Parkinson’s, study investigates the brain’s mechanisms before the disease

The study entitled LRRK2 regulates synaptic function through modulation of actin cytoskeletal dynamics, published in eLife, with Giulia Tombesi as first author and scientific coordination by Elisa Greggio, lecturer in Physiology at the Department of Biology of the University of Padua, has identified a new function of the LRRK2 protein in regulating connections between nerve cells. The discovery helps shed light on the very earliest cellular mechanisms triggered in the brain even before the symptoms of Parkinson’s disease appear.

The work represents the culmination of the STARS project, supported by the University through the funding programme entitled “LRRKing”, created precisely to understand how this protein shapes the structure of neurons.

The LRRK2 protein has long been under close scrutiny in the fight against Parkinson’s: mutations in the gene that produces it are in fact one of the most frequent hereditary causes of the disease. In addition, abnormal activity of this protein has also been found in the “sporadic” forms of the disease, namely those that develop without a genetic family history. For scientists, clarifying what LRRK2 does under normal conditions within nerve cells is a crucial step towards understanding how its dysregulation may then lead to neurodegeneration.

The study showed that LRRK2 plays a leading role in preserving the architecture and proper functioning of synapses, namely the extremely fine points of contact through which neurons communicate and exchange information. In particular, the research team discovered a direct link between LRRK2, the response to BDNF - a neurotrophic factor, that is, a small protein that stimulates the survival and growth of neurons - and the management of the actin cytoskeleton. The latter is nothing other than the cell’s internal framework: a dynamic and flexible structure that is essential for enabling neurons to change shape and to ensure synaptic plasticity, namely the ability of nerve contacts to strengthen or change in response to stimuli.

“One of the most interesting aspects of our study is that we identified a role for LRRK2 in highly dynamic processes that allow synapses to adapt to stimuli,” explains Professor Elisa Greggio of the Department of Biology. “Understanding what happens before a neuron degenerates is essential if we want to identify mechanisms on which to intervene in the earliest, and ideally reversible, stages of the disease.”

The working group combined several cutting-edge techniques: from molecular biology to omics analyses - an approach that makes it possible to map simultaneously the totality of genes, proteins or molecules present in a tissue - through to high-resolution microscopy and electrophysiology, that is, the measurement of the electrical activity of neurons. These analyses were also carried out on human neurons obtained in the laboratory by reprogramming stem cells. The results clearly indicate that, when LRRK2 activity is altered, neurons lose the ability to respond appropriately to growth signals and are no longer able to remodel their connection structures properly.

The importance of the study lies in the fact that, in Parkinson’s, problems in communication between synapses occur long before the actual death of dopaminergic neurons - the brain cells that produce dopamine, whose disappearance causes the classic motor disorders of the disease. Shifting the focus to the early stages of the condition makes it possible to stop concentrating solely on the final phase of cellular destruction, which is by then irreversible, and instead focus on the molecular processes that progressively make the neuron fragile.

The Padua research project funded through the STARS Programme of the University of Padua made it possible to establish a solid network of cooperation with centres of excellence in Italy and abroad, bringing together different areas of expertise ranging from the study of individual molecules to the physiology of the entire nervous system.

“The path that began with STARS shows how funding for basic research can have effects that go beyond the individual project,” concludes Elisa Greggio. “It has enabled us to develop new scientific questions, produce results now published in eLife and build international collaborations that continue to generate new research directions.”

Among these, the collaboration with Loukia Parisiadou of Northwestern University in Chicago, co-author of the study, stands out most recently. Together with her, the University of Padua is developing new lines of investigation into the cellular mechanisms of Parkinson’s. The international alliance will also continue within Aligning Science Across Parkinson’s (ASAP), a prestigious and ambitious global programme dedicated to the study of the biological basis of the disease. In the new project, researchers Greggio and Parisiadou will investigate specifically the relationships between brain ageing, oxidative stress affecting RNA and alterations in ribosomes - the cellular organelles responsible for protein synthesis - in dopaminergic neurons most exposed to degenerative risk.