Biology subjects

Liao, F.-F.

Publications and source records attributed to Liao, F.-F..

4 recordsLinked to original sources

bioRxiv2025

The deubiquitinase OTULIN regulates tau expression and RNA metabolism in neurons

The degradation of aggregation-prone tau is regulated by the ubiquitin-proteasome system (UPS) and autophagy, which are impaired in Alzheimers disease (AD) and related tauopathies causing tau aggregation. Protein ubiquitination with linkage specificity determines the fate of proteins that can be either degradative or stabilization signals. While the linear M1-linked ubiquitination on protein aggregates is a signaling hub that recruits various ubiquitin-binding proteins for coordinated actions of protein aggregates turnover and inflammatory NF-kB activation, the deubiquitinase OTULIN counteracts with the M1-linked ubiquitin signaling. However, the exact role of OTULIN on tau aggregate clearance in AD is unknown. Based on our bulk RNA sequence analysis, human inducible pluripotent stem cell (iPSC)-derived neurons (iPSNs) from an individual with late-onset sporadic AD (sAD2.1) show downregulation of ubiquitin ligase activating factors (MAGEA2B and MAGEA) and OTULIN long non-coding RNA (lncRNA-OTULIN) compared to healthy control WTC11 iPSNs. In sAD2.1 iPSNs, downregulated lncRNA-OTULIN is inversely correlated with increased levels of OTULIN protein and phosphorylated tau at p-S202/p-T205 (AT8), p-T231 (AT180), and p-S396/p-S404 (PHF-1). Loss of OTULIN deubiquitinase function using pharmacological inhibitor UC495 or CRISPR-Cas9-mediated OTULIN gene knockout causes a significant reduction of total tau and phosphorylated tau at AT8 epitope in sAD2.1 iPSNs. Whereas in SH-SY5Y neuroblastoma cells, either treating with the UC495 compound or knocking out of the OTULIN gene causes a significant reduction of total tau at both mRNA and protein levels and consequently decreases phosphorylated tau at AT8, AT180, and PHF-1 epitopes. An additional bulk RNA sequence analysis of OUTLIN knockout SH-SY5Y shows a 14-fold down-regulation of tau mRNA levels and differential expression of many other genes associated with autophagy, UPS, NF-kB pathway, and RNA metabolism. Together, our results suggest for the first time a non-canonical function for OTULIN in regulating gene expression and RNA metabolism, which may have a significant pathogenic role in AD and related tauopathies.

neuroscience↗

bioRxiv2025

OTULIN Interactome Reveals Immune Response and Autophagy Associated with Tauopathy in a Mouse Model

Tauopathies are neurodegenerative diseases that are pathologically characterized by accumulation of misfolded microtubule-associated protein tau aggregates in the brain. Deubiquitination, particularly by OTULIN, a unique deubiquitinase targeting methionine-1 (M1) linkages from linear ubiquitin chain assembly complex (LUBAC)), is reportedly associated with the accumulation of neurotoxic proteins in several neurodegenerative diseases, likely including tauopathies. To investigate the potential roles of OTULIN in tauopathies, we analyzed the OTULIN interactome in hippocampal tissues from PS19 transgenic (Tg) mice and their non-transgenic (nTg) littermate controls using affinity purification-mass spectrometry (AP-MS). We identified 705 and 800 proteins enriched in Tg and nTg samples, respectively, with a protein false discovery rate (FDR) of <1%. Of these, 189 and 205 proteins were classified as probable OTULIN interactors in Tg and nTg groups, respectively, based on Significance Analysis of INTeractome (SAINT) score of [≥]0.80 and FDR of [≤] 5%. A total of 84 proteins were identified as OTULIN interactors in the PS19 Tg group, while 100 proteins were associated with OTULIN in the nTg controls. Functional enrichment analyses revealed that OTULIN-interacting proteins in the nTg group were enriched in pathways related to spliceosome, complement and coagulation cascades, and ribosome, whereas those in the Tg group were associated with immune response and autophagy. These findings suggest that OTULIN-interacting proteins may play a critical role in the pathogenesis of tauopathy in this mouse model. HighlightsO_LIOTULIN interactome in hippocampal tissues from PS19 transgenic (Tg) mice and their non-transgenic (nTg) littermate controls is analyzed. C_LIO_LIOTULIN-interacting proteins in the nTg group are enriched in pathways related to spliceosome, complement and coagulation cascades, and ribosome. C_LIO_LIOTULIN-interacting proteins in Tg are implicated in immune response and autophagy. C_LIO_LIATP2A2 is identified as an OTULIN-interacting protein specifically enhanced in Tg mice. C_LI

neuroscience↗

bioRxiv2024

TRPC3 suppression ameliorates synaptic dysfunctions and memory deficits in Alzheimer's disease

Transient receptor potential canonical (TRPC) channels are widely expressed in the brain; however, their precise roles in neurodegeneration, such as Alzheimers disease (AD) remain elusive. Bioinformatic analysis of the published single-cell RNA-seq data collected from AD patient cohorts indicates that the Trpc3 gene is uniquely upregulated in excitatory neurons. TRPC3 expression is also upregulated in post-mortem AD brains, and in both acute and chronic mouse models of AD. Functional screening of TRPC3 antagonists resulted in a lead inhibitor JW-65, which completely rescued A{beta}-induced neurotoxicity, impaired synaptic plasticity (e.g., LTP), and learning memory in acute and chronic experimental AD models. In cultured rat hippocampal neurons, we found that treatment with soluble {beta}-amyloid oligomers (A{beta}Os) induces rapid and sustained upregulation of the TRPC3 expression selectively in excitatory neurons. This aberrantly upregulated TRPC3 contributes to A{beta}Os-induced Ca2+ overload through the calcium entry and store-release mechanisms. The neuroprotective action of JW-65 is primarily mediated via restoring A{beta}Os-impaired Ca2+/calmodulin-mediated signaling pathways, including calmodulin kinases CaMKII/IV and calcineurin (CaN). The synaptic protective mechanism via TRPC3 inhibition was further supported by hippocampal RNA-seq data from the symptomatic 5xFAD mice after chronic treatment with JW-65. Overall, these findings not only validate TRPC3 as a novel therapeutic target for treating synaptic dysfunction of AD but most importantly, disclose a distinct role of upregulated TRPC3 in AD pathogenesis in mediating Ca2+ dyshomeostasis.

neuroscience↗

bioRxiv2024

Dopaminergic inhibition of the inwardly rectifying potassium current in direct pathway medium spiny neurons in normal and parkinsonian striatum

Despite the profound behavioral effects of the striatal dopamine (DA) activity and the inwardly rectifying potassium channel (Kir) being a key determinant of striatal medium spiny neuron (MSN) activity that also profoundly affects behavior, previously reported DA regulations of Kir are conflicting and incompatible with MSN function in behavior. Here we show that in normal mice with an intact striatal DA system, the predominant effect of DA activation of D1Rs in D1-MSNs is to cause a modest depolarization and increase in input resistance by inhibiting Kir, thus moderately increasing the spike outputs from behavior-promoting D1-MSNs. In parkinsonian (DA-depleted) striatum, DA increases D1-MSN intrinsic excitability more strongly than in normal striatum, consequently strongly increasing D1-MSN spike firing that is behavior-promoting; this DA excitation of D1-MSNs is stronger when the DA depletion is more severe. The DA inhibition of Kir is occluded by the Kir blocker barium chloride (BaCl2). In behaving parkinsonian mice, BaCl2 microinjection into the dorsal striatum stimulates movement but occludes the motor stimulation of D1R agonism. Taken together, our results resolve the long-standing question about what D1R agonism does to D1-MSN excitability in normal and parkinsonian striatum and strongly indicate that D1R inhibition of Kir is a key ion channel mechanism that mediates D1R agonistic behavioral stimulation in normal and parkinsonian animals.

neuroscience↗