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A major new $9 million project funded by the Aligning Science Across Parkinson’s (ASAP) initiative will map the original circuits vulnerable to Parkinson’s on an unprecedented scale. The project is a collaboration between a core team of Stephanie Cragg, Richard Wade-Martins, and Peter Magill at Oxford, Mark Howe at Boston University and Dinos Meletis at the Karolinska Institute, as well as collaborators Yulong Li at Peking University and Michael Lin at Stanford University.

Fluorescently labelled dopamine axons in the mouse striatum

Parkinson's is the most common progressive neurodegenerative movement disorder, affecting around ten million people worldwide. Typical symptoms include tremors, a slowness of movement or loss of ability to move muscles voluntarily, rigidity of limbs and balance problems. Pathology in dopamine neurons in the brain plays a critical role.  In particular, the dopamine neurons of the substantia nigra, located in the midbrain, progressively degenerate, leading to a loss of the neurotransmitter dopamine in the striatum. The striatum is part of a network of neurons in the brain collectively called the basal ganglia, which is involved in the selection and control of our voluntary movements, known as ‘goal-directed movements’. While other systems are involved in Parkinson’s, the loss of dopamine is understood to be primarily responsible for patients becoming increasingly unable to select and tune their movements, and eventually losing the ability to move entirely. Disease therapy was revolutionised in the 1960s by introduction of L-DOPA, a precursor to dopamine that allows the brain to make the missing dopamine. However, this long-standing mainstay of therapy loses its efficacy over time and can lead to major debilitating side effects, and so research continues to seek other potential treatments and strategies for preventing the disease progression and replacing the missing dopamine.

A new large-scale funding initiative, Aligning Science Across Parkinson’s (ASAP), was launched in 2019 to transform research into Parkinson’s. ASAP is establishing an international network of collaborating investigators who will address high-priority basic science questions to accelerate our understanding of the disorder. It has also set an agenda for open and collaborative research on a scale that is unprecedented in the field. ASAP is funding a multidisciplinary hub of scientists to collaborate at all stages of their research from the very earliest stages, sharing methods and data throughout the discovery process. It aims to promote transformative research through this approach of open science across its network. This year, ASAP opened a funding call for teams to identify the circuits that are going wrong in Parkinson’s, and how the disease progresses, in order to illuminate new ways to rescue dysfunction in the brain in the future. The Michael J. Fox Foundation for Parkinson’s Research is ASAP’s implementation partner and issued the grants. 

A landmark collaboration led by Stephanie Cragg in DPAG Oxford, has been awarded $9 million from ASAP for a team of investigators from the Oxford Parkinson’s Disease Centre, the MRC Brain Network Dynamics Unit at Oxford as well as Boston University and the Karolina Institute in Sweden, to fully map out a key set of the neuronal circuitry relevant to Parkinson’s. The team will assess how circuit activity changes during progression of Parkinson’s in vulnerable compared to resistant circuits and define how circuit dysfunction in vulnerable circuits relates to disease symptoms. In particular, the team will focus on studying the circuits that govern dopamine output. According to Stephanie Cragg: “We know dopamine neurons die, and that the messages they transmit on to other cells are lost in Parkinson’s, but we don't really understand how all the other interacting circuits contribute to that and either make it worse or attempt to offset it, so we are looking to identify what the sequence of dysfunction is.”

Strikingly, preliminary research has shown that the nigrostriatal dopamine neurons that are known to die in Parkinson’s have uniquely large axon arbors, the main branching structures stemming from the neuron cell bodies, despite having relatively limited dendrites. “They are the most branched of all central nervous system neurons documented to date, which makes their physiology particularly interesting,” Stephanie Cragg says. “It means that these axons have huge biological relevance in dopamine signalling because a large number of other systems can talk to these axons with the potential to powerfully transform dopamine output. The message emerging from dopamine axons can be tweaked along the way by lots of different things acting on these incredible axons.”

“Over the years my lab and others have shown that a range of different neuromodulators seem to act on these axons, proving that the axons are a really important site for other circuits to govern dopamine function. We then started acquiring preliminary data showing that this scope is far bigger than we imagined.”

The Cragg Group has been able to demonstrate that it is not just other neurons that interact with these axons to govern dopamine function; non-neuronal cells in the brain are also important. These include astrocytes, previously thought of as support cells, which actively support dopamine release and are sites of early dysfunction in parkinsonism, as shown in their recent paper published last year (Roberts et al, Nature Communications, 2020). According to Stephanie Cragg: “This paper made us realise that the dopamine function that's so critical to our movements can be controlled by a colossal range of circuits, cell types and modulators all acting at the level of the axons in the striatum.”

“With more than 99% of the neuron comprising these unusually large axon trees, we decided to focus our ASAP grant on systematically defining the neuromodulators and circuits that are talking to dopamine axons. We will also compare whether these mechanisms are different in brain regions that are dying in Parkinson's compared to brain regions that are resistant, to see if there are circuits that might make good targets for future therapies that could fix the vulnerable neurons but leave the resistant ones unaffected.”

“We also think that the neuromodulatory circuits that control dopamine function are themselves also changed during progression of the disease. This could underpin some of the symptomology and provide fresh rationale for future therapies to start to fix the imbalances in circuits and restore normal balance of operation.”

With the advent of new and improved cutting-edge technologies that have revolutionised neuroscience research, the collaborative team will together have unprecedented ability to research how these circuits talk to each other and become dysfunctional in disease, at levels spanning from molecules to behaviour. The work will build on key foundations laid by the Oxford Parkinson’s Disease Centre to develop physiological genetic animal models of Parkinson’s and corresponding human-derived cell lines from Parkinson’s patients – IPSC-derived reprogrammed dopamine neurons. This will enable the team to map their findings in the mouse models onto human cells and vice versa. Stephanie Cragg says: “The animal models represent the disease better than ever before, and we will be able to translate and correlate our animal findings with those in human cells through some of the best models available.”

As a first step, the team will gather genetic data to characterise the differences in genetic signatures of the neuromodulatory networks in both the vulnerable and unaffected regions. This stage of research will focus on activity in the healthy brain to gain a better understanding of the wider range of neuromodulators that shape dopamine output. According to Stephanie Cragg: “We believe we will quickly expand our insights into identifying new neuromodulators and circuits that might be important. We will also better understand the genetic factors that might flag circuits and molecules we hadn't previously considered.”

The ASAP funding will enable the team to work on an unprecedented international collaborative scale. ASAP grantees, members of its Collaborative Research Network, work together by interacting at regular virtual meetings, sharing unpublished data and protocols, and publishing in gold standard open access journals. Stephanie Cragg says: “ASAP is really helping to break down the obstacles to openness in science. They will encourage open discussion before publication with our colleagues internationally on a level we really haven't done enough of before. This is not just a normal collaborative project grant; it is one that is pushing at the boundaries of collaborative open science in a way that has never been done before in this field. We are very excited to be part of this transformative effort in Parkinson's disease research.”

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