When amyloids age: structural shifts and memory impairment in flies
Dr. Pablo Adrian Guillen Poza (Post-doctoral Fellow)
[Supervisor: Professor Ruben Hervas Millan]

Amyloids are best known for their roles in neurodegenerative diseases, yet some adopt regulated conformations that support normal cellular functions. How such functional amyloids assemble, remodel, and impact physiology over time in living organisms remains poorly understood.

Using the synaptic RNA binding protein Orb2 as an in vivo model, we combined purification with cryo-electron microscopy to examine amyloid structure across the lifespan of Drosophila melanogaster. We find that Orb2 amyloid exists in multiple structurally distinct states whose prevalence changes with age. Amyloid conformations predominant in young flies promote synaptic translation and support long term memory, whereas structurally remodeled forms that emerge with aging fail to activate translation and coincide with memory impairment. Genetic manipulation of memory associated chaperones shifts Orb2 between these states, rescuing memory in aged flies or inducing premature cognitive decline in young adults.

These results reveal that functional amyloids undergo age dependent structural evolution in vivo and directly link amyloid conformation to synaptic translation and cognitive aging.

Characterization of transcriptional regulations of telomerase in cancer
Dr. Lap Hang Tse (Post-doctoral Fellow)
[Supervisor: Professor David Shih]

Telomerase reverse transcriptase (TERT) enables unlimited cellular replication by elongating telomeres and maintaining chromosome stability. Although TERT expression is tightly repressed at the transcriptional level in normal somatic cells, it is reactivated in approximately 85% of human cancers, representing a hallmark of oncogenic transformation and cellular immortalization.

TERT is subject to complex transcriptional regulations involving multiple transcription factors, chromatin modifiers, and epigenetic regulators. However, the combinatorial and context-dependent nature of these transcriptional controls remains incompletely understood. Here, we aim to systematically define the transcriptional regulation of TERT.

We are generating CRISPR knock-in GFP reporter cell lines at the endogenous TERT locus from multiple cancer types (including glioblastoma, ovarian cancer, and adenocarcinoma), each harboring either a wild-type or hotspot-mutated promoter. Through high-throughput screening of a transcription factor library at varying multiplicities of infection, we will profile individual and combinatorial regulators of TERT across distinct genetic and cellular contexts. By integrating the screening results with genomic, transcriptomic, methylation, and histone modification data, we aim to dissect how promoter mutations, epigenetic marks, and transcription factors jointly modulate TERT expression.

Ultimately, we seek to identify key regulatory nodes and interactions, provide mechanistic insight into TERT reactivation in cancer, and highlight potential therapeutic strategies targeting TERT dysregulation.

All are welcome.