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07/11/2022
Meet the Neuro Team – Modelling Neurodegeneration in a Dish
We caught up with Senior Scientists Gabriela Vilema Enríquez and Matthew Williamson on their work within the neuroscience team at Samsara.
Small but Mighty
Although dopaminergic (DA) neurons make up a relatively small population of neurons in the brain, around half a million compared to the average total 86 billion, they are essential for controlling key functions such as voluntary movement, reward processing, and working memory (Roeper, 2013).
Autophagy is the major degradation pathway for these protein aggregates, and autophagy dysregulation is observed in patients with Parkinson’s disease (PD).
Matthew adds ‘Autophagy decreases with age and age is the biggest risk factor for neurodegenerative diseases such as PD, Amyotrophic lateral sclerosis (ALS) and Alzheimer’s so there is an obvious link between age, disease and autophagy’
The focus of the neuro team is to develop disease models to assess the activity of autophagy-inducing compounds as a potential therapeutic avenue for neurogenerative diseases.
Differentiating Stem Cells
A large amount of the team’s time is spent converting induced pluripotent stem cells (iPSCs), usually derived from the skin or blood of patients with PD or ALS, into mature mid-brain DA neurons or spinal motor neurons, respectively. The process takes around two months and, to ensure successful differentiation, the cells must be monitored daily, handled appropriately to avoid contamination and supplemented with media containing a variety of select small molecules and growth factors to best mimic embryonic development.
‘The protocol we have is well established, giving us mature DA neurons with all the necessary electrophysiological properties. Although challenging to reproduce iPSC data, these are the best kind of disease models you can get using human cells and the closest you can get to a patient, which is an exciting task to accomplish’ says Gabriela.
By 30 days …
Midbrain neuronal progenitor cells express key transcription factors such as Foxa2 and Lmx1a, which are essential for the differentiation and development of dopaminergic neurons
Cells also express neuronal markers such as β-tubulin and even begin to express tyrosine hydroxylase, the enzyme involved in the synthesis of dopamine
Modelling Neurodegeneration in a Dish
After successfully producing in vitro cultures of neuronal cells, the team assess whether Samsara’s autophagy inducing compounds reverse or alleviate any of the differences in phenotypes seen between the patient and healthy control lines.
‘Autophagy is a complex multi-step pathway, however we have developed a panel of biological and cellular assays that we can use to investigate if and how our compounds are inducing autophagy and improving cellular health. For example, one of the steps we are particularly interested in, is whether our compound can remove these toxic protein aggregates, which we see accumulate in post-mortem tissue from PD and ALS patients’ explains Matthew.
‘It’s important to note that we are part of a much bigger team helping to build a package of valuable data for a candidate molecule that we hope may eventually go into people for clinic trials’ says Gabriela.
By 60 days …
The majority of cells express tyrosine hydroxylase and have electrophysiological properties characteristic of neurons. These cells are now regarded as mature midbrain dopaminergic neurons
Why Autophagy?
‘We are one of few companies trying to take autophagy inducers to the clinic. With lots of compelling evidence that autophagy dysregulation is a key player within neurodegeneration, we believe that by boosting autophagy we can not only target one disease such as Parkinson’s, but several diseases where autophagy has shown to be affected’ summarises Gabriela.
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References
Hou, X. et al. (2020) “Autophagy in Parkinson’s Disease,” Journal of Molecular Biology, 432(8), pp. 2651–2672. Available at: https://doi.org/10.1016/j.jmb.2020.01.037.
Roeper, J. (2013) “Dissecting the diversity of midbrain dopamine neurons,” Trends in Neurosciences, 36(6), pp. 336–342. Available at: https://doi.org/10.1016/j.tins.2013.03.003.