One major focus in the laboratory is studying the hereditary spastic paraplegias (HSPs) and other motor neuron diseases. We are specifically interested in genetic conditions in which the axons of the corticospinal motor pathway degenerate. We want to understand the normal functions of motor neuron proteins and how disruption of these functions causes axonal degeneration. Our previous work concentrated on the two most frequent HSPs, SPG4 and SPG11 and their respective proteins, spastin and spatacsin.
Spastin, a microtubule severing enzyme, functions at membrane sites, including endosomes and the endoplasmic reticulum, where it couples microtubule severing to membrane modelling processes. Using neurons derived from patients´ fibroblasts, we examine the relevance of spastin in neurons and axons.
Mutations in spatacsin are found in a spectrum of CNS and PNS diseases ranging from autosomal-recessive complicated hereditary spastic paraplegia (HSP) with thin corpus callosum, termed Spastic Paraplegia Gene 11 (SPG11), to familial young-onset amyotrophic lateral sclerosis (ALS5), and Charcot-Marie-Tooth disease (CMT2X). In neurons derived from patients with SPG11, we found an accumulation of vesicle-like structures and inclusions within the neurites from SPG11 patients indicating axonal pathology and impaired axonal function (Perez-Branguli, Mishra et al., HMG 2014). The specific transcriptome signature showed that roughly half of the differentially expressed genes in SPG11-neural progenitor cells (NPCs) were related to neural development and included transcriptional changes in the regulation of neurogenesis, neuronal differentiation, and nervous system development. An impaired GSK3ß/ß-Catenin signaling in SPG11-NPCs that could be rescued by tideglusib, an antagonist of GSK3 (Mishra et al., Annals of Neurology 2016). A novel link between a GSK3 dependent pathway and a cortical developmental phenotype in SPG11 patients is currently evaluated by taking advantage of life-cell imaging and three-dimensional organoid models.