The implications of the extracellular space on the etiology and progression of neurodegenerative diseases remain largely underexplored. The extracellular space components such as heparan sulfate control the diffusion of misfolded aggregates in the interstitial fluid and, therefore, may impact the progression of neurodegenerative diseases. Our laboratory aims to define the interplay between the extracellular matrix organization, the interstitial fluid diffusion and the progression of prion and α-syn pathologies.

Synucleinopathies, including Parkinson’s disease (PD) and Dementia with Lewy bodies (DLB), are among the most prevalent neurodegenerative disorders globally. These disorders are caused by the accumulation of aggregated protein α-synuclein (α-syn) in the brain. Predictable spread of α-syn pathology in PD and DLB patients and animal models suggest α-syn propagates between synaptically interconnected brain regions and underlies disease progression. In vitro, α-syn aggregates transmit neuron-to-neuron trans-synaptically, via tunneling nanotubes or by release and uptake processes. Mounting evidence suggests that extracellular α-syn exerts a key role in the progression of syn pathology and that α-syn pathogenesis is not only a self-contained cellular phenomenon, but also an extracellular event. Heparan sulfate proteoglycans (HSPGs) are integral components of the neuronal glycocalyx and synapses where they interact with α-syn aggregates, modulating their internalization, aggregation and toxicity in cell culture. Our laboratory aims to define the role of heparan sulfate suring synuclein pathology.

Protein misfolding, aggregation and accumulation are common features of multiple neurodegenerative disorders including Alzheimer’s Disease, Parkinson’s Disease or Prion Clearance of protein aggregates may occur either through the boost of the intracellular degradation systems or through the release of the damaged proteins in the extracellular space. Despite the availability of these options for the cells to remove misfolded proteins, in a minority of cases, seeds may persist and initiate a nucleation event, offering the basis for the progressive maturation of amyloid fibrils. Our laboratory is developing techniques to promote the intracellular and extracellular degradation of misfolded proteins based on manipulating the interactions of these protein aggregates with glycans.