Biology subjects

Lee, T.-T.

Publications and source records attributed to Lee, T.-T..

3 recordsLinked to original sources

bioRxiv2024

The voltage-gated potassium channel Shal (Kv4) contributes to active hearing in Drosophila

The full complement of ion channels which influence insect auditory mechanotransduction, and the mechanisms by which their influence is exerted, remain unclear. Shal (Kv4), a Shaker family member encoding voltage-gated potassium channels in Drosophila melanogaster, has been shown to localize to dendrites in some neuron types, suggesting a potential role for Shal in Drosophila hearing, including mechanotransduction. A GFP-protein trap was used to visualize the localization of the Shal channel in Johnstons organ neurons responsible for hearing in the antenna. Shal protein was localized to the cell body and the proximal dendrite region of sensory neurons, suggesting its involvement not only in general auditory function, but specifically in mechanotransduction. Electrophysiological recordings conducted to assess neural responses to auditory stimuli in mutant Shal flies revealed significant decreases in auditory responses. Laser Doppler Vibrometer recordings indicated abnormal antennal free fluctuation frequencies in mutant lines, indicating an effect on active antennal tuning, and thus active transduction mechanisms. This suggests that Shal participates in coordinating energy-dependent antennal movements in Drosophila that are essential for tuning the antenna to courtship song frequencies. Significance StatementThe study of fruit fly hearing has revealed mechanosensitive ion channels that participate in mechanotransduction, and as in mammalian hearing, energy-dependent mechanisms actively amplify and tune auditory processes. Identifying distinct roles played by different ion channels is essential to better understand this process. Here, we explore the influence of a specific voltage-gated potassium channel, Shal, on fly hearing, and find that it affects specific parts of the mechanotransduction process. Our research uncovers Shals localization in sensory dendrite regions of auditory neurons, where it contributes to shaping mechanotransduction and active antennal tuning. Understanding Shals involvement in auditory function and mechanotransduction deepens our knowledge of fly hearing and unveils a key player in the coordination of energy-dependent active antennal movements.

neuroscience↗

bioRxiv2023

Proteostasis and lysosomal quality control deficits in Alzheimer's disease neurons

Aging is the most prominent risk factor for Alzheimers disease (AD). However, the cellular mechanisms linking neuronal proteostasis decline to the characteristic aberrant protein deposits in AD brains remain elusive. Here, we develop transdifferentiated neurons (tNeurons) from human dermal fibroblasts as a neuronal model that retains aging hallmarks and exhibits AD-linked vulnerabilities. Remarkably, AD tNeurons accumulate proteotoxic deposits, including phospho-Tau and A{beta}, resembling those in AD patient and APP mouse brains. Quantitative tNeuron proteomics identify aging and AD-linked deficits in proteostasis and organelle homeostasis, most notably in endosome-lysosomal components. Lysosomal deficits in aged tNeurons, including constitutive lysosomal damage and ESCRT-mediated lysosomal repair defects, are exacerbated in AD tNeurons and linked to inflammatory cytokine secretion and cell death. Supporting lysosomal deficits centrality in AD, compounds ameliorating lysosomal function reduce A{beta} deposits and cytokine secretion. Thus, the tNeuron model system reveals impaired lysosomal homeostasis as an early event of aging and AD.

cell biology↗

bioRxiv2022

Ribotoxic collisions on CAG expansions disrupt proteostasis and stress responses in Huntington's Disease

Huntingtons disease (HD) is a devastating neurodegenerative disorder caused by CAG trinucleotide repeat expansions encoding a polyglutamine (polyQ) tract in the Huntingtin (HTT) gene1. Although mutant HTT (mHTT) protein tends to aggregate, the exact causes of neurotoxicity in HD remain unclear2. Here we show that altered elongation kinetics on CAG expansions cause ribosome collisions that trigger ribotoxicity, proteotoxicity and maladaptive stress responses. CAG expansions cause an elongation rate conflict during HTT translation, when ribosomes rapidly decoding the optimal polyQ encounter a flanking slowly-decoded polyproline tract. The ensuing ribosome collisions lead to premature termination and release of aggregation-prone mHTT fragments. Due to the presence of a stress-responsive upstream open reading frame (uORF), HTT translation and aggregation are limited under normal conditions but enhanced under stress, seeding a vicious cycle of dysfunction. mHTT further exacerbates ribotoxicity by progressively sequestering eIF5A, a key regulator of translation elongation, polyamine metabolism and stress responses. eIF5A depletion in HD cells leads to widespread ribosome pausing on eIF5A-dependent sites, impaired cotranslational proteostasis, disrupted polyamine metabolism and maladaptive stress responses. Importantly, drugs that reduce translation initiation attenuate ribosome collisions and mitigate this escalating cascade of ribotoxic stress and dysfunction in HD.

neuroscience↗