Dr Alex Clark

2019 Post-doctoral Non-clinical Fellowship

Hereditary Sensory Neuropathy type I (HSN1) Associated with mutations in SPTLC1

Hereditary sensory and autonomic neuropathy type 1 (HSN1) is an exemplar of a monogenic neuropathic pain disorder, associated with profound loss of peripheral sensation and severe shooting pain. The most common cause for HSN1 are mutations in a gene called SPTLC1. This gene encodes a subunit of an enzyme responsible for the synthesis of important proteins that are vital for cell membrane stability and neuronal signalling.

Mutations in SPTLC1 result in a toxic gain of enzyme function, which ultimately results in the production of neurotoxic metabolites. These are unable to be degraded and therefore accumulate in patients with HSN1. However, despite several studies demonstrating the toxicity of these metabolites, and that disease progression correlates with their accumulation, the mechanism by which these are toxic to neurons remains unknown.

Therefore, in order to investigate the pathophysiology of HSN1, we will use patient skin cells (obtained via a non-invassive skin biopsy) that we transform into stem cells (known as induced pluripotent stem cells or iPSCs). These iPSCs can theorerically be differentiatied into any cell type of the human body. We will then use the patient iPSCs to grow sensory neurons, the specific neuronal subtype that sense painful stimuli, and those that are predominantly affected in this disease.

This methodology allows us an exciting opportunity to investigate human patient neurons in the lab, without any associated ethical concerns. We have already found that the patient neurons have higher levels of cell death and major deficits in detecting neurotrophins, which are important signalling molecules essential for neuronal survival. 

The major focus of my Guarantors of Brain Non-Clinical Fellowship will be to understand why DSB accumulation results in neuronal cell death, and investigate possible therapeutic agents to slow and/or prevent this neuronal death.


Co-cultures with stem cell-derived human sensory neurons reveal regulators of peripheral myelination

Alex J. Clark, Malte S. Kaller, Jorge Galino, Hugh J. Willison, Simon Rinaldi, David L. H. Bennett


April 2017, Volume 140, Issue 4, p 898-913 https://doi.org/10.1093/brain/awx012 https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(21)00194-4