Biology subjects

Luu, L.

Publications and source records attributed to Luu, L..

5 recordsLinked to original sources

bioRxiv2021

Treatment with sodium butyrate has therapeutic benefits for Machado-Joseph disease through the induction of autophagy

Spinocerebellar ataxia type 3 (SCA3, also known as Machado Joseph disease) is a fatal neurodegenerative disease caused by expansion of the trinucleotide repeat region within the ATXN3/MJD gene. Mutation of ATXN3 causes formation of ataxin-3 protein aggregates, neurodegeneration and motor deficits. Here we investigated the therapeutic potential and mechanistic activity of sodium butyrate (SB), the sodium salt of butyric acid, a metabolite naturally produced by gut microbiota, on cultured SH-SY5Y cells and transgenic zebrafish expressing human ataxin-3 containing 84 glutamine (Q) residues to model SCA3. SCA3 SH-SY5Y cells were found to contain high molecular weight ataxin-3 species and detergent insoluble protein aggregates. Treatment with SB increased activity of the autophagy protein quality control pathway in the SCA3 cells, decreased presence of ataxin-3 aggregates and presence of high molecular weight ataxin-3 in an autophagy-dependent manner. Treatment with SB was also beneficial in vivo, improving swimming performance, increasing activity of the autophagy pathway and decreasing presence of insoluble ataxin-3 protein species in the transgenic SCA3 zebrafish. Co-treating the SCA3 zebrafish with SB and chloroquine, an autophagy inhibitor, prevented the beneficial effects of SB on zebrafish swimming, indicating that the improved swimming performance was autophagy-dependent. To understand the mechanism by which SB induces autophagy we performed proteomic analysis of protein lysates from the SB treated and untreated SCA3 SH-SY5Y cells. We found that SB treatment had increased activity of Protein Kinase A and AMPK signalling, with immunoblot analysis confirming that SB treatment had increased levels of AMPK protein and its substrates. Together our findings indicate that treatment with SB can increase activity of the autophagy pathway through a PKA/AMPK-dependent process and that this has beneficial effects in vitro and in vivo. We propose that treatment with sodium butyrate warrants further investigation as a potential treatment for neurodegenerative diseases underpinned by mechanisms relating to protein aggregation including SCA3.

neuroscience↗

bioRxiv2021

Sodium valproate increases activity of the sirtuin pathway resulting in beneficialeffects for spinocerebellar ataxia-3 in vivo

Machado-Joseph disease (MJD, also known as spinocerebellar ataxia-3) is a fatal neurodegenerative disease that impairs control and coordination of movement. Here we tested whether treatment with the histone deacetylase inhibitor sodium valproate (SV) prevented a movement phenotype that develops in larvae of a transgenic zebrafish model of the disease. We found that treatment with SV improved the swimming of the MJD zebrafish, increased levels of acetylated histones 3 and 4, but also increased expression of polyglutamine expanded human ataxin-3. Proteomic analysis of protein lysates generated from the treated and untreated MJD zebrafish also predicted that SV treatment had activated the sirtuin longevity signaling pathway and this was confirmed by findings of increased SIRT1 protein levels and sirtuin activity in SV treated MJD zebrafish and HEK293 cells expressing ataxin-3-84Q, respectively. Treatment with resveratrol (another compound known to activate the sirtuin pathway), also improved swimming in the MJD zebrafish. Co-treatment with SV alongside EX527, a SIRT1 activity inhibitor, prevented induction of autophagy by SV and the beneficial effects of SV on the movement in the MJD zebrafish, indicating that they were both dependent on sirtuin activity. These findings provide the first evidence of sodium valproate inducing activation of the sirtuin pathway. Further, they indicate that drugs that target the sirtuin pathway, including sodium valproate and resveratrol, warrant further investigation for the treatment of MJD and related neurodegenerative diseases.

neuroscience↗

bioRxiv2020

Categorical judgments do not modify sensory information in working memory

Categorical judgments can systematically bias the perceptual interpretation of stimulus features. However, it remained unclear whether categorical judgments directly modify working memory representations or, alternatively, generate these biases via an inference process down-stream from working memory. To address this question we ran two novel psychophysical experiments in which human subjects had to revert their categorical judgments about a stimulus feature, if incorrect based on feedback, before providing an estimate of the feature. If categorical judgments indeed directly altered sensory representations in working memory, subjects’ estimates should reflect some aspects of their initial (incorrect) categorical judgment in those trials.We found no traces of the initial categorical judgment. Rather, subjects seem to be able to flexibly switch their categorical judgment if needed and use the correct corresponding categorical prior to properly perform feature inference. A cross-validated model comparison also revealed that feedback may lead to selective memory recall such that only memory samples that are consistent with the categorical judgment are accepted for the inference process. Our results suggest that categorical judgments do not modify sensory information in working memory but rather act as top-down expectation in the subsequent sensory recall and inference process down-stream from working memory.Competing Interest StatementThe authors have declared no competing interest.View Full Text

animal behavior and cognition↗

bioRxiv2019

Benefits of commitment in hierarchical inference

Humans have the tendency to commit to a single interpretation of what has caused some observed evidence rather than considering all possible alternatives. This tendency can explain various forms of confirmation and reference biases. However, committing to a single high-level interpretation seems short-sighted and irrational, and thus it is unclear why humans seem motivated to pursue such strategy.\n\nIn a first step toward answering this question, we systematically quantified how this strategy affects estimation accuracy at the feature level in the context of two universal hierarchical inference tasks, categorical perception and causal cue combination. Using model simulations, we demonstrate that although estimation is generally impaired when conditioned on only a single high-level inter-pretation, the impairment is not uniform across the entire feature range. On the contrary, compared to a full inference strategy that considers all high-level interpretations, accuracy is actually better for feature values for which the probability of an incorrect categorical/structural commitment is relatively low. That is to say, if an observer is reasonably certain about the high-level interpretation of the feature, it is advantageous to condition subsequent feature inference only on that particular interpretation. We also show that this benefit of commitment is substantially amplified if late noise corrupts information processing (e.g., during retention in working memory). Our results suggest that top-down inference strategies that solely rely on the most likely high-level interpretation can be favorable and at least locally outperform a full inference strategy.

animal behavior and cognition↗

bioRxiv2017

High- to low-level decoding does not generally improve perceptual performance

Ding et al. (1) recently proposed that the brain automatically encodes high-level, relative stimulus information (i.e. the ordinal relation between two lines), which it then uses to constrain the decoding of low-level, absolute stimulus features (i.e. when recalling the actual lines orientation). This is an interesting idea that is in line with the self-consistent Bayesian observer model (2, 3) and may have important implications for understanding how the brain processes sensory information. However, the notion suggested in Ding et al. (1) that the brain uses this decoding strategy because it improves perceptual performance is misleading. Here we clarify the decoding model and compare its perceptual performance under various noise and signal conditions.

animal behavior and cognition↗