Impaired cholesterol metabolism restored
Impaired human pluripotent stem cell derived neurons associated with SPG3A disrupted cholesterol transfer between cell types leading to cholesterol deficiency in the neurons.
Restoration of cholesterol levels rescued axonal degeneration in SPG3A neurons
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.
SOURCE: Acta Neuropathol Commun. 2020 Dec 7;8(1):214. doi: 10.1186/s40478-020-01088-0. PMID: 33287888
Impaired lipid metabolism in astrocytes underlies degeneration of cortical projection neurons in hereditary spastic paraplegia
1 Department of Biomedical Sciences, University of Illinois College of Medicine Rockford, Rockford, IL, 61107, USA.
2 Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, 60607, USA.
3 Waisman Center, Department of Neuroscience, Department of Neurology, University of Wisconsin, Madison, WI, 53705, USA.
4 Department of Neuroscience, University of Connecticut Health Center, Farmington, CT, 06030, USA.
5 Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, CT, 06030, USA.
6 Cell Biology Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892, USA.
7 Department of Biomedical Sciences, University of Illinois College of Medicine Rockford, Rockford, IL, 61107, USA.
8 Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, 60607, USA.