Abstract
Hypomyelinating leukodystrophy 7 (HLD7) is an autosomal recessive oligodendroglial cell-related myelin disease, which is associated with some nucleotide mutations of the RNA polymerase 3 subunit a (polr3a) gene. POLR3A is composed of the catalytic core of RNA polymerase III synthesizing non-coding RNAs, such as rRNA and tRNA. Here, we show that an HLD7-associated nonsense mutation of Arg140-to-Ter (R140X) primarily localizes POLR3A proteins as protein aggregates into lysosomes in mouse oligodendroglial FBD−102b cells, whereas the wild type proteins are not localized in lysosomes. Expression of the R140X mutant proteins, but not the wild type proteins, in cells decreased signaling through the mechanistic target of rapamycin (mTOR), controlling signal transduction around lysosomes. While cells harboring the wild type constructs exhibited phenotypes with widespread membranes with myelin marker protein expression following the induction of differentiation, cells harboring the R140X mutant constructs did not exhibit them. Ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), which is also known as an mTOR signaling activator, ameliorated defects in differentiation with myelin marker protein expression and the related signaling in cells harboring the R140X mutant constructs. Collectively, HLD7-associated POLR3A mutant proteins are localized in lysosomes where they decrease mTOR signaling, inhibiting cell morphological differentiation. Importantly, ibuprofen reverses undifferentiated phenotypes. These findings may reveal some of the pathological mechanisms underlying HLD7 and their amelioration at the molecular and cellular levels.
Highlights
Brain imaging shows that Hypomyelinating leukodystrophy 7 (HLD7) leads to thin myelin sheaths in the corpus callosum and other brain regions [9,10]
Consistent with the in vivo data, we demonstrate that HLD7associated R140X mutant proteins of POLR3A, but not the wild type proteins, are primarily localized as aggregates in lysosomes in FBD−102b cells, inhibiting the morphological differentiation in FBD−102b cells
The fact that the R140X mutation is associated with blunted morphological differentiation might be related to the thin myelin sheaths found in HLD7 patients
Summary
Hypomyelinating leukodystrophies (HLDs) are a recently classified group of hereditary neuropathies, which are primarily linked to oligodendrocytes ( called oligodendroglial cells) [1–4]. These diseases are rare, affecting one out of every 250,000 to. PLP1 is the major myelin structural protein generated by oligodendroglial cells in the central nervous system (CNS) [5–8]. Myelin sheaths contribute to the propagation of saltatory conduction, and to protecting neuronal axons from various stresses, such as physical and physiological stresses [5–8]. They play an important role in nerve functions
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