2026-07-09 | Mutation-specific cellular mechanisms in Drosophila models of ATL1-associated hereditary spastic paraplegia.
Mutations in ATL1 are a frequent cause of autosomal dominant hereditary spastic paraplegia (HSP), yet patients display a wide range of clinical severity, from slowly progressive "pure" to severe, early-onset "complex" forms. The cellular mechanisms underlying this heterogeneity remain poorly defined, and mammalian model systems have thus far failed to distinguish between these subtypes. This study investigates the cellular basis of these clinically distinct forms of HSP using Drosophila models carrying homologous disease-causing mutations in the gene encoding Atlastin-1 (ATL1). Drosophila harbouring a complex ATL1-HSP mutation display reduced locomotor function, impaired development, and decreased survival relative to those carrying mutations associated with pure ATL1-HSP, recapitulating key aspects of clinical heterogeneity. Moreover, cellular analyses identify distinct pathological features across genotypes. Models of pure ATL1-HSP display disrupted lipid homeostasis, including lipid droplet accumulation within nerves comprising long motor neuron axons, which is partially ameliorated by treatment with a liver X receptor (LXR) agonist. In contrast, complex ATL1-HSP Drosophila lack lipid droplet abnormalities and do not respond to LXR activation but instead show disruption of the neuronal endoplasmic reticulum, consistent with aberrant ER network regulation. Together, these findings suggest that different mutations in Atl give rise to distinct cellular perturbations, suggesting a potential basis for phenotypic heterogeneity in ATL1-HSP.
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2026-06-29 | Rescue of mitochondrial and neurite pathology in SPG7 hereditary spastic paraplegia patient-derived cortical neurons.
Biallelic pathogenic variants in SPG7 are a frequent cause of hereditary spastic paraplegia leading to progressive disability due to a length-dependent degeneration of cerebellar and cortical projection neurons. While underlying mechanisms have been linked to impaired mitochondrial function, no disease-modifying therapy is available. We generated induced pluripotent stem cell-derived cortical neurons from SPG7 patients with non-sense or truncating variants and from matched controls. We performed detailed phenotyping of neuronal differentiation, as well as mitochondrial and neuritic morphology and function. We explored the effects of Bz-423, a modulator of the mitochondrial permeability transition pore, as a potential rescue of SPG7-specific cellular phenotypes. We successfully differentiated SPG7 patient-derived neurons, without quantitative differences in differentiation compared with controls. However, we delineate neurite-specific aberrations of mitochondrial morphology and ultrastructure. Moreover, anterograde axonal mitochondrial transport was impaired in SPG7. Exposure to Bz-423 rescued ultrastructural and functional phenotypes. In summary, our data show impaired neuritic mitochondria in a patient-specific human model, and we here demonstrate for the first time beneficial effects of Bz-423 on neuritic ultrastructure and function in a human neuronal SPG7 system. Moreover, we identify the mitochondrial permeability transition pore as a molecular target to rescue phenotypes also in carriers of non-sense or truncating SPG7 variants.
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2026-06-20 | Proteomic analysis reveals early pathological defects in corticospinal motor neurons of a spastin model of hereditary spastic paraplegia, which are improved by NU-9 treatment.
Upper motor neuron (UMN) degeneration is a characteristic feature of hereditary spastic paraplegia (HSP), a genetically heterogeneous heritable neurodegenerative disorder resulting from mutations in over ninety genes. The mutations in the SPAST gene, which encodes the microtubule-severing protein spastin, are responsible for about 40% of all HSP cases. To date, the cellular and molecular mechanisms linking mutant spastin protein to UMN vulnerability in HSP patients remain unknown and there are no disease modifying therapies. To address this knowledge gap, we isolated pure populations of corticospinal motor neurons (CSMN; a.k.a. UMN in mice) from SPASTC448Y-UeGFP reporter mice at two pre-symptomatic time points and performed bottom-up proteomic analyses to reveal changes in their proteome that informs the underlying causes of their initial vulnerability. We find dynamic changes in their proteome and that limitations with cytoarchitectural integrity and stability of key organelles contribute to their neuronal vulnerability. Since the compound NU-9 was shown to improve similar cellular problems in CSMN that are diseased due to misfolded SOD1 toxicity and TDP-43 pathology, we further investigated its effect on the well-established pathological features of HSP that are recapitulated in the SPASTC448Y mice. We find that NU-9 treatment (100 mg/kg, for 100 days) significantly prevented degeneration of corticospinal axons, restored the integrity of mitochondria and endoplasmic reticulum, and reduced the presence of electron-dense accumulations in the CSMN of SPASTC448Y mice.
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