Michael J. Fox Foundation for Parkinson's Research
*Update - April 2013
Alpha-Synuclein Viral Vectors
Alpha-synuclein was the first gene to be linked to Parkinson’s disease (PD) and remains the most promising link to PD pathogenesis. Alpha-synuclein is a major component of Lewy bodies, a cardinal feature of PD pathology and the evidence that it may play a causal role in PD comes from variety of human genetic studies. These include mutations (such as A53T), duplication/triplication effects and polymorphisms, all of which point to alpha-synuclein as a potentially toxic protein in both sporadic and familial PD, and not just simply a marker of PD pathology. Given its clinical impact in pathogenesis, alpha-synuclein represents a clear and compelling molecular target for drug development.
Given all of this information however, evaluation of therapeutics targeting alpha-synuclein levels are hampered due to the paucity of pre-clinical models that faithfully re-constitute the pathological changes associated with PD – including lewy bodies and nigral degeneration. Moreover, the field is still working to determine whether alpha-synuclein plays a true causal role in the initiation of PD or whether it is a byproduct of a cascade of factors that have already occurred during the course of this disease’s progression.
In an effort to assist the field with addressing these key questions, The Michael J. Fox Foundation for Parkinson’s Research (MJFF) has generated a key tool to aid researchers in expressing alpha-synuclein, and addressing how therapeutics may alter its expression. Working with the UNC Vector Core, MJFF has supported the generation of AAV2 and AAV5 viral vectors encoding alpha-synuclein. Details of these vectors, as well as control vectors can be found below:
These vectors are concurrently being characterized by PD experts – Drs. Deniz Kirik (Lund University) and Ron Mandel (University of Florida) -- in in vivo models for their ability to express either alpha-synuclein or eGFP. Below, you will find data from an early time point demonstrating expression of both proteins in the substantia nigra.
Assessment of these vectors at longer time points is planned in an effort to determine the extent to which they can recapitulate the degeneration and associated pathology that has previously been demonstrated in the published literature.
GFP or Alpha-Synuclein expression in the rat striatum (top panel) and midbrain substantia nigra (SN) (bottom panel) 2 weeks post-injection. Animals received unilateral SN injections (2-ml volume) with one of the following vectors: rAAV2-GFP (first column), rAAV2-Alpha-Synuclein (second column), rAAV5-GFP (third column), or rAAV5-Alpha-Synuclein (fourth column).
Vectors were constructed, produced, and titered by UNC Vector Core.
Figure courtesy of Dr. Joseph Flores and Dr. Deniz Kirik (BRAINs Unit, Lund University, Lund, Sweden).
For investigators wishing to access these viral vectors, please complete the Viral Vector Request Form and return via email to Lori Nisi.
Please note the following points:
- Requests greater than 10 aliquots/viral vector/requester will not be possible
- Requesters will need to provide a FedEx account number for shipment
- There is a $50 processing fee per shipment
- Requestors agree to provide MJFF with feedback regarding use of these viral vector