Non-neuronal cells enable transmission of α-synuclein in Parkinson’s disease

Abstract

The molecular hallmark of Parkinson’s disease (PD) is the aggregation of alpha-synuclein (a- syn) into fibrillary assemblies in nerve cells. The aggregates, termed Lewy bodies and Lewy neurites, are first found in the vagus nerve and olfactory bulb. More and more evidence is showing that a-syn spreads in a prion-like fashion transferring aggregated a-syn from cell to cell. The involvement of non-neuronal cells in this process has been studied, but evidence of the underlying mechanisms in human tissue is lacking. For the first time, we utilize primary neuronal cultures from human biopsies (consisting of functional neurons, microglia, astrocytes, oligodendrocytes and pericytes) and pure pericyte cultures. Our in vitro results show α-syn precipitates are endocytosed by all cell types, but most efficiently by microglia and pericytes. Using pure pericyte cultures, we demonstrate intercellular transport of α-syn through tunnelling nanotubes and the induction of an inflammatory response. Our in situ work shows that the number of cells with intracellular α-syn precipitates is case dependent but affects all major cell types. Within the human olfactory bulb, neurons contain large lewy bodies whereas the non-neuronal cells contain smaller aggregates. This is the first time that a human study quantified the relative importance of all cell types involved in a-syn pathology. We show evidence that α-syn spread is attributed, in part, to intercellular transmission between non-neuronal cells trough tunnelling nanotubes. The active involvement of non-neuronal cells such as pericytes in a-syn transfer has previously been overlooked, but may offer additional therapeutic targets to conventional PD therapy.