Troyer Syndrom (SPG 20 ) genetic and functional analysis of a microtubli-associated disease


Applicants:
Dr. med. Beate Winner, Dr. med. Gökhan Uyanik, Dr. med. Norbert Weidner, Dr. rer. nat. Sebastien Couillard-Despres, Dr. rer. nat. Ludwig Aigner, Prof. Dr. med. Jürgen Winkler
Klinik und Poliklinik für Neurologie der Universität Regensburg am Bezirksklinikum
Universitätsstrasse 84
93053 Regensburg

More than 20 gene loci for hereditary spastic paraplegia (HSP) have been discovered, which are associated with a degeneration of the corticospinal tract. Considering that different molecular mechanisms and interactions may be responsible for the degeneration of long-projecting axons, some of the thus far identified gene products have in common that they interact with microtubuli. Microtubuli play an important role for both axonal and intracellular transport. It has been suggested that disturbed microtubuli interaction in long-projecting axons leads to degenerative changes. Therefore, the functional characterization of microtubuli for the development and maintainance of long projecting axons has become a central focus of HSP research.

Spartin, a microtubule interacting and trafficking molecule

For the Troyer syndrome (SPG 20) a frameshift mutation encoding spartin has been identified (Patel et al., 2002). Multiple sequence alignment has revealed the presence of a sequence domaine of about 80 amino acids that is mutated in both Spartin and Spastin associated HSP. For this domaine the descriptive name MIT (microtutule interacting and trafficking molecules) has been proposed (Ciccarelli et al., 2003). Due to the existing homology of Spastin and Spartin, this project hypothezises that Spartin (9 Exons, 43,3 kB) plays a crucial role for the microtubuli interaction. The project aims at characterizing the molecular mechanisms of Spartin.

The following approaches are propos

  1. Analysis of genes both mutated in HSP and involved in microtubuli trafficking with special focus on Spartin.
  2. By generation of a polyclonal antibody against Spartin a temporal and spatial expression analysis will be performed in vivo (using a rodent model with lesions of the corticospinal tract).
  3. The interaction between Spartin and microtubuli will be characterized by using a green flourescent Spartin construct in adult neuronal and glial progenitors in vitro.
The people from Regensburg: Uyanik, Couillard-Desprès, Weidner, Winner, Aigner, Winkler
Final reporting

Please refer to the German page and/or to there mentioned litarature citations.