NDLI: Bortezomib Induces the Formation of Nuclear poly(A) RNA Granules Enriched in Sam68 and PABPN1 in Sensory Ganglia Neurons

Content Provider	Springer Nature Link
Author	Casafont, Iñigo Berciano, Maria T. Lafarga, Miguel
Copyright Year	2009
Abstract	The ubiquitin-dependent proteasome system (UPS) is the major pathway responsible for selective nuclear and cytoplasmic protein degradation. Bortezomib, a boronic acid dipeptide, is a reversible 20S proteasome inhibitor used as novel anticancer drug, particularly in the treatment of multiple myeloma and certain lymphomas. Bortezomib-induced peripheral neuropathy (BIPN) is a widely recognized dose-limiting neurotoxicity of this proteasome inhibitor, which causes a significant negative impact on the quality of life. The pathogenic mechanisms underlying bortezomib neurotoxicity are little known. In this study a rat was used as our animal model to investigate the bortezomib-induced nuclear changes in dorsal root ganglia (DRG) neurons. Our results indicate that this neuronal population is an important target of bortezomib neurotoxicity. Nuclear changes include accumulation of ubiquitin–protein conjugates, reduction of transcriptional activity, and nuclear retention of poly(A) RNAs in numerous spherical or ring-shaped dense granules. They also contained the RNA-binding proteins PABPN1 (poly(A) binding protein nuclear 1) and Sam68, but lacked the mRNA nuclear export factors REF and Y14. At the cytoplasmic level, most neurons exhibited chromatolysis, supporting the inhibition of mRNA translation. Our results indicate that bortezomib interferes with transcription, nuclear processing and transport, and cytoplasmic translation of mRNAs in DRG neurons. They also support that this neuronal dysfunction is an essential pathogenic mechanism in the BIPN, which is characterized by sensory impairment including sensory ataxia.
Starting Page	167
Ending Page	178
Page Count	12
File Format	PDF
ISSN	10298428
Journal	Neurotoxicity Research
Volume Number	17
Issue Number	2
e-ISSN	14763524
Language	English
Publisher	Springer-Verlag
Publisher Date	2009-07-16
Publisher Place	New York
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Proteasome inhibitors Bortezomib Sensory ganglia neurons poly(A) RNA retention Sam68 Chromatolysis Rat Neurobiology Pharmacology/Toxicology Neurochemistry Neurology Pharmaceutical Sciences/Technology Neurosciences
Content Type	Text
Resource Type	Article
Subject	Neuroscience Toxicology

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