Clinically relevant intronic splicing enhancer mutation in myelin proteolipid protein leads to progressive microglia and astrocyte activation in white and gray matter regions of the brain

Table 3 Proteolipid protein (PLP) mutant mouse models show glial activation

Mouse model	Type of mutation	PMD	Major pathology	Reactive glia response
PLP1-null [26]	Targeted KO of PLP and DM20	yes [48, 49]	Myelin ↔ / OL # ↔ / motor ↓↓↓ @ 16mo / normal lifespan	Astrocytes ↑↑ / microglia ↑↑ after 12 months [22]
PLP-ISEdel [35]	KI of intronic splicing enhancer	yes [34]	Myelin ↔ / OL # ↔ / motor ↓ / normal lifespan	Astrocytes ↑↑↑ / microglia ↑↑↑ [current]
PLP1dub [21]	Genomic duplication PLP1 locus	yes [50]	Myelin ↓ / OL # (nr) / motor ↓↓ / lifespan (nr)	Astrocytes ↑↑ / microglia ↑↑ [21]
PLP1tg [20]	Overexpresses native PLP1		Myelin ↓↓ / OL # ↓↓ / motor ↓↓↓/ lethal (2 to 6 months)	Astrocytes ↑↑↑ / microglia ↑↑↑ [16, 19, 20]
PLP1-rsh [51]	Spontaneous single amino acid substitution	yes [52]	Myelin ↓↓ / OL # ↔ / motor ↓↓ / normal lifespan	Astrocytes ↑↑ / microglia ↑↑ [18]
PLP1-jp [53]	Spontaneous deletion of exon 5		Myelin ↓↓↓ / OL # ↓↓↓ / motor ↓↓↓ / lethal (around P30)	Astrocytes ↑↑ / microglia ↑↑ [16, 17]
PLP1-msd [54]	Spontaneous mutation of exon 6	yes [55]	Myelin ↓↓↓/ OL # ↓↓↓ / motor ↓↓ / lethal (around P30)	Astrocytes ↑↑↑ / microglia ↑↑↑ [15]

PLP mutant mice models are sorted by the severity of the pathophysiology, and summarized for type of PLP mutation, if mutation is found in clinical PMD population, major pathology (myelin/oligodendrocyte death/motor behavior ability/premature mortality) and reactive glia (astrocyte and microglia). Abbreviations: oligodendrocyte (OL); arrows indicate degree of change = no change ↔, mild ↑ or ↓, moderate ↑↑ or ↓↓, severe ↑↑↑ or ↓↓↓, or not reported (nr). Numbers in brackets represent relevant references.

ISSN: 1742-2094