Impaired lipid metabolism in astrocytes underlies degeneration of cortical projection neurons in hereditary spastic para
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RESEARCH
Impaired lipid metabolism in astrocytes underlies degeneration of cortical projection neurons in hereditary spastic paraplegia Yongchao Mou1,2, Yi Dong3, Zhenyu Chen1,2, Kyle R. Denton4, Michael O. Duff5, Craig Blackstone6, Su‑Chun Zhang3 and Xue‑Jun Li1,2*
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 earlyonset 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. Impor‑ tantly, ATL1 mutations dysregulated proteolipid gene expression, reduced lipid droplet size in astrocytes, and unex‑ pectedly 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, res‑ cued 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: Hereditary spastic paraplegia, Human pluripotent stem cells, Cortical projection neurons, Cholesterol homeostasis, Axonal degeneration, Astrocytes Introduction Hereditary spastic paraplegias (HSPs) are a large and diverse group of inherited neurodegenerative diseases with the common feature of a length-dependent axonopathy of the corticospinal axons, resulting in spasticity of lower-limb muscles and gait abnormalities [3, 22, 67]. To date, over 80 distinct genetic loci (SPG1-80, plus others) have been associated with HSP [2]. The respective gene products fall into a relatively small number of *Correspondence: [email protected] 1 Department of Biomedical Sciences, University of Illinois College of Medicine Rockford, Rockford, IL 61107, USA Full list of author information is available at the end of the article
cellular pathogenic themes, include organelle shaping/ distribution, endolysosomal function, intracellular transport, mitochondrial function, myelination, and lipid metabolism [2, 62]. The most common forms—SPG4, SPG3A, and SPG31—are caused by autosomal dominant mutations in proteins that shape and distribute the tubular endoplasmic reticulum (ER) [44, 52]. How mutations in these ER-shaping proteins result in the common axonal degeneration of cortical projection neurons (PNs) remains an enigma. SPG3A is the most common early-onset, autosomal dominant
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