Drosophila Smt3 negatively regulates JNK signaling through sequestering Hipk in the nucleus.

Post-translational modification by the small ubiquitin-related modifier (SUMO) is important for a variety of cellular and developmental processes. However, the precise mechanism(s) that connects sumoylation to specific developmental signaling pathways remains relatively less clear. Here, we show that Smt3 knockdown in Drosophila wing discs causes phenotypes resembling JNK gain of function, including ectopic apoptosis and apoptosis-induced compensatory growth. Smt3 depletion leads to an increased expression of JNK target genes Mmp1 and puckered. We show that, although knockdown of the homeodomain-interacting protein kinase (Hipk) suppresses Smt3 depletion-induced activation of JNK, Hipk overexpression synergistically enhances this type of JNK activation. We further demonstrate that Hipk is sumolylated in vivo, and its nuclear localization is dependent on the sumoylation pathway. Our results thus establish a mechanistic connection between the sumoylation pathway and the JNK pathway through the action of Hipk. We propose that the sumoylation-controlled balance between cytoplasmic and nuclear Hipk plays a crucial role in regulating JNK signaling.

P4HA2 hydroxylates SUFU to regulate the paracrine Hedgehog signaling and promote B-cell lymphoma progression.

Aberrations in the Hedgehog (Hh) signaling pathway are significantly prevailed in various cancers, including B-cell lymphoma. A critical facet of Hh signal transduction involves the dynamic regulation of the suppressor of fused homolog (SUFU)-glioma-associated oncogene homolog (GLI) complex within the kinesin family member 7 (KIF7)-supported ciliary tip compartment. However, the specific post-translational modifications of SUFU-GLI complex within this context have remained largely unexplored. Our study reveals a novel regulatory mechanism involving prolyl 4-hydroxylase 2 (P4HA2), which forms a complex with KIF7 and is essential for signal transduction of Hh pathway. We demonstrate that, upon Hh pathway activation, P4HA2 relocates alongside KIF7 to the ciliary tip. Here, it hydroxylates SUFU to inhibit its function, thus amplifying the Hh signaling. Moreover, the absence of P4HA2 significantly impedes B lymphoma progression. This effect can be attributed to the suppression of Hh signaling in stromal fibroblasts, resulting in decreased growth factors essential for malignant proliferation of B lymphoma cells. Our findings highlight the role of P4HA2-mediated hydroxylation in modulating Hh signaling and propose a novel stromal-targeted therapeutic strategy for B-cell lymphoma.

DJ-1 promotes the proteasomal degradation of Fis1: implications of DJ-1 in neuronal protection.

Mutations in DJ-1/PARK7 (Parkinson protein 7) have been identified as a cause of autosomal-recessive PD (Parkinson's disease) and the antioxidant property of DJ-1 has been shown to be involved in the regulation of mitochondrial function and neuronal cell survival. In the present study, we first found that the DJ-1 transgene mitigated MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced DA (dopamine) neuron cell death and cell loss. We then observed that the protein levels of DJ-1 were significantly decreased, whereas levels of Fis1 [fission 1 (mitochondrial outer membrane) homologue] were noticeably increased in the striatum of MPTP-treated mice. In addition to our identification of RNF5 (RING-finger protein-5) as an E3-ligase for Fis1 ubiquitination, we demonstrated the involvement of the DJ-1/Akt/RNF5 signalling pathway in the regulation of Fis1 proteasomal degradation. In other experiments, we found that Akt1 enhances the mitochondrial translocation and E3-ligase activity of RNF5, leading to Fis1 degradation. Together, the identification of Fis1 degradation by DJ-1 signalling in the regulation of oxidative stress-induced neuronal cell death supplies a novel mechanism of DJ-1 in neuronal protection with the implication of DJ-1 in a potential therapeutic avenue for PD.

Registered Clinical Trials Comprising Pregnant Women in China: A Cross-Sectional Study.

Background: In this study, an investigation was conducted on clinical drug trials comprising pregnant women in China that provided data on the quantity, properties, source of funding, and geographical distribution regarding registration and post-marketing studies. Methods: We conducted a cross-sectional descriptive study of clinical trials of pregnant women in China on 30 December 2021, and it was registered on the official Drug Clinical Trial Information Management Platform (ChiCTR) (http://www.chinadrugtrials.org.cn) established by the State Food and Drug Administration of China (Chinese FDA). Results: This study encompassed 72 registered trials (0.46%, 72/15,539) for data analysis. Of these trials, 43.1% of trials were started between 2013 and 2016, and nearly half of the trials (48.6%) were completed. Industries were listed as the primary sponsor for 95.8% trials. Economically developed eastern China and northern China, accounting for 69.5% of the 72 registered trials, were the most frequently identified study locations. Regarding study designs of these trials, more than half of the trials (70.8%) were randomized, 61.1% were a parallel assignment, 33.3% were phase 3, and half of the trials (54.2%) were open label. In total, 23 trials met the requirements after excluding trials of cancer and/or of postmenopausal women, accounting for 0.15% of the 15,539 registered trials in the ChiCTR websites. Of the 72 clinical trials, 54 drugs for 18 indications were included. Of these indications, the highest proportion of the trials is osteoporosis (27.8%), followed by cancer (22.2%), assisted reproduction (13.9%), and other indications (13.9%). Conclusion: This survey revealed a significant shortage of the development, evaluation, and safety trials of pregnancy-related drugs in China. Modifying or adding legislation and providing financial incentives may therefore encourage pharmaceutical companies to conduct additional clinical trials on pregnant women.

Alzheimer's Model Develops Early ADHD Syndrome.

We describe the first invertebrate model of attention deficit hyperactivity disorder (ADHD) that reproduces its major features, including hyperactivity, male predominance, marked exacerbation by simple carbohydrates, reversible response to dextroamphetamine, and a "paradoxical response" to stimulants. This model may offer new insight into ADHD pathogenesis and treatment. Furthermore, these findings are of particular interest in light of the recent epidemiological evidence showing that patients with dementia have a high frequency of antecedent ADHD symptoms.

Uif, a large transmembrane protein with EGF-like repeats, can antagonize Notch signaling in Drosophila.

BACKGROUND: Notch signaling is a highly conserved pathway in multi-cellular organisms ranging from flies to humans. It controls a variety of developmental processes by stimulating the expression of its target genes in a highly specific manner both spatially and temporally. The diversity, specificity and sensitivity of the Notch signaling output are regulated at distinct levels, particularly at the level of ligand-receptor interactions. METHODOLOGY/PRINCIPAL FINDINGS: Here, we report that the Drosophila gene uninflatable (uif), which encodes a large transmembrane protein with eighteen EGF-like repeats in its extracellular domain, can antagonize the canonical Notch signaling pathway. Overexpression of Uif or ectopic expression of a neomorphic form of Uif, Uif*, causes Notch signaling defects in both the wing and the sensory organ precursors. Further experiments suggest that ectopic expression of Uif* inhibits Notch signaling in cis and acts at a step that is dependent on the extracellular domain of Notch. Our results suggest that Uif can alter the accessibility of the Notch extracellular domain to its ligands during Notch activation. CONCLUSIONS/SIGNIFICANCE: Our study shows that Uif can modulate Notch activity, illustrating the importance of a delicate regulation of this signaling pathway for normal patterning.

To prevent neurodegeneration: HDAC6 uses different strategies for different challenges.

Neurodegenerative diseases are characterized by progressive dysfunction and death of neurons in specific areas of the nervous system. Loss of neurons is often associated with multiple stresses such as abnormal aggregation of misfolded proteins, deficiency of protein degradation system, mitochondrial dysfunction and excessive oxidative products. HDAC6 has recently been suggested to be an integral factor that copes with these stresses. In this mini-review, we summarize our current understanding of how HDAC6 promotes inclusion formation, facilitates autophagic degradation of protein aggregates and dysfunctional mitochondria. Finally, the possibility for HDAC6 to be a potential preventional and therapeutical target of some neurodegenerative diseases is put forward.

Drosophila histone deacetylase 6 protects dopaminergic neurons against {alpha}-synuclein toxicity by promoting inclusion formation.

Parkinson's disease (PD) is associated with progressive degeneration of dopaminergic (DA) neurons. We report for the first time that the Drosophila histone deacetylase 6 (dHDAC6) plays a critical role in the protection of DA neurons and the formation of alpha-synuclein inclusions by using a Drosophila PD model constructed by ectopic expression of human alpha-synuclein. Depletion of dHDAC6 significantly enhances the effects caused by ectopic expression of alpha-synuclein, namely, loss of DA neurons, retinal degeneration, and locomotor dysfunction. Expression of alpha-synuclein in the DA neurons leads to fewer inclusions in the brains of dHDAC6 mutant flies than in wild-type flies. Conversely, overexpression of dHDAC6 is able to suppress the alpha-synuclein-induced DA neuron loss and retinal degeneration and promote inclusion formation. Furthermore, mutation of dHDAC6 reinforces the accumulation of oligomers that are suggested to be a toxic form of alpha-synuclein. We propose that alpha-synuclein inclusion formation in the presence of dHDAC6 protects DA neurons from being damaged by oligomers, which may uncover a common mechanism for synucleinopathies.