Pre/post-doctoral fellowship: Investigating common pathogenic mechanisms of rare genetic hereditary spastic paraplegia

We seek motivated applicants for a pre-doctoral / post-doctoral fellowship aimed at investigating molecular mechanisms of rare genetic forms of hereditary spastic paraplegia. The project combines in vitro, in silico and clinical approaches aimed at better understanding the pathogenesis of these still incurable pathologies. For the in vitro approach, the successful applicant will have a background in cellular / molecular neurobiology, with some experience in culturing primary neurons and astroglia and human fibroblasts. For more information and to send your application, please contact Dr. Fabrizia Cesca at fcesca@units.itby April 30^th, 2024. Please note that the starting date is flexible. Below a detailed abstract of the Research Project.

Hereditary Spastic Paraplegia (HSP) is linked to mutations in several genetic loci with a broad variety of clinical manifestations; despite this complexity, most HSP genes converge into a relatively small group of cellular pathways. We study two early onset, childhood forms of HSP due to mutations in the Kinase D-interacting substrate of 220 kDa (KIDINS220) gene that codes for Kidins220, a membrane protein implicated in the neurotrophic pathways controlling neural cell survival and maturation, and in the Alsin Rho Guanine Nucleotide Exchange Factor (ALS2) gene, coding for Alsin, an endosome-associated Rac1 and Rab5 activator. Kidins220 and Alsin share a number of pathways, as they are both involved in brain-derived neurotrophic factor (BDNF) signaling, AMPA receptor trafficking, mitochondrial functionality and actin cytoskeleton dynamics.

In this project, we aim at finding common pathways that are altered in rare genetic HSPs and explore their druggability as treatment option for a restricted number of patients. Our approach will be based on: (i) neurobiology experiments on primary neural cell models; (ii) patient-derived induced pluripotent stem cells differentiated into neural cells; (iii) a dedicated in silico approach. The in vitro research will address how Kidins220 and Alsin mutations affect the above-mentioned pathways. The in silico approach will inform about pathogenic mechanisms and, through virtual drug screening, about therapeutic molecules that will be cross-tested in cell-based assays. Finally, the collaboration with clinicians who are presently following KIDINS220 and ALSIN children will provide the clinical framework for our analysis. The project is intrinsically multidisciplinary, as the teams involved cover complementary aspects of the proposed research: Dr. Cesca (UniTS) for the neurobiology and neurophysiology experiments, Dr. Ermondi (UniTO) for the in silico approach, and Dr. Santorelli (IRCCS Fondazione Stella Maris, Pisa) for the clinical information of KIDINS220 and ALSIN patients.

The clinical data about KIDINS220- and ALSIN-HSP is limited and no information is available to newly diagnosed patients about their conditions or possible treatments. However, we are aware of an increasing number of patients through web-based groups and family associations, who are in contact with the Applicants and already express their will to participate to the study. Indeed, the strict collaboration between families and researchers is one of the strengths of this proposal, and one of our aims is to create a network of scientists, clinicians and family foundations working together to raise awareness about these rare conditions both within the scientific community and within the wider society. Importantly, we believe that the information collected through our study could be extended to other rare genetic HSPs impinging on the same pathways, to identify personalized treatments to improve the lives of patients and their families.