Mechanisms and rescue of axonal degeneration in hereditary spastic paraplegia neurons

SUMMARY Axonal degeneration of cortical projection neurons underlies several debilitating neurodegenerative disorders including hereditary spastic paraplegia (HSP) and amyotrophic lateral sclerosis. HSPs are a large heterogeneous group of inherited diseases characterized by length-dependent degeneration of corticospinal motor neuron axons, leading to spasticity and weakness of lower limb muscles. SPG11 and SPG15, two common autosomal recessive forms of HSP, are caused by mutations in the SPG11 and ZFYVE26 that encode spatacsin and spastizin protein, respectively. Spatacsin and spastizin are mediators for autophagy lysosomal reformation that is critical for maintaining lysosome homeostasis. However, how this impairment results in axonal degeneration and how this pathway can be targeted to rescue nerve degeneration in HSP remain unknown. Using patient induced pluripotent stem cell (iPSC)-based models of SPG11 and SPG15, our previous work has identified impaired mitochondrial dynamics in these patient stem cell-derived neurons. We further found aberrant autophagy influx and reduced lysosome transport in these neurons, implying their involvement in HSP. The goal of this proposed study is to dissect the interplays between these pathological processes and to determine their roles in axonal degeneration in HSP neurons. Based on strong preliminary data, we hypothesize that perturbed spatacsin and spastizin result in autophagy lysosomal defects and impaired mitochondrial dynamics, which interact with each other to impair cytoskeleton organization and axonal transport, leading to axonal degeneration in SPG11 and SPG15. This hypothesis will be tested by pursuing the following three aims: 1) to identify the role of spatacsin and spastizin in axonal and autophagy lysosomal defects of patient cortical projection neurons; 2) to determine the interplay between autophagy lysosomal and mitochondrial defects in axonal degeneration of SPG11 and SPG15 cortical neurons; and 3) to rescue axonal degeneration by targeting autophagy lysosomal and mitochondrial defects in vitro and in vivo. By regulating autophagy lysosomal and mitochondrial pathways both genetically and pharmacologically, this study will delineate their roles in axonal degeneration in HSP. The efficacy of targeting these pathways in rescuing axonal defects will be evaluated both in vitro using iPSC models and in vivo using HSP mouse models. Thus, the combination of iPSC model, gene targeting, and HSP animal model in this study provides unique opportunities to identify novel targets and develop potential therapeutics to effectively rescue axonal degeneration in HSP. Project Number: 1R56NS142274-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: XUE-JUN LI | Institution: UNIVERSITY OF ILLINOIS AT CHICAGO, Chicago, IL | Award Amount: $400,825 | Activity Code: R56 | Study Section: Neural Oxidative Metabolism and Death Study Section[NOMD] View on NIH RePORTER: https://reporter.nih.gov/project-details/11528579