A new therapeutic target that could slow the progression of Parkinson’s disease

Left: a) Microfluidic device used in the study. Primary cortical neurons can be seen after 15 days in vitro. b)Immunolocalization of the malignant version of α-synuclein (green) growing in microfluidic devices after inoculation with recombinant α-synuclein. c) Photomicrograph showing examples of adult cortical neurons with relevant degenerated synuclein content 45 days after α-synuclein injection in the striatum.

In their study published this week, the researchers found that aside from carrying out these functions, PrPc also binds to and increases the spreading of damaged α-synuclein – the protein responsible for neuronal degeneration and death in diseases such as Parkinson’s – between neurons. This points to PrPc as a possible pharmacological target to slow neurodegeneration in these types of pathologies.

This breakthrough, a result of a collaboration of three research groups at IBEC together with colleagues in the Tokyo Metropolitan Institute of Medical Science, Barcelona’s Bellvitge Hospital and Vall d’Hebron Research Institute, and the Aragón Institute for Engineering Research at the University of Zaragoza, could also apply to other types of neurodegenerative diseases, including some types of dementia such as Alzheimer’s disease, or multiple system atrophy.

Parkinson’s is a chronic neurodegenerative disease that affects movement. It develops when a particular type of neurons degenerate and die off, affecting the central nervous system’s motor and cognitive functions. The culprits responsible for this degeneration are Lewy bodies, abnormal aggregates of a malignant version of α-synuclein, a protein found in the neuron’s cytoplasm, that develop inside neurons. When α-synuclein cannot degrade properly, it changes shape, undergoes phosphorylation and begins to clump together, creating these dense and insoluble structures.

This aggregation increases inside the neuron and awakens its autoimmune response, which ends up causing the cell’s own death. The process is fast and devastating, as the pathogenic form of α-synuclein is able to spread through connections between neurons of different brain regions before forming new Lewy bodies, causing irreversible damage to an incremental number of cells over time.

The IBEC researchers and their collaborators found that overexpression of PrPc in the membrane of neurons increases the binding and the expansion of pathogenic α-synuclein between neurons and, later, the formation of Lewy bodies. “We saw more clearly how α-synuclein was able to travel from one region of the brain to others, leaving behind countless dead and dying neurons,” says Laura Urrea, the study’s first author.

“PrPc is a key player in the spreading of Lewy bodies,” adds José Antonio Del Río, University of Barcelona (UB) professor and leader of one of the IBEC groups involved – the others were those of Josep Samitier, IBEC Director and also a professor at the University of Barcelona (UB), and Eduard Torrents – and coordinator of the study. “If we could prevent them from propagating and grouping to form these accumulations, we could stop the progression of neuronal death in diseases like Parkinson’s.”

In addition to their in vivo and in vitro experiments, Prof. Del Río’s team developed a microfluidic device able to distinguish the specific interaction between PrPc and the α-synuclein that facilitates its transport between neurons. “To date, we’ve identified a domain in the PrPc that could be the key therapeutic target to contain α-synuclein transport and thus slow the progression of the disease,” he says.

The work was carried out thanks to funding from La Marató de TV3, MINECO and the Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), among others.

Article: Urrea L, Segura-Feliu M, Masuda-Suzukake M, Hervera A, Pedraz L, Aznar JM, Vila M, Samitier J, Torrents E, Ferrer I, Gavín R, Hagesawa M, Del Río JA. (2017). Involvement of Cellular Prion Protein in α-Synuclein Transport in Neurons. Mol Neurobiol., epub ahead of print