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A major new $9 million (£6.6 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. It is the only UK-led ASAP project this year, and the first ever to be led by Oxford.

Dopamine axons in the mouse brain
Fluorescently labelled dopamine axons in the mouse striatum

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 Professor Dinos Meletis at the Karolinska Institute, as well as collaborators Yulong Li at Peking University and Michael Lin at Stanford University.

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 Professor Stephanie Cragg in Department of Physiology, Anatomy & Genetics website (DPAG), 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 the University of 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 Cragg team will focus on studying the circuits that govern dopamine output. According to Professor 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.”

Read the full story on the Department of Physiology, Anatomy & Genetics website

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