Coregulation of light neurofilament mRNA by poly(A)-binding protein and aldolase C: implications for...

The multifunctional proteins aldolase C and poly (A)-binding protein (PABP) undergo competitive interactions in cells coexpressing aldolase C and NF-L. A specific in vivo interaction between aldolase C and NF-L mRNA had been localized to a 68 nt segment of the transcript spanning the translation termination signal. It is shown here that the poly (A)-binding protein (PABP) binds the body of the NF-L transcript and increases its levels of expression when an excess of PABP is transiently provided in trans. Immunoprecipitation of PABP-associated ribonucleoprotein complexes of human spinal cord pulls down the dimeric form of aldolase C suggesting that their co-regulation of NF-L expression could be linked to the oligomerization status of aldolase C. An ex vivo model of mRNA decay has assessed mechanisms whereby aldolase C and PABP control NF-L expression. This model shows that aldolase C is a zinc-activated ribonuclease that cleaves the transcript at sites closed to the end-terminal structures. Immunological and biochemical depletion of endogenous PABP increases the instability of the transcript suggesting that PABP shields the NF-L mRNA from aldolase attack. An in vitro model shows that a mutant NF-L 68, in which the 45 nt of proximal 3'-UTR is replaced with unrelated sequence, is not degraded by aldolase C. Taken together, the findings might have important consequences for understanding causal mechanisms underlying neurodegeneration.