| First Author | Underwood R | Year | 2021 |
| Journal | Acta Neuropathol Commun | Volume | 9 |
| Issue | 1 | Pages | 13 |
| PubMed ID | 33413679 | Mgi Jnum | J:365456 |
| Mgi Id | MGI:6727708 | Doi | 10.1186/s40478-020-01110-5 |
| Citation | Underwood R, et al. (2021) 14-3-3 mitigates alpha-synuclein aggregation and toxicity in the in vivo preformed fibril model. Acta Neuropathol Commun 9(1):13 |
| abstractText | Alpha-synuclein (alphasyn) is the key component of proteinaceous aggregates termed Lewy Bodies that pathologically define a group of disorders known as synucleinopathies, including Parkinson's Disease (PD) and Dementia with Lewy Bodies. alphaSyn is hypothesized to misfold and spread throughout the brain in a prion-like fashion. Transmission of alphasyn necessitates the release of misfolded alphasyn from one cell and the uptake of that alphasyn by another, in which it can template the misfolding of endogenous alphasyn upon cell internalization. 14-3-3 proteins are a family of highly expressed brain proteins that are neuroprotective in multiple PD models. We have previously shown that 14-3-3theta acts as a chaperone to reduce alphasyn aggregation, cell-to-cell transmission, and neurotoxicity in the in vitro pre-formed fibril (PFF) model. In this study, we expanded our studies to test the impact of 14-3-3s on alphasyn toxicity in the in vivo alphasyn PFF model. We used both transgenic expression models and adenovirus associated virus (AAV)-mediated expression to examine whether 14-3-3 manipulation impacts behavioral deficits, alphasyn aggregation, and neuronal counts in the PFF model. 14-3-3theta transgene overexpression in cortical and amygdala regions rescued social dominance deficits induced by PFFs at 6 months post injection, whereas 14-3-3 inhibition by transgene expression of the competitive 14-3-3 peptide inhibitor difopein in the cortex and amygdala accelerated social dominance deficits. The behavioral rescue by 14-3-3theta overexpression was associated with delayed alphasyn aggregation induced by PFFs in these brain regions. Conversely, 14-3-3 inhibition by difopein in the cortex and amygdala accelerated alphasyn aggregation and reduction in NECAB1-positive neuron counts induced by PFFs. 14-3-3theta overexpression by AAV in the substantia nigra (SN) also delayed alphasyn aggregation in the SN and partially rescued PFF-induced reduction in tyrosine hydroxylase (TH)-positive dopaminergic cells in the SN. 14-3-3 inhibition in the SN accelerated nigral alphasyn aggregation and enhanced PFF-induced reduction in TH-positive dopaminergic cells. These data indicate a neuroprotective role for 14-3-3theta against alphasyn toxicity in vivo. |
