Team Vila

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Circuitry and Brain-Body Interactions | 2021

Activity and Connectivity Drive Neuronal Vulnerability and Disease Progression in Parkinson’s Disease

Study Rationale: Specific brain circuits that are highly melanized (build-up of the dark pigment neuromelanin) with age are primarily affected, particularly early, in Parkinson’s disease (PD). Models incorporating this aspect of PD have only been developed recently and show that increased neuromelanin production causes neurodegenerative changes consistent with Parkinson’s. The regulators of cellular neuromelanin metabolism have not been determined, the effect of neuromelanin on normal activity in these pathways has not been defined, the potential for neuromelanin aggregates to increase alpha-synuclein accumulation has not been evaluated, and the impact of extracellular neuromelanin on detrimental inflammatory processes has not been assessed.

Hypothesis: Activity in melanized brain circuits is a dominant factor in the initiation of PD and sustains its progression by seeding pathology in connected regions and providing the stimulus for chronic inflammation. Manipulating neuromelanin production and/or brain circuit activity can ameliorate these deficits. 

Study Design: Parallel experiments will be performed in mice and non-human primates in which neuromelanin production has been induced for comparison with neuromelanin-producing neurons in people with prodromal and early Parkinson’s. To test whether activity in melanized brain circuits is a dominant factor in the initiation of PD, spatiotemporal activity mapping, imaging, and other techniques will be used, and manipulating neuromelanin production and/or brain circuit activity will be assessed as potential treatments. To determine if neurons spread PD pathology through their connectivity, seeding experiments will be performed and impacts on behavior and neurodegeneration assessed. To determine how non-neuronal mechanisms are involved in disease progression, high-resolution microscopy and cell-specific details of changes in extracellular spaces and infiltration of non-neuronal cells into the brain will be assessed.

Impact on Diagnosis: Diagnosis of neuromelanin changes in the brain are already being assessed for their diagnostic potential, but this study will determine their focus and rate of change with respect to neural activity and clinical features. Team Vila will also identify if reducing neuromelanin levels stabilizes pathology and restores brain activity.

Leadership
Miquel Vila, MD, PhD
Coordinating Lead PI

Miquel Vila, MD, PhD

Vall d'Hebron Research Institute (VHIR)
Glenda Halliday, PhD
Co-Investigator

Glenda Halliday, PhD

University of Sydney
Nicola Mercuri, MD
Co-Investigator

Nicola Mercuri, MD

Tor Vergata University
Jose Obeso, MD, PhD
Co-Investigator

Jose Obeso, MD, PhD

Network Center for Biomedical Research in Neurodegenerative Diseases
Matthias Prigge, PhD
Co-Investigator

Matthias Prigge, PhD

Leibniz Institute for Neurobiology
Javier Hoyo, PhD
Project Manager

Javier Hoyo, PhD

Vall d'Hebron Research Institute (VHIR)

Project Outcomes

The project will unravel molecular mechanisms linking brain circuit activity to PD vulnerability, identify brain circuits through which PD pathology spreads across the brain and periphery, establish non-neuronal mechanisms of PD progression and determine whether modulation of neuromelanin levels and/or brain circuit activity can restore PD circuit dysfunction & pathology. View Team Outcomes.

Team Outputs

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Overall Contributions

Here is an overview of how this team’s article findings have contributed to the PD field as of November 2023. There are two different categorizations of these contributions – one by impact to the PD community and a second by scientific theme.

Impact

Theme

Featured Output

Below is an example of a research output from the team that contributes to the ASAP mission of accelerating discoveries for PD.

Modelling human brain-wide pigmentation in rodents recapitulates age-related multisystem neurodegenerative deficits

The potential influence of age-dependent neuromelanin (NM) accumulation on neuronal function and viability has been largely overlooked in experimental animal modeling because, in contrast to humans, common laboratory animal species such as rodents lack this pigment. Team Vila has developed and characterized tissue-specific transgenic mice exhibiting age-dependent NM production within all catecholaminergic neurons. These mice constitutively overexpress the melanin-producing enzyme tyrosinase (hTyr) in tyrosine hydroxylase (TH)-containing regions. They found that progressive brain-wide bilateral NM pigmentation is associated with age-related neuronal dysfunction and degeneration, affecting numerous brain neurotransmission systems and tissues in the body, and linked to a myriad of motor and non-motor alterations, equivalent to prodromal/early stages of PD.

Team Accolades

Members of the team have been recognized for their contributions. 

Other Team Activities

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