Franciosa F, Maffei M, Hussain AF, de Castro Reis F, Reymond L, Perlas E, Garcovich S, Barth S, Johnsson K, Lechner SG, Heppenstall PA.  


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