This report describes Parkinson disease (postulated), NSF-related. NSF (N-Ethylmaleimide Sensitive Factor, Vesicle Fusing ATPase) encodes a protein required for vesicle-mediated transport, including transport from the endoplasmic reticulum to the Golgi stack. NSF has been associated with Parkinson disease in several GWAS studies. In Drosophila, there are several genes orthologous to NSF: comt and Nsf2 are high-scoring orthologs. For both fly genes, loss-of-function mutations, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.
Multiple UAS constructs of the wild-type human Hsap\NSF gene have been introduced into flies, but have not been used in the context of this disease model.
Animals homozygous for severe loss-of-function mutations of either fly gene, comt or Nsf2, typically die during the larval stage. A dominant-negative mutation of Dmel\Nsf2 expressed in neurons disrupts the structure and function of larval neuromuscular synapses. Conditional (temperature-sensitive) mutations of comt exhibit locomotor defects, shortened lifespan and progressive neurodegeneration, including loss of dopaminergic neurons. It has been shown that mutations of comt also disrupt autophagy in response to stress; it is postulated that the inability to sustain autophagy is what leads to the progressive neuronal loss and neurodegenerative phenotypes. Extensive genetic and physical interactions have been described for both Drosophila genes; see below and in the comt and Nsf2 gene reports.
See FBrf0236145 for a review of the role of autophagy in other neurodegenerative diseases that have been modeled in flies.
[updated Oct. 2017 by FlyBase; FBrf0222196]
Parkinson disease (PD) is a neurodegenerative disease usually typified by slow onset in mid to late adulthood; there are also early-onset and juvenile forms of the disease. Symptoms worsen over time and include resting tremor, muscular rigidity, bradykinesia [abnormal slowness of movement], and postural instability [impaired balance and coordination]; additional symptoms may include postural abnormalities, dysautonomia [symptoms caused by malfunction of the autonomic nervous system], dystonic cramps, and dementia. Parkinson disease is the second-most common neurodegenerative disease (after Alzheimer disease), affecting approximately 1% of the population over 50 (Polymeropoulos et al., 1996, pubmed:8895469). [from MIM:168600; 2013.07.23]
Parkinson disease is described as early-onset disease if signs and symptoms begin before age 50. Early-onset cases that begin before age 20 may be referred to as juvenile-onset disease. [from Genetics Home Reference, GHR_condition:parkinson-disease, 2015.02.13]
NSF is associated with Parkinson disease in multiple GWAS studies (see GWAS Catalog, below in 'External links').
The protein encoded by NSF (N-Ethylmaleimide Sensitive Factor, Vesicle Fusing ATPase) is required for vesicle-mediated transport. It catalyzes the fusion of transport vesicles within the Golgi cisternae and is required for transport from the endoplasmic reticulum to the Golgi stack. [Gene Cards, NSF; 2017.10.05]
High-scoring ortholog of human NSF (2 Drosophila to 1 human); one additional more distantly related gene in Drosophila. Dmel\comt shares 63% identity and 79% similarity with human NSF.
High-scoring ortholog of human NSF (2 Drosophila to 1 human); one additional more distantly related gene in Drosophila. Dmel\Nsf2 shares 63% identity and 79% similarity with human NSF.
