Roles for the VCP co-factors Npl4 and Ufd1 in neuronal function in Drosophila melanogaster. (20th October 2017)

• Record Type: Journal Article
• Authors: Byrne, Dwayne J.; Harmon, Mark J.; Simpson, Jeremy C.; Blackstone, Craig; O'Sullivan, Niamh C.
• Is Part Of: Journal of genetics and genomics. Volume 44:Number 10(2017)
• Page Start: 493
• Page End: 501
• Publication Date: 2017-10-20
• Subjects: Proteasome -- TDP-43 accumulation -- Neurodegeneration -- Drosophila; ALS amyotrophic lateral sclerosis -- IBMPDF inclusion body myopathy with Paget's disease of the bone and frontotemporal dementia -- NMJ neuromuscular junction -- Npl4 nuclear protein localization homolog 4 -- TBPH TAR DNA-binding protein-43 homolog -- Ufd1 ubiquitin fusion degradation 1 -- UPS ubiquitin proteasome system -- VCP valosin-containing protein; Genetics -- Periodicals; Genomics -- Periodicals; 576.505
• DOI: 10.1016/j.jgg.2017.06.003
• Languages: English
• ISSNs: 1673-8527

Abstract

Abstract: The VCP-Ufd1-Npl4 complex regulates proteasomal processing within cells by delivering ubiquitinated proteins to the proteasome for degradation. Mutations in VCP are associated with two neurodegenerative diseases, amyotrophic lateral sclerosis (ALS) and inclusion body myopathy with Paget's disease of the bone and frontotemporal dementia (IBMPFD), and extensive study has revealed crucial functions of VCP within neurons. By contrast, little is known about the functions of Npl4 or Ufd1 in vivo . Using neuronal-specific knockdown of Npl4 or Ufd1 in Drosophila melanogaster, we infer that Npl4 contributes to microtubule organization within developing motor neurons. Moreover, Npl4 RNAi flies present with neurodegenerative phenotypes including progressive locomotor deficits, reduced lifespan and increased accumulation of TAR DNA-binding protein-43 homolog (TBPH). Knockdown, but not overexpression, of TBPH also exacerbates Npl4 RNAi-associated adult-onset neurodegenerative phenotypes. In contrast, we find that neuronal knockdown of Ufd1 has little effect on neuromuscular junction (NMJ) organization, TBPH accumulation or adult behaviour. These findings suggest the differing neuronal functions of Npl4 and Ufd1 in vivo .