Results using the Drosophila Npl4 gene support the hypothesis that the orthologous human gene, NPLOC4, a component of the VCP-NPL4-UFD1 ATPase complex, may be implicated in neurodegenerative disease. The human gene VCP, also a component of the VCP-NPL4-UFD1 ATPase complex, is implicated in several neurodegenerative diseases that have been effectively modeled in Drosophila (see human disease model reports for 'amyotrophic lateral sclerosis 14', FBhh0000021, and 'inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 1', FBhh0000075). Thus, other components of the complex have been investigated. RNAi-targeting constructs and alleles caused by insertional mutagenesis have been generated for Dmel\Npl4.
The human NPLOC4 has not been introduced into flies.
Pan-neuronal knockdown of Npl4 effected by RNAi causes a progressive decline in locomotor activity during the adult stage and reduced lifespan. At neuromuscular junctions, morphological neural phenotypes similar to those seen in dome (fly VSP) mutants are observed. Npl4 knockdown exacerbates neurodegeneration associated with loss of TBPH (see human disease model reports for 'amyotrophic lateral sclerosis 10', FBhh0000017). Physical interactions of Dmel\Npl4 have been described; see below and in the Npl4 gene report.
[updated Jul. 2018 by FlyBase; FBrf0222196]
The VCP-NPL4-UFD1 AAA ATPase complex is required for the efficient dislocation of ER-lumenal degradation substrates, and their subsequent proteolysis by the proteasome. (GO:0034098; https://www.ebi.ac.uk/QuickGO/term/GO:0034098)
One to one: 1 human to 1 Drosophila.
High-scoring ortholog of human NPLOC4 (1 Drosophila to 1 human). Dmel\Npl4 shares 49% identity and 67% similarity with the human gene.
