ArticleActa neuropathologica communications2020
Impaired lipid metabolism in astrocytes underlies degeneration of cortical projection neurons in hereditary spastic paraplegia.
Article in Acta neuropathologica communications, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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29 citing papers in PubMed, 54 citations in OpenAlex.
- Inter-Organelle Membrane Contact Sites as Physiological Regulatory Hubs in the Brain: From Neurons to Glial Cells.Biomolecules · 2026Review
- Role of LXRβ in oligodendrocytes in neuronal survival.Molecular psychiatry · 2026Article
- Small peptide P110 mitigates axonal degeneration of SPG15 patient iPSC-derived neurons by targeting mitochondrial dysfunction.Neurobiology of disease · 2025Article
- LXR agonist rescues synaptic dysfunction and degeneration in SPG3A patient-specific iPSC-derived neurons.Acta neuropathologica communications · 2025Article
- Review
- ER nests are specialized ER subdomains in Arabidopsis where peroxisomes and lipid droplets form.Developmental cell · 2025Article
- Glycerophospholipids in ALS: insights into disease mechanisms and clinical implication.Molecular neurodegeneration · 2025Review
- Role of glial cells in motor neuron degeneration in hereditary spastic paraplegias.Frontiers in cellular neuroscience · 2025Review
- Interplay between lipid droplets and alpha-synuclein: implication in Parkinson's disease pathogenesis.Frontiers in molecular neuroscience · 2025Review
- Development of Calcium-Dependent Phospholipase A2 Inhibitors to Target Cellular Senescence and Oxidative Stress in Neurodegenerative Diseases.Antioxidants & redox signaling · 2024Review
- Cell type-specific gene therapy confers protection against motor neuron disease caused by a TFG variant.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Axon demyelination and degeneration in a zebrafishOpen biology · 2024Article
- An Automated Imaging-Based Screen for Genetic Modulators of ER Organisation in Cultured Human Cells.Cells · 2024Article
- Distinct forebrain regions define a dichotomous astrocytic profile in multiple system atrophy.Acta neuropathologica communications · 2024Article
- Metabolite profile in hereditary spastic paraplegia analyzed using magnetic resonance spectroscopy: a cross-sectional analysis in a longitudinal study.Frontiers in neuroscience · 2024Article
- Liver-X-receptor agonists rescue axonal degeneration in SPG11-deficient neurons via regulating cholesterol trafficking.Neurobiology of disease · 2023Article
- Disruption of cortical cell type composition and function underlies diabetes-associated cognitive decline.Diabetologia · 2023Article
- The Role ofInternational journal of molecular sciences · 2023Article
- RINT1 deficiency disrupts lipid metabolism and underlies a complex hereditary spastic paraplegia.The Journal of clinical investigation · 2023Article
- Bioorthogonal Stimulated Raman Scattering Imaging Uncovers Lipid Metabolic Dynamics inGEN biotechnology · 2023Article
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Authors and funding
8 authors at 5 institutions in 1 country.
Funding
Abstract
Hereditary spastic paraplegias (HSPs) are caused by a length-dependent axonopathy of long corticospinal neurons, but how axons of these cortical projection neurons (PNs) degenerate remains elusive. We generated isogenic human pluripotent stem cell (hPSC) lines for two ATL1 missense mutations associated with SPG3A, the most common early-onset autosomal dominant HSP. In hPSC-derived cortical PNs, ATL1 mutations resulted in reduced axonal outgrowth, impaired axonal transport, and accumulated axonal swellings, recapitulating disease-specific phenotypes. Importantly, ATL1 mutations dysregulated proteolipid gene expression, reduced lipid droplet size in astrocytes, and unexpectedly disrupted cholesterol transfer from glia to neurons, leading to cholesterol deficiency in SPG3A cortical PNs. Applying cholesterol or conditioned medium from control astrocytes, a major source of cholesterol in the brain, rescued aberrant axonal transport and swellings in SPG3A cortical PNs. Furthermore, treatment with the NR1H2 agonist GW3965 corrected lipid droplet defects in SPG3A astrocytes and promoted cholesterol efflux from astrocytes, leading to restoration of cholesterol levels and rescue of axonal degeneration in SPG3A cortical PNs. These results reveal a non-cell autonomous mechanism underlying axonal degeneration of cortical PNs mediated by impaired cholesterol homeostasis in glia.
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