Loss ofDrosophila NUS1results in cholesterol accumulation and Parkinson’s disease‐related neurodegeneration

Abstract

NgBR is the Nogo‐B receptor, encoded by NUS1 gene. As NgBR contains a C‐terminal domain that is similar to cis‐isoprenyltransferase (cis‐IPTase), NgBR was speculated to stabilize nascent Niemann‐Pick type C 2 (NPC2) to facilitate cholesterol transport out of lysosomes. Mutations in the NUS1 were known as risk factors for Parkinson's disease (PD). In our previous study, it was shown that knockdown of Drosophila NUS1 orthologous gene tango14 causes decreased climbing ability, loss of dopaminergic neurons, and decreased dopamine contents. In this study, tango14 mutant flies were generated with a mutation in the C‐terminal enzyme activity region using CRISPR/Cas9. Tango14 mutant showed a reduced lifespan with locomotive defects and cholesterol accumulation in Malpighian tubules and brains, especially in dopaminergic neurons. Multilamellar bodies were found in tango14 mutants using electron microscopy. Neurodegenerative‐related brain vacuolization was also detected in tango14 knockdown flies in an age‐dependent manner. In addition, tango14 knockdown increased α‐synuclein (α‐syn) neurotoxicity in α‐syn‐overexpressing flies, with decreased locomotive activities, dopamine contents, and the numbers of dopaminergic neurons in aging flies. Thus, these observations suggest a role of NUS1, the ortholog of tango14, in PD‐related pathogenesis.

Development of CRISPR Cas9, spin-off technologies and their application in model construction and potential therapeutic methods of Parkinson’s disease

“…Specifically, the loss of UCH deubiquitination promotes mitochondrial autophagy by activating the expression of AMPK and ULK1 (Ham et al, 2021). In Drosophila, researchers used CRISPR-Cas9 to knock out tango14, the homologous gene of NUS1, and found that the lifespan of Drosophila was shortened, and cholesterol accumulation appeared in dopaminergic neurons, which confirms that this gene is associated with the occurrence of PD due to lipid metabolism abnormalities (Xue et al, 2022).…”

Case report: Identification of a recurrent pathogenic DHDDS mutation in Chinese family with epilepsy, intellectual disability and myoclonus

“…Previous studies have suggested that dolichol plays a crucial role in membrane trafficking, particularly between the ER and lysosomal-endosomal system, which is critical for brain development ( Wu et al, 2017 ; Stojkovska et al, 2022 ). In addition, DHDDS can form a complex with the NUS1-encoded Nogo-B receptor (NgBR) ( Bar-El et al, 2020 ), another key gene involved in neurodegeneration ( Xue et al, 2022 ), which can further regulate protein glycosylation ( Edani et al, 2020 ). In this study, the recurrent pathogenic mutation (NM_001243564.1, c.113G>A/p.…”