Loss of Drosophila NUS1 results in cholesterol accumulation and Parkinson's disease-related neurodegeneration.

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.

Eg5 UFMylation promotes spindle organization during mitosis.

UFMylation is a highly conserved ubiquitin-like post-translational modification that catalyzes the covalent linkage of UFM1 to its target proteins. This modification plays a critical role in the maintenance of endoplasmic reticulum proteostasis, DNA damage response, autophagy, and transcriptional regulation. Mutations in UFM1, as well as in its specific E1 enzyme UBA5 and E2 enzyme UFC1, have been genetically linked to microcephaly. Our previous research unveiled the important role of UFMylation in regulating mitosis. However, the underlying mechanisms have remained unclear due to the limited identification of substrates. In this study, we identified Eg5, a motor protein crucial for mitotic spindle assembly and maintenance, as a novel substrate for UFMylation and identified Lys564 as the crucial UFMylation site. UFMylation did not alter its transcriptional level, phosphorylation level, or protein stability, but affected the mono-ubiquitination of Eg5. During mitosis, Eg5 and UFM1 co-localize at the centrosome and spindle apparatus, and defective UFMylation leads to diminished spindle localization of Eg5. Notably, the UFMylation-defective Eg5 mutant (K564R) exhibited shorter spindles, metaphase arrest, spindle checkpoint activation, and a failure of cell division in HeLa cells. Overall, Eg5 UFMylation is essential for proper spindle organization, mitotic progression, and cell proliferation.

Strategic Implementation of Fragile X Carrier Screening in China: A Focused Pilot Study.

Fragile X syndrome is the leading genetic cause of intellectual disability and autism spectrum disorders. Female premutation carriers exhibit no obvious symptoms during reproductive age, but the premutation allele can expand to full mutation when transmitted to the fetus. Given the relatively low prevalence but large population, the distinct health care system, the middle-income economic status, and low awareness among public and medical professionals, the optimal genetic screening strategy remains unknown. We conducted a pilot study of Fragile X carrier screening in China, involving 22,245 pregnant women and women with childbearing intentions, divided into control and pilot groups. The prevalence of Fragile X carriers in the control group was 1 of 850, similar to East Asian populations. Strikingly, the prevalence of Fragile X carriers in the pilot group was 1 of 356, which can be attributed to extensive medical training, participant education, and rigorous genetic counseling and testing protocols. Cost-effectiveness analyses of four strategies-no screening, population-based screening, targeted screening, and our pilot screening-indicated that our pilot screening was the most cost-effective option. A follow-up survey revealed that 55% of respondents reported undergoing screening because of their family history. We have successfully established a standardized system, addressing the challenges of low prevalence, limited awareness, and genetic testing complexities. Our study provides practical recommendations for implementing Fragile X carrier screening in China.