Proteolipid protein 1 pre-messenger RNA (PLP1 pre-mRNA)

Proteolipid protein 1 (PLP1) pre-messenger RNA is the primary transcript of the PLP1 gene, which encodes the most prevalent protein in the myelin sheath of the central nervous system (CNS). The PLP1 gene is subject to alternative splicing, producing both the full-length PLP1 protein and a smaller isoform known as DM20, both of which are critical for oligodendrocyte maturation and myelin stability (UniProt P60201). Mutations in the PLP1 gene, most commonly duplications, lead to Pelizaeus-Merzbacher Disease (PMD), a devastating X-linked leukodystrophy characterized by the failure of myelination and subsequent neurodegeneration (PubMed: 32612235). In PMD patients with PLP1 duplication, the resulting protein overexpression is toxic to oligodendrocytes, triggering the unfolded protein response (UPR) and cell death (PubMed: 31581071). Consequently, PLP1 pre-mRNA is a high-priority therapeutic target for antisense oligonucleotides (ASOs) like ION464, which are designed to bind the pre-mRNA and induce its degradation via RNase H (Ionis Pharmaceuticals). By reducing the dosage of PLP1 transcripts, these therapies aim to lower toxic protein levels, alleviate cellular stress, and restore the capacity for myelination in the CNS (PubMed: 32612235).

Other names

Myelin proteolipid protein pre-mRNAPLP pre-mRNALipophilin pre-mRNAPLP1 primary transcript

Antisense oligonucleotide-mediated RNase H degradation of pre-mRNA to reduce toxic protein overexpression