Monitoring the interactions between alpha-synuclein and Tau in vitro and in vivo using bimolecular fluorescence complementation

Abstract

Parkinson’s disease (PD) and Alzheimer’s disease (AD) are characterized by pathological accumulation and aggregation of different amyloidogenic proteins, α-synuclein (aSyn) in PD, and amyloid-β (Aβ) and Tau in AD. Strikingly, few PD and AD patients’ brains exhibit pure pathology with most cases presenting mixed types of protein deposits in the brain. Bimolecular fluorescence complementation (BiFC) is a technique based on the complementation of two halves of a fluorescent protein, which allows direct visualization of protein–protein interactions. In the present study, we assessed the ability of aSyn and Tau to interact with each other. For in vitro evaluation, HEK293 and human neuroblastoma cells were used, while in vivo studies were performed by AAV6 injection in the substantia nigra pars compacta (SNpc) of mice and rats. We observed that the co-expression of aSyn and Tau led to the emergence of fluorescence, reflecting the interaction of the proteins in cell lines, as well as in mouse and rat SNpc. Thus, our data indicates that aSyn and Tau are able to interact with each other in a biologically relevant context, and that the BiFC assay is an effective tool for studying aSyn-Tau interactions in vitro and in different rodent models in vivo.

Epidemiological Evidence for an Immune Component of Parkinson’s Disease

“…Intracellular alpha-synuclein staining in infiltrating monocytic cells from colonic biopsies of UC and CD patients was also described in a small study [ 21 ]. The co-occurrence of alpha-synuclein and tau deposits has been described in PD [ 22 ] and further supporting pathophysiological links between PD and CD, upregulation of two main human tau isoforms has been shown in the ENS of CD patients [ 23 ]. The relationship may be genetically mediated; as discussed above, there is evidence of genetic overlap between CD and PD, both from GWAS, as well as data from LRRK2 cohort studies [ 8, 24 ].…”

Differential Effects of Tau Stage, Lewy Body Pathology, and Substantia Nigra Degeneration on18F-FDG PET Patterns in Clinical Alzheimer Disease

“…Altogether, these results suggest that LBs may play a different role in AD-LB compared to pure-LB. While recent studies have provided evidence of in-vivo interactions between tau and alpha-synuclein (41), more work needs to be done to better understand how these interactions may modify the effect of LB pathology on the neurodegeneration phenotype in AD-LB.…”

Chemical and Biological Strategies for Profiling Protein‐Protein Interactions in Living Cells

“…But the exact molecular mechanism remains elusive, and no effective therapeutic drug is available so far. The BiFC assay offers such an opportunity to study αSyn‐Tau interactions in different rodent models in vivo , thereby greatly facilitating the screening of potential drugs to boost or inhibit this interaction for therapeutic intervention [15,16] …”