Advanced Scholarship for the research into Hereditary Spastic Paraplegia
Carol Marchetto, Fred H. Gage
Zacharias Kohl, Jürgen Winkler
Individualized human in vitro model for hereditary spastic paraplegia
Hereditary spastic paraplegia (HSP) is a heterogeneous group of neurodegenerative disorders in which the most prominent characteristic is the degeneration of spinal cord tracts. Clinically patients suffer from progressive spasticity and weakness of the lower limbs. Neuropathologically retrograde axonal degeneration of the corticospinal tracts and posterior columns are described. In recent years, genetic studies have identified key genes in HSP. Mechanistically, impaired axonal transport due to defects in microtubuli interactions as well as mitochondrial dysfunction were suggested, leading to dying back of long-projecting axons. Part of the lack of causal therapeutic options is a lack in humanized models of the disease.
The entire field has changed since the discovery of induced pluripotent stem (iPS) cells. Somatic cells can be directly reprogrammed
in vitro into a pluripotent embryonic stem cell-like state. These iPS cells can be generated from human skin cells and in particular have been shown to be able to differentiate into neurons and motor neurons. The aim of our study will be to establish phenotypic iPS cells from patients with hereditary spastic paraplegia (HSP) skin samples and differentiate those into motor neurons. We will investigate axonal pathology of those human patient derived motor neurons. We will focus on genetically defined SPG4 (most frequent dominant form of HSP) and SPG11 (most frequent recessive form of HSP). We will investigate cellular and molecular abnormalities that may underlie the disturbance in axonal transport and maintenance in these patient’s motor neurons and test the individual potential of drug candidates and targets for pharmacological intervention.