Biology subjects

Sang, T.-K.

Publications and source records attributed to Sang, T.-K..

3 recordsLinked to original sources

bioRxiv2025

BCHS acts as a stress transducer connecting autophagic quality control with DNA damage repair

Cellular homeostasis relies on complex mechanisms that sense and respond to genotoxic stress. While autophagy adaptors are well-known for their role in removing cytoplasmic protein aggregates, their involvement in DNA damage responses is less clear. In this study, we show that Blue cheese (BCHS), the Drosophila homolog of mammalian Alfy/WDFY3, functions as a critical regulator connecting autophagy, DNA repair, and intercellular communication. Using a Drosophila eye model with TER94 (VCP ortholog) deficiency, we observed that genotoxic stress specifically increases expression and nuclear buildup of ref(2)P (p62/SQSTM1 homolog). Reducing BCHS worsens nuclear ref(2)P accumulation and DNA damage, while increasing BCHS levels alleviates these effects, highlighting BCHS as a vital regulator of nuclear proteostasis and genome stability. Mechanistically, genotoxic stress triggers reversible separation of the ref(2)P-BCHS complex, temporally coordinated with ref(2)P nuclear translocation. Strikingly, BCHS undergoes dynamic redistribution from the nuclear periphery to the extracellular matrix (ECM) via an exosome-dependent pathway involving Rab11, Rab27, Rab35, VAMP7, and tetraspanin Tsp96F. Blocking BCHS secretion significantly hampers DNA repair, demonstrating that extracellular BCHS export is functionally required for genome maintenance. These findings establish a paradigm wherein autophagy adaptors serve dual roles--coordinating nuclear stress responses while communicating cellular damage status to the tissue microenvironment. Given the conservation between BCHS and human Alfy, this mechanism may have broad implications for diseases characterized by defective proteostasis and genome instability, including neurodegeneration and cancer.

cell biology↗

bioRxiv2020

CyDAP-A fluorescent probe for cytosolic dopamine detection

Dopamine (DA) is an essential neurotransmitter modulating motor and cognitive functions. Several neurological disorders, including Parkinsons disease (PD) and drug addiction, are the result of DA system dysfunction; however, it remains incomplete understood of why DA neuron is selectively more vulnerable than other neurons. Here we utilize the spectral feature of human MAO B (monoamine oxidase B) to design a genetic-amenable, GFP-based fluorescent probe CyDAP. Upon genetic and pharmacological manipulations to elevate the cytosolic DA levels in cells and Drosophila models, CyDAP shows enhanced GFP emission, suggesting this probe is feasible for DA detection. Furthermore, we observe that expressing human -Synuclein in Drosophila elicited GFP emission from CyDAP, suggesting a link between cytosolic DA imbalance and regional vulnerability in PD context. Importantly, CyDAP can detect the change of cytosolic DA in live Drosophila brains, as demonstrated by time-lapse and the 4D light-sheet confocal recording. CyDAP may serve as a tool for evaluating metabolic deregulation of DA in brain models of PD and other DA system-related psychiatric disorders.

neuroscience↗

bioRxiv2019

Codon-optimized TDP-43-mediated neurodegeneration in a Drosophila model for ALS/FTLD

Transactive response DNA binding protein-43 (TDP-43) is known to mediate neurodegeneration associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). The exact mechanism by which TDP-43 exerts toxicity in the brains of affected patients remains unclear. In a novel Drosophila melanogaster model, we report gain-of-function phenotypes due to misexpression of insect codon-optimized version of human wild-type TDP-43 (CO-TDP-43) using both the binary GAL4/UAS system and direct promoter fusion constructs. The CO-TDP-43 model showed robust tissue specific phenotypes in the adult eye, wing, and bristles in the notum. Compared to non-codon optimized transgenic flies, the CO-TDP-43 flies produced increased amount of high molecular weight protein, exhibited pathogenic phenotypes, and showed cytoplasmic aggregation with both nuclear and cytoplasmic expression of TDP-43. Further characterization of the adult retina showed a disruption in the morphology and function of the photoreceptor neurons with the presence of acidic vacuoles that are characteristic of autophagy. Based on our observations, we propose that TDP-43 has the propensity to form toxic protein aggregates via a gain-of-function mechanism, and such toxic overload leads to activation of protein degradation pathways such as autophagy. The novel codon optimized TDP-43 model is an excellent resource that could be used in genetic screens to identify and better understand the exact disease mechanism of TDP-43 proteinopathies and find potential therapeutic targets.

neuroscience↗