Skip to main content

The Impact of Oligomerization on Alpha-Synuclein Toxicity

Objective/Rationale:
We aim to find mutants of alpha-synuclein that form oligomers but do not form fibrils to specifically test their underlying toxicity in an in vivo model. This approach will establish a correlation between the formation of alpha-synuclein oligomers in vitro and the in vivo toxicity.
Project Description:
We will establish a structure toxicity relationship of alpha-synuclein by using a structure-based design of mutants that either interfere with or promote fibril formation. These data will allow us to know about the potential and speed of different (human and artificial) α-synuclein variants to form oligomers or proceed to fibril formation.
In a second step we will test the toxicity of these mutants in an experimental system by investigating dopaminergic loss in the substantia nigra. We will investigate the loss of dopaminergic cells due to alpha-synuclein variant expression and compare it to a GFP-lentivirus as well as to the non-injected contralateral side. This procedure will establish a ranking scale for the different alpha-synuclein variants from a toxic to a nontoxic form.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
In PD the process of aggregation of alpha-synuclein from monomers via oligomeric intermediates into amyloid fibrils is considered to be the disease-causative toxic mechanism. It is unknown—but essential for causative treatment—which of the various conformational entities of alpha-synuclein is the most toxic. We aim to establish a structure-toxicity relationship of alpha-synuclein. This information is essential for establishing a causative treatment to alter/hinder aggregation of alpha-synuclein.
Anticipated Outcome:
The dual approach (in vitro characterization in a cell free system and the in vivo approach) will allow us to correlate the extent of oligomer formation in vitro and toxicity in vivo and the tendency to form amyloid fibrils in vitro and toxicity in vivo. These experiments will allow us to determine the specific characteristics and action of alphasynuclein oligomerization that ultimately trigger the PD-relevant motor deficits.

Progress Report

We aim to find mutants of alpha-synuclein that are specifically forming oligomers but do not form fibrils. We will then test their underlying toxicity in an experimental in vivo model.

In the past months we have used a structure-based design of mutants that interfere with or promote fibril formation. By analyzing recombinant protein of the different mutants we have learned about the potential and speed of different alpha-synuclein variants to form oligomers or proceed to fibril formation. In a second step we tested the toxicity of these mutants in an experimental system by investigating dopaminergic loss in the substantia nigra. So far, our results indicate that oligomerizing mutants are more toxic than non-oligomerizing ones.


Researchers

Discover More Grants

Within the Same Program

Within the Same Funding Year

We use cookies to ensure that you get the best experience. By continuing to use this website, you indicate that you have read our Terms of Service and Privacy Policy.