Hereditary Spastic Paraplegias (HSPs) represent a heterogeneous group of neurodegenerative disorders that result in lower limb spasticity and weakness. Mutations that affect more than 80 unique proteins, which function in disparate cellular processes, have been linked to these debilitating neuropathies. Our goal is to understand how seemingly unrelated mutations underlying HSPs can result in highly similar clinical outcomes. To address this issue, we have created a series of pre-clinical rat models of HSP, based on pathological mutations identified in patients that are believed to regulate distinct cellular processes. We are now uniquely poised to make headway in defining disease etiology, having demonstrated recently that several of our rat models recapitulate human disease phenotypes much more accurately as compared to previously established murine models. In particular, preliminary studies using a subset of our rat models have revealed progressive loss of hind limb function, spasticity, cortical atrophy, and thinning of the corpus callosum, phenotypes typically associated with HSP in humans. In this proposal, we will investigate disease onset and progression in multiple genetic contexts to identify commonalities across multiple HSPs and define early hallmarks of disease. Although HSP-related genes function in different cellular processes, we hypothesize that dysregulation of specific cellular stress pathways, including the unfolded protein response represent a unifying feature of HSP progression. We plan to quantitatively assess unfolded protein response activation in each of our animal models from birth to disease onset and subsequently throughout disease progression. Additionally, we will leverage an unbiased proteomic examination of cerebrospinal fluid collected from our animals at various timepoints during disease progression to identify potential biomarkers that are common to multiple forms of HSP. Together these studies will further our understanding of the pathomechanisms of neurodegeneration underlying HSP and potentially reveal therapeutic targets, which will facilitate the identification of treatments that are broadly efficacious across the HSP disease spectrum.
Many neurodegenerative diseases involve dysfunction of cellular stress pathways, including the unfolded protein response (UPR). The proposed research will determine how defects in neuronal proteostasis within the central nervous system contributes to axonopathy, enhancing our fundamental understanding of neurodegenerative disorders, which should facilitate the future identification of therapeutic targets for disease intervention.
