Impaired lipid metabolism in astrocytes underlies degeneration of cortical projection neurons in hereditary spastic paraplegia

Acta Neuropathol Commun. 2020 Dec 7;8(1):214. doi: 10.1186/s40478-020-01088-0.


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.

Keywords: Astrocytes; Axonal degeneration; Cholesterol homeostasis; Cortical projection neurons; Hereditary spastic paraplegia; Human pluripotent stem cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Astrocytes / drug effects
  • Astrocytes / metabolism*
  • Astrocytes / pathology
  • Axons / drug effects
  • Axons / metabolism
  • Axons / pathology
  • Benzoates / pharmacology
  • Benzylamines / pharmacology
  • Cerebral Cortex / cytology
  • Cerebral Cortex / metabolism*
  • Cholesterol / metabolism*
  • GTP-Binding Proteins / genetics
  • Humans
  • Lipid Metabolism / drug effects
  • Lipid Metabolism / physiology*
  • Liver X Receptors / agonists
  • Membrane Proteins / genetics
  • Neurons / drug effects
  • Neurons / metabolism*
  • Neurons / pathology
  • Pluripotent Stem Cells
  • Pyramidal Tracts / cytology
  • Pyramidal Tracts / metabolism*
  • Spastic Paraplegia, Hereditary / genetics
  • Spastic Paraplegia, Hereditary / metabolism*
  • Spastic Paraplegia, Hereditary / pathology


  • Benzoates
  • Benzylamines
  • GW 3965
  • Liver X Receptors
  • Membrane Proteins
  • Cholesterol
  • ATL1 protein, human
  • GTP-Binding Proteins

Supplementary concepts

  • Spastic paraplegia 3, autosomal dominant