Human Molecular Genetics Advance Access originally published online on February 19, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 8 829-838
DOI: 10.1093/hmg/ddh101
Oculopharyngeal muscular dystrophy-like nuclear inclusions are present in normal magnocellular neurosecretory neurons of the hypothalamus
1Department of Anatomy and Cell Biology, Biomedicine Unit Associated to the CSIC, University of Cantabria, 39011 Santander, Spain and 2Institute of Molecular Medicine, Faculty of Medicine, University of Lisbon, 1649-028 Lisboa, Portugal
Received December 12, 2003; Accepted February 13, 2004
Intranuclear inclusions composed of tubular filaments constitute a pathological hallmark of oculopharyngeal muscular dystrophy (OPMD). Autosomal dominant OPMD is caused by (GCG) repeat expansions in the gene that encodes for poly(A) binding protein nuclear 1 (PABPN1). The mutation results in the expansion of a polyalanine stretch in the N-terminus of the protein. It has been proposed that mutated PABPN1 induces protein aggregation, which in turn causes the formation of the filamentous nuclear inclusions. Here we report the presence of intranuclear inclusions composed of tubular filaments in oxytocin-producing neurons from normal rat hypothalamus. Like OPMD inclusions, the filamentous structures in neurosecretory neurons accumulate PABPN1, poly(A) RNA, ubiquitin and proteasomes. These inclusions do not contain members of Hsp40 and HDJ-2/DNAJ families of chaperones. The proportion of oxytocin-producing neurons that contain inclusions decreases during parturition and lactation (when synthesis and release of oxytocin is maximal) and increases at 1 day post-weaning (when occurs a drastic reduction in the production of the hormone). Thus, PABPN1 filaments in normal neurons are dynamic structures, the appearance of which correlate with changes in cellular activity. These data provide the first physiological evidence that polyalanine expansions are not essential to induce polymerization of PABPN1 into filamentous nuclear inclusions.
* To whom correspondence should be addressed at: Institute of Molecular Medicine, Faculty of Medicine, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal. Tel: +351 217934340; Fax: +351 217951780; Email: carmo.fonseca{at}fm.ul.pt
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