Stereotypic spreading of protein aggregation through the nervous system is a hallmark of many neurodegenerative diseases. This was demonstrated for Alzheimer’s disease (AD, amyloid-β & tau protein) and Parkinson’s disease (PD, α-synuclein, or α-syn). α-syn is a natively unfolded, presynaptic protein of unknown function and unusual conformational plasticity.  Evidence accumulates that progression of synucleinopathies not only involves transmission of simple “protein misfolding” but rather specific “structural information” from one cell to the next, leading to the progressive proliferation of “structural α-syn strains”. It is now suspected, that different forms of α-syn inclusions lead to different phenotypes of neurodegeneration, i.e., lead to different synucleinopathy diseases, such as PD, or Dementia with Lewy body disease. To date the patho-mechanisms are unknown, but a prion-like transmission via an intrusion of protein nanoparticles imprinting their specific folding onto native host proteins is most likely.

Today’s biophysical (e.g., mass spectrometry) methods can trace the presence of proteins, but do not allow detecting and monitoring the structural arrangement of the involved assemblies. In this project we will develop a novel method for single cell analyses, not only detecting proteins, but also providing structural information. This approach is geared for the study of “structural strains” of neurodegerative diseases. Project goals are:

(i) Development of a targeted proteomics and electron microscopy (EM) labelling method for single cell analysis using magnetic nano particles.

(ii) Study the prion-like mechanism of the spreading of α-syn nanoparticles from diseased cells to healthy cells. Identify determinants defining different structural strains of α-syn.