Coregulation of light neurofilament mRNA by poly(A)-binding protein and aldolase C: implications for neurodegeneration.
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.
Stefanizzi
Ida
I
Division of Neuropathology, Department of Pathology and Laboratory Medicine, 608 Stellar Chance, University of Pennsylvania Medical Center, Philadelphia, PA 19104, USA.
Cañete-Soler
Rafaela
R
D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002478:Cells, Cultured; D005634:Fructose-Bisphosphate Aldolase / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes; D051379:Mice; D008969:Molecular Sequence Data; D009046:Motor Neurons / Q000201:enzymology / Q000378:metabolism; D009410:Nerve Degeneration / Q000378:metabolism*; D016900:Neurofilament Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000201:enzymology / Q000378:metabolism*; D039102:Poly(A)-Binding Proteins / Q000378:metabolism*; D020871:RNA Stability / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism
D007527:Isoenzymes; D016900:Neurofilament Proteins; D039102:Poly(A)-Binding Proteins; D012333:RNA, Messenger; C044882:neurofilament protein L; D005634:Fructose-Bisphosphate Aldolase