The Genetic Basis of Resilience in Hereditary Spastic Paraplegia Type SPG4

• Applicants: Professor Dr. Stephan Ossowski, Ph.D.; Professorin Dr. Rebecca Schüle
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Clinical Neurology; Neurosurgery and Neuroradiology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 514208594

Hereditary Spastic Paraplegia (HSP) type 4 (SPG4) is the most common form of HSP, manifesting with progressive lower-limb spasticity and weakness due to degeneration of corticospinal tract motoneurons. SPG4 is caused by mutations in the SPAST gene, coding for the microtubule severing enzyme spastin, which are transmitted in an autosomal dominant manner.Attempts to develop causal or disease modifying therapies for SPG4 have failed, as a heterogeneous mutation spectrum with mostly private mutations and a complex disease biology have hampered both mutation-targeting as well as pathway-directed approaches.Age of onset can differ dramatically between SPG4 cases and range from congenital manifestations to old age. The underlying SPAST mutation does not fully explain this variability as we frequently observe discordant age of onset even within families sharing the same causal SPAST mutation.We postulate that a shift in focus from risk to resilience – from pathogenic SPAST variants to genomic resilience factors allowing some individuals to maintain normal motor function well into old age despite presence of a harmful SPAST mutation – presents an opportunity to identify promising new therapeutic targets as well as enable a better understanding of processes involved in motoneuron health and longevity.To uncover these genomic resilience factors, we will apply three principal approaches: (1) Case/control approach: We will select ‘extreme phenotypes’, i.e. individuals with very early and very late disease onset from a large cohort of ~1300 SPG4 index cases. We will then perform single variant and gene-based rare variant association studies (RVAS) based on whole genome (WGS) and transcriptome (RNA-Seq) sequencing data. (2) Discordant family approach: To control for effects of the underlying SPAST mutation we will select family trios with discordant age of onset, i.e. age of onset differences between parent and offspring of > 20 years. Family based association testing (FBAT) based on WGS and RNA-Seq will be performed under different model assumptions (protective / harmful variants; inheritance from affected / unaffected parent). (3) In a large SPG4 family with > 90 family members in 5 generations we will perform WGS and RNA-Seq and adapt the RVAS and FBAT methodologies to this uniquely large pedigree. Candidate modifiers identified in all three approaches will be validated in an independent SPG4 cohort (n=800); their impact on other genetic subtypes of HSP will be evaluated and functional validation of modifier effects on cellular phenotypes will be performed in cellular model systems. In this project we hope to identify genomic variants mediating resilience towards harmful effects of pathogenic variants in SPG4 and potentially other forms of HSP. If successful, these variants could be prime targets for therapy development that would benefit many patients with this so far untreatable progressive condition.

• DFG Programme: Research Grants