Current models of neurological dysfunction aren’t very good
Much of our work revolves around the development of model systems that are more representative of the disease they model than current systems.
Our major focus is on Parkinson’s disease, a profoundly debilitating neurodegenerative condition, it affects 1-2% of individuals over 50 years of age. It also accounts for ~20% of all deaths due to “Diseases of the nervous system” (Australian Bureau of Statistics). Patients with Parkinson's disease suffer a variety of well documented motor and non-motor symptoms. The motor symptoms include hypokinesia, muscle rigidity and shaking tremor, while the non-motor symptoms include depression, apathy, anxiety, hallucinations, sleep disorders, urinary urgency, nocturia, sexual dysfunction, dysphagia, fecal incontinence and paresthesia.
Although it affects many brain regions, the classically described motor symptoms of Parkinson’s disease are suspected to result from the loss of tyrosine hydroxylase positive dopaminergic (A9) neurons of the substantia nigra pars compacta. The loss of these neurons results in a deficit of striatal dopamine and, consequently, impaired motor function.
Generally, current pharmacotherapeutics increase dopamine production or availability (for example, L-dopa or metabolism inhibitors), or mimic the post-synaptic effects of dopamine (dopamine agonists). It is disturbing to realize that the gold standard therapy for Parkinson’s disease, extending over a period of 50 years, is still L-dopa. While these therapeutics manage symptoms for a period there are significant side effects, and they will ultimately fail.
From the tail end of the 20th Century we saw new approaches to the treatment of Parkinson’s disease which have been trialed with variable success; the two most promising and demonstrably inconsistent have been neural progenitor cell transplantation and the promotion of neuron survival with glial derived neurotrophic factor. While they look good in the lab, they’re not so good in practice. We believe that these examples of therapeutic inconsistency probably result from the disconnect between the pathophysiology of disease and the systems used to model it. It is, after all, difficult to create a new therapeutic when the model you’re using for target identification and drug candidate validation may only partially recapitulate the essential features of disease pathology.
Our recent work on Parkinson’s disease model development has revealed two factors; NR0B1 and RSPO2, that
- show evidence of dysregulation in Parkinson’s disease and
- have the ability to change the specification of dopaminergic neurons derived from human pluripotent stem cells late in maturation.
Our current work focusses on how these factors regulate dopaminergic neuron identity and most importantly, whether the changes in their expression relate to the changes in dopaminergic neurons associated with Parkinson’s disease pathology.
- Much of our recent work involves tracking the putative mechanisms underlying the expression of genes of interest. This involves investigation of databases to identify genes of interest (such as NR0B1, NEUROD1 & RSPO2) and assessing the role that these genes play in the expression and function of proteins associated with dopaminergic neuron phenotype (tyrosine hydroxylase or aldehyde dehydrogenase, for example) using sh-, si-RNA or gene containing lentiviral constructs to regulate expression (see this recent paper).
- We have recently invested considerable energy into the development of microfluidic chamber systems that enable the assessments of neuron-to-neuron communication in culture. The idea behind this work is to generate a simple model of the neural circuits that contribute to neuropsychiatric & Parkinson’s disease. The recapitulation of these networks enables the selective modulation of pools of neurons without directly impacting others (see this recent paper). We believe that this approach may, in particular, be of great use in the development, assessment and validation of drug candidates for both movement disorder (Parkinson’s, Huntington’s) and also neuropsychiatric diseases (schizophrenia).