Authors: Alice Weatherston
While it is well-known that the protein alpha-synuclein aggregates within the neurons of individuals with Parkinson’s disease and propagates across connected brain regions, the mechanism underlying these changes has so far remained unclear. Many studies have proposed ‘prion-like’ behavior of the protein triggered by alterations in the formation of alpha-synuclein, however a recent study carried out by a team of researchers at the German Center for Neurodegenerative Diseases (DZNE; Bonn, Germany) has proposed an alternative mechanism for disease progression. The findings were published recently in BRAIN.
Utilizing a custom viral vector, a blueprint of the human alpha-synuclein gene was transferred into neurons within the medulla oblongata of mice, and accumulated. Specific antibodies were then used to identify and track the spread of human alpha-synuclein through the mouse brain for 6–12 weeks. Spread and pathology in normal mice, expressing both exogenous and endogenous alpha-synuclein, was also recorded and compared to the mutant, endogenous protein-lacking mice.
The team, led by Donato Di Monte (DZNE), discovered that prion-like seeding is not necessarily exhibited during the aggregation and propagation of alpha-synuclein. In both mouse groups, increased human alpha-synuclein expression resulted in its progressive spread from the medulla oblongata to more rostral brain regions. Significantly, this progression involved at least one trans-synaptic jump and occurred in a pattern consistent with diffusion via anatomically interconnected pathways.
Di Monte explained how this differed from their expectations: “we were expecting less efficient protein transmission and less pronounced pathology in mutant mice lacking endogenous alpha-synuclein. We were also expecting spreading and pathology to be associated with the accumulation of amyloidogenic alpha-synuclein; these are forms of the protein capable of producing insoluble fibrous aggregates.” Despite this, alpha-synuclein spread was increased rather than decreased by the removal of the endogenous protein in mutant mice.
“We believe that these findings bear a number of important implications for disease pathogenesis. Not only can we conclude that long-distance diffusion of alpha-synuclein does not necessarily require the generation of prion-like species. Our data also reveal that spreading and pathology can be triggered by simple overexpression of the protein and are mediated, at least initially, by monomeric and/or oligomeric alpha-synuclein,” further commented Di Monte.
The research team now plan to further analyze alpha-synuclein and to investigate how it could be targeted to slow or prevent the progression of Parkinson’s disease.
Source: DZNE press release