Growing mini brains to study Parkinson's disease
Parkinson's is a disease that causes dementia – you can read more about this in our blog post on dementia's relationship with Parkinson's.
It is well understood that a type of brain cell that releases a chemical messenger called dopamine is damaged in Parkinson's disease. Less clear is how these faulty neurons affect their neighbouring cells. Quyen Do, a DPhil (PhD) student at Oxford University, is using DPUK's Stem Cell Network to investigate this.
Having secured a national science scholarship from Singapore to study at Imperial College London, Quyen completed her undergraduate degree in Biomedical Science, specialising in Neuroscience. Prior to joining Oxford, she also spent a year working on the brain networks involved in fruit fly behaviour at the Institute of Cell and Molecular Biology in Singapore.
Quyen said: 'One of the unique features of certain brain cells called neurons is their ability to exhibit electrical activities as the major form of self-expression and communication. That drives my interest in the working of brain networks and electrophysiology – the branch of Neuroscience focused on the electrical processes of brain cells. For my PhD, I'm building more advanced models of neurons in a dish and investigating the various electrophysiological disturbances they experience.'
Quyen is tackling this subject using two different models, both of which use induced pluripotent stem cells (iPSCs) from DPUK's Stem Cell Network. iPSCs are living human cells that have the potential to grow into any cell type in the human body in a process called differentiation.
2D model mini circuit
One approach to better model the physiological environment of neurons in the human brain is to surround them with their usual neighbours. Using iPSC samples taken from people with healthy brains and people with Parkinson's disease, Quyen has grown clusters of the three cell types in the cortico-striato-nigral pathway. This pathway is made up of neurons coming from various parts of the brain: cortical cells from the cortex, striatal cells from the striatum, and dopamine-releasing dopaminergic cells from the substantia nigra – you can learn more about different brain areas in this blog post.
Disruption in this mini circuit is involved in the abnormal motor symptoms experienced by patients with Parkinson's disease. Therefore, it has become a huge research interest for scientists aiming to understand the development of Parkinson's disease and how it can be treated.
Quyen said: 'In my mini-circuit, different neurons are not just co-existing on the same dish, they are also specifically oriented to more accurately mimic the connectivity pattern of the similar network in the brain.'
The striatal and cortical cells in her network are grown from the healthy iPSCs, while the dopaminergic cells are grown from iPSCs from people with Parkinson's disease. This allows Quyen to study how the faulty dopaminergic cells affect the rest of the circuit – particularly the previously healthy striatal cells. She has also made a control group where all three cell types are from the healthy iPSCs, to use as a comparison.
Quyen added: 'I'm using electrophysiological techniques to measure the electrical properties exhibited by the neurones, and I can already see some differences between the Parkinsonian groups and the controls.'
3D mini brains
In her other model, to establish a more brain-like environment for her brain cells in a dish, Quyen let the iPSCs accumulate of their own accord in the presence of certain chemicals into 'mini brains in a dish'. These 3D models enable her to study the natural development of the human brain and explore how the surrounding area affects the dopaminergic cells in the substantia nigra.
She has made separate mini brains of the midbrain – the structure located at the central base of the brain just above the stem – from iPSCs of Parkinson's patients and those from healthy volunteers. This will allow her to compare the differences between them to better understand how Parkinson's disease affects the brain.
Quyen concluded: 'Such advanced models of Parkinson's disease using human cells that replicate more aspects of the complex makeup and development of the human brain will open windows to a vast array of molecular and translational research. This will include new insights on disease pathophysiology of complex and intrinsically human neurological conditions like Parkinson's disease.'