Inborn Errors of Long-Chain Fatty Acid β-Oxidation Link Neural Stem Cell Self-Renewal to Autism

Abstract

SUMMARY Inborn errors of metabolism (IEMs) occur with high incidence in human populations. Especially prevalent among these are inborn deficiencies in fatty acid β-oxidation (FAO) clinically associated with developmental neuropsychiatric disorders, including autism. We now report that neural stem cell (NSC)-autonomous insufficiencies in activity of TMLHE (an autism-risk factor that supports long-chain FAO by catalyzing carnitine biosynthesis), of CPT1A (enzyme required for long-chain FAO transport into mitochondria), or of fatty acid mobilization from lipid droplets reduced NSC pools in mouse embryonic neocortex. Lineage tracing experiments demonstrated that reduced flux through the FAO pathway potentiated NSC symmetric differentiating divisions at the expense of self-renewing stem cell division modes. The collective data reveal a key role for FAO in controlling NSC-to-IPC transition in mammalian embryonic brain, and suggest NSC self-renewal as a cellular mechanism underlying the association between IEMs and autism.

Neural Stem Cells and Nutrients: Poised Between Quiescence and Exhaustion

“…Along similar lines, inhibition of FA mobilization from lipid droplets or transport into mitochondria reduces the NSC pool in mouse embryonic neocortex by favoring NSC symmetric differentiating division. This observation, which confirms previous findings on the key role of FA oxidation (FAO) in HSC self-renewal [36], is particularly relevant, since inborn defects in FAO are associated with developmental neuropsychiatric disorders including autism in humans [37]. Of note, FAO capacity is not restricted to embryonic NSCs, but also occurs in adult cells from SVZ [38].…”

“…These studies have indeed confirmed that NSC exit from quiescence is marked by downregulation of glycolysis [37], and FAO [38], and by an increase in ribosome biogenesis, protein synthesis, and mitochondrial oxidative phosphorylation.…”

Extensive exploration of a novel rat model of Parkinson's disease using partial 6‐hydroxydopamine lesion of dopaminergic neurons suggests new therapeutic approaches

“…It is widely supposed that brain did not use fatty acids as energy substrates (Panov et al, 2014;Schönfeld and Reiser, 2013). However, although this is true for neurons, the carnitine palmitoyl transferase (CPT) system, which allows the entry of long-chain fatty acids into the mitochondria for ß-oxidation, is functional in astrocytes (Jernberg et al, 2017;Panov et al, 2014) and in embryonic (Xie et al, 2016) and adult (Knobloch et al, 2017) neural stem cells. The role of carnitine in its anti-inflammatory or energetic functions remains to be elucidated in this model and may constitute for the future a starting point for the development of innovative therapeutic.…”

Lipid Mediated Regulation of Adult Stem Cell Behavior

“…As noted above, in HSCs, a decrease in FAO leads to an increase of symmetric divisions giving rise to differentiating cells, which ultimately leads to exhaustion of the stem cell pool (Ito et al, 2012). Remarkably, deficiencies in FAO also increase the rate of mouse NSC symmetric differentiating divisions, at the expense of asymmetric divisions that normally maintain the pool of stem cells (Xie et al, 2016).…”

“…Strikingly, the presence of malonyl-CoA, which inhibits the rate-limiting step in FAO, was sufficient to induce exit from quiescence to proliferation (Knobloch et al, 2017), indicating that the tight regulation of FAO plays an important role in the regulation of NSPC behavior. FAO is also required in embryonic NSCs, where CPT1A and the breakdown of FAs from LDs have been shown to regulate the asymmetric divisions and maintenance of these stem cells (Xie et al, 2016).…”