Project Portugal 2030

Summary

During the past decades it has been observed a strong increment in the life expectancy of the population. While being a clear societal objective this increase is also bringing new challenges that require a stronger investment on controlling/treating age-related pathologies. In this context, neurodegenerative disorders (ND) are gaining importance as they are usually age-related, with a strong incidence in elderly people. It is important to note that it is estimated that between 10-30% of the population above 65 years old present at least one ND, and the incidence above 85 years old can reach 50% or higher. Parkinson’s Disease (PD) is one of the most common ND in the World. Its main hallmark is the deposition of cytotoxic aggregates of alfa-synuclein (aS) generating Lewy bodies and neurites. Importantly, large intracellular deposits impart perturbation of the normal functioning of the neurons, however, there are also reports that show that smaller aS species are strongly correlated with cytotoxicity, and the spreading of the disease to the neighboring tissue, being at the basis of the progression of the disease. In the case of PD, as well as other NDs, we and others have proven that there are several compounds (e.g., sugars) that are able to modulate ND-related protein/peptide cytotoxicity, through the remodeling of their secondary structure. However, this has been achieved at very high concentrations, of up to 50mM. Under these circumstances, we propose here the use of sugar-conjugated dendrimer nanoparticles to overcome this hurdle. In fact, depending on the generation of the dendrimer, they can present between 6 and 48 monosaccharides per nanoparticle, increasing the local concentration of the sugars, making them an interesting therapeutic approach. We will then test the functionalization of the nanoparticles with monosaccharides that are able to reduce the toxicity of aS (selected from our preliminary data using the sugar molecules alone). These sugar-functionalized dendrimers will be tested for their ability to interact with aS reducing its toxicity in neuron-like cells. We will also assess their biostability, as well as their ability to cross the BBB, a vital characteristic to reach the brain areas affected by PD and exert their therapeutic outcome. The project is outlined to generate bioactive nanosystems that can: 1) cross the BBB reaching the affected regions of the brain and 2) modulate the aggregation of aS reducing its cytotoxicity. Nanosystems that address both objectives in a single molecule will significantly improve its potential impact in the clinical practice and its ability to halt or revert the progression of PD. Importantly, while the project is focused on PD, the same strategies can be used to address other NDs, as for example Alzheimer’s Disease, with small adjustments in the molecular design. The concept proposed under NanoSugar, will contribute to significant advances in the development of efficient PD treatment strategies, as well as other NDs, that are the main responsibles for the increasing cases of dementia in our increasing elderly society.