title: Understanding disease modulators of SPG11‐linked hereditary spastic paraplegia.
Creators: name: Krumm, Laura
Publisher: name: Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)
Year: 2024

description: Hereditary spastic paraplegia (HSP) is a diverse group of motor neuron disorders that is characterized by lower-limb weakness and spasticity due to a length-dependent axonopathy of the corticospinal tract. HSP type 11 (SPG11-HSP) is the most frequent form of autosomal recessive HSP and is caused by pathogenic variants in the SPG11 gene, encoding the protein spatacsin. In this complicated form, motor neuron symptoms are accompanied by a thin corpus callosum, white matter abnormalities, and progressive cognitive decline. Currently, there are no effective treatments or reliable biomarkers available. Although inflammation is pivotal in several neurological diseases, SPG11-HSP research has mainly focussed on the neurodegenerative hallmarks. For this reason, we hypothesized that neuroinflammation is a significant disease mechanism in SPG11-HSP patients which can contribute to neurodegeneration. Both aspects of the disease can therefore provide potential biomarkers for monitoring disease progression and validating treatment strategies. We performed a detailed immunological characterization of SPG11-HSP patients by analyzing human postmortem brains, peripheral blood samples, and induced pluripotent stem cell-derived microglia-like cells (iMGL). Postmortem examination of three SPG11-HSP patient brains revealed profound microgliosis, signatures of disease-associated microglia, and lipid accumulations in myeloid cells. In a larger patient cohort, the ratio of proinflammatory monocytes in the blood was increased along with elevated serum levels of IL-6 that correlated with disease severity. Moreover, we delineated a novel interplay between SPG11 and IFNγ. In control iMGL, IFNγ triggered the upregulation of SPG11, whereas, in patient-specific SPG11 iMGL, IFNγ caused hyperactivation, which was characterized by increased secretion of inflammatory factors, such as CXCL10. Enhanced STAT1 phosphorylation was identified as a mechanism connecting IFNγ-mediated hyperactivation and SPG11 loss of function. Blocking STAT1 signaling by ruxolitinib prevented the upregulation of CXCL10 and rescued the neurotoxic effects of SPG11 iMGL. Examination of human postmortem brain tissue and an Spg11-/- mouse model confirmed increased numbers of STAT1+ cells. These findings highlight the impact of innate immunity in SPG11-HSP and indicate the potential of immunomodulators to slow down disease progression. To evaluate such therapeutic approaches, biomarkers are essential to monitor disease progression. For other neurodegenerative diseases, peripheral neurofilaments have emerged as promising indicators of neuronal damage. Therefore, we aimed to assess the potential of neurofilament light (NfL) and heavy (NfH) chains as biomarkers of neurodegeneration in SPG11-HSP. Both NfL and NfH were significantly increased in the plasma of SPG11-HSP patients with excellent discriminatory performance from controls and other HSP types. In a follow-up study, the NfL level in SPG11-HSP patients increased further within one year. These data emphasize the potential of neurofilaments as a fluidic biomarker for monitoring disease progression in this complicated subtype of HSP. Overall, this study demonstrates the role of innate immunity on SPG11-related neurodegeneration and highlights inflammatory factors and neurofilaments as potential biomarkers for SPG11-HSP.