Issues of COVID-19-related distance learning for children with neuronopathic mucopolysaccharidoses.

The COVID-19 pandemic has impacted the education of children around the world, forcing a large proportion of teaching to be carried out remotely. The implications of this disruption have yet to be fully elucidated, but initial assessments suggest that COVID-19-related school closures and reliance on virtual learning may have a long-term negative impact on educational attainment and future earnings as well as life expectancy of children in the United States. Among children with neurodegenerative disorders, such as neuronopathic mucopolysaccharidoses (MPS disorders), the effects of the pandemic are likely to be even greater. We aim to shine a spotlight on the impact of COVID-19 on the education, treatment and general wellbeing of children and families affected by MPS disorders by highlighting the important role that educators and therapists play in supporting the neurocognitive function and quality of life of children with neuronopathic MPS disorders. This article will serve as a resource that caregivers, educators, clinicians and therapists can use when considering how best to advocate for children with neuronopathic MPS disorders in circumstances where in-school teaching or in-clinic treatment is compromised or not possible. Given that the current pandemic is likely to have a prolonged course and impact and that similar epidemics and pandemics are a near certainty in the future, it is essential that steps are taken to support the learning and care of children with neuronopathic MPS disorders. We must prioritize strategies to safely resume this fragile community's access to in-person education and supportive care, and to address gaps that have emerged during prolonged pauses in access, whenever possible.

HTRA2 variations in Taiwanese Parkinson's disease.

Mutations in HTRA2 have been reported to associate with Parkinson's disease (PD). This study investigates if the genetic variants in HTRA2 contribute to Taiwanese PD. HTRA2 cDNA fragments from 80 patients with early-onset PD (onset ≤50 years) were sequenced. The identified variants were further examined for a cohort of PD and ethnically matched controls. A novel heterozygous R36W was identified in one early-onset and two late-onset PD patients, which was absent in 606 normal controls. The clinical features and 99mTc-TRODAT-1 SPECT image of the early-onset patient carrying R36W were similar to that of idiopathic PD. The R36W mutation of the patient was inherited from his mother whose SPECT revealed asymmetric reduction of 99mTc-TRODAT-1 uptake in the left striatum, suggesting that the defect of the nigrostriatal pathway may be attributable to the R36W in this family. Protein subcellular fractionation further revealed that R36W affected the processing of the proprotein after transport into mitochondria. Although the functional assays are promising, a larger cohort of both cases and controls should be screened to clarify the role of R36W in Taiwanese PD pathogenicity.

Associations between early trajectories of amygdala development and later school-age anxiety in two longitudinal samples.

Amygdala function is implicated in the pathogenesis of autism spectrum disorder (ASD) and anxiety. We investigated associations between early trajectories of amygdala growth and anxiety and ASD outcomes at school age in two longitudinal studies: high- and low-familial likelihood for ASD, Infant Brain Imaging Study (IBIS, n = 257) and typically developing (TD) community sample, Early Brain Development Study (EBDS, n = 158). Infants underwent MRI scanning at up to 3 timepoints from neonate to 24 months. Anxiety was assessed at 6-12 years. Linear multilevel modeling tested whether amygdala volume growth was associated with anxiety symptoms at school age. In the IBIS sample, children with higher anxiety showed accelerated amygdala growth from 6 to 24 months. ASD diagnosis and ASD familial likelihood were not significant predictors. In the EBDS sample, amygdala growth from birth to 24 months was associated with anxiety. More anxious children had smaller amygdala volume and slower rates of amygdala growth. We explore reasons for the contrasting results between high-familial likelihood for ASD and TD samples, grounding results in the broader literature of variable associations between early amygdala volume and later anxiety. Results have the potential to identify mechanisms linking early amygdala growth to later anxiety in certain groups.

ADHD-related symptoms, emotional/behavioral problems, and physical conditions in Taiwanese children with epilepsy.

BACKGROUND/PURPOSE: Little is known about whether Asian children with epilepsy have more attention-deficit hyperactivity disorder (ADHD)-related symptoms, emotional/ behavioral problems, and physical conditions compared with those described in Western studies. The authors investigated the rates of ADHD-related symptoms, emotional/behavioral problems, and physical conditions among pediatric patients with epilepsy. METHODS: We recruited 61 patients with epilepsy, aged 6-16 years, and 122 age-, sex-, and parental education-matched school controls. Data on demographics, parental reports on the Child Behavior Checklist (CBCL) and Swanson, Nolan, and Pelham, version IV scale (SNAP-IV), and medical records were collected. RESULTS: The average full-scale intelligence quotient of the case group was 95.8. There were 11 (18.0%), 7 (11.5%), 26 (42.6%), and 26 (42.6%) of children with epilepsy ever clinically diagnosed with developmental delay, overt ADHD symptoms, allergies reported by physicians, and behavior problems measured by the CBCL, respectively. Those children with epilepsy had more severe ADHD-related symptoms and a wider range of emotional/behavioral problems than controls (Cohen's d 0.36-0.80). The rate of potential cases of ADHD among children with epilepsy was 24.6%. A history of developmental delay predicted ADHD- related symptoms and internalizing and externalizing problems. Among children with epilepsy, a longer duration of treatment with antiepileptic drugs predicted externalizing problems, and an earlier onset of epilepsy predicted inattention and hyperactivity/impulsivity. CONCLUSION: Our findings imply that clinicians should assess physical and emotional/behavioral problems among children with epilepsy in order to provide interventions to offset possible adverse psychiatric outcomes.

Why are only some children with autism spectrum disorder misclassified by the social communication questionnaire? An empirical investigation of individual differences in sensitivity and specificity in a clinic-referred sample.

BACKGROUND: The Social Communication Questionnaire (SCQ) is a checklist for autism spectrum disorder (ASD) commonly used in research and clinical practice. While the original validation study suggested that the SCQ was an accurate ASD screener with satisfactory sensitivity and specificity, subsequent studies have yielded mixed results, with some revealing low sensitivity, low specificity, and low utility in some settings. METHOD: The present study examined the psychometric properties of the SCQ as well as the individual difference characteristics of 187 individuals with and without autism spectrum disorder (ASD) who were misclassified or accurately classified by the SCQ in a clinic-referred sample. RESULTS: The SCQ showed suboptimal sensitivity and specificity, regardless of age and sex. Compared to true positives, individuals classified as false positives displayed greater externalizing and internalizing problems, whereas individuals classified as false negatives displayed better social communication and adaptive skills. CONCLUSIONS: The findings suggest that non-autistic developmental and behavioral individual difference characteristics may explain high rates of misclassification using the SCQ. Clinicians and researchers could consider using the SCQ in combination with other tools for young children with internalizing and externalizing symptoms and other more complex clinical presentations.

Agreement of parent-reported cognitive level with standardized measures among children with autism spectrum disorder.

Assessing cognitive development is critical in clinical research of autism spectrum disorder (ASD). However, collecting cognitive data from clinically administered assessments can add a significant burden to clinical research in ASD due to the substantial cost and time required, and it is often prohibitive in large-scale studies. There is a need for more efficient, but reliable, methods to estimate cognitive functioning for researchers, clinicians, and families. To examine the degree to which caregiver estimates of cognitive level agree with actual measured intelligence/developmental scores and understand factors that may impact that agreement, 1,555 autistic individuals (81.74% male; age 18 months-18 years) were selected from a large cohort (Simons Foundation Powering Autism Research for Knowledge, SPARK). Results suggest that querying parents about recent testing results and developmental diagnoses can provide valid and useful information on cognitive ability. The agreement of parental estimates varied with age, measured cognitive ability, autistic traits, and adaptive skills. In the context of large-scale research efforts, parent-reported cognitive impairment may be a good proxy for categorical IQ range for survey-based studies when specific IQ scores are not available, circumventing the logistical and financial obstacles of obtaining neuropsychological or neurodevelopmental testing.

Association of Sex With Neurobehavioral Markers of Executive Function in 2-Year-Olds at High and Low Likelihood of Autism.

Importance: Children with autism and their siblings exhibit executive function (EF) deficits early in development, but associations between EF and biological sex or early brain alterations in this population are largely unexplored. Objective: To investigate the interaction of sex, autism likelihood group, and structural magnetic resonance imaging alterations on EF in 2-year-old children at high familial likelihood (HL) and low familial likelihood (LL) of autism, based on having an older sibling with autism or no family history of autism in first-degree relatives. Design, Setting, and Participants: This prospective cohort study assessed 165 toddlers at HL (n = 110) and LL (n = 55) of autism at 4 university-based research centers. Data were collected from January 1, 2007, to December 31, 2013, and analyzed between August 2021 and June 2022 as part of the Infant Brain Imaging Study. Main Outcomes and Measures: Direct assessments of EF and acquired structural magnetic resonance imaging were performed to determine frontal lobe, parietal lobe, and total cerebral brain volume. Results: A total of 165 toddlers (mean [SD] age, 24.61 [0.95] months; 90 [54%] male, 137 [83%] White) at HL for autism (n = 110; 17 diagnosed with ASD) and LL for autism (n = 55) were studied. The toddlers at HL for autism scored lower than the toddlers at LL for autism on EF tests regardless of sex (mean [SE] B = -8.77 [4.21]; 95% CI, -17.09 to -0.45; η2p = 0.03). With the exclusion of toddlers with autism, no group (HL vs LL) difference in EF was found in boys (mean [SE] difference, -7.18 [4.26]; 95% CI, 1.24-15.59), but EF was lower in HL girls than LL girls (mean [SE] difference, -9.75 [4.34]; 95% CI, -18.32 to -1.18). Brain-behavior associations were examined, controlling for overall cerebral volume and developmental level. Sex differences in EF-frontal (B [SE] = 16.51 [7.43]; 95% CI, 1.36-31.67; η2p = 0.14) and EF-parietal (B [SE] = 17.68 [6.99]; 95% CI, 3.43-31.94; η2p = 0.17) associations were found in the LL group but not the HL group (EF-frontal: B [SE] = -1.36 [3.87]; 95% CI, -9.07 to 6.35; η2p = 0.00; EF-parietal: B [SE] = -2.81 [4.09]; 95% CI, -10.96 to 5.34; η2p = 0.01). Autism likelihood group differences in EF-frontal (B [SE] = -9.93 [4.88]; 95% CI, -19.73 to -0.12; η2p = 0.08) and EF-parietal (B [SE] = -15.44 [5.18]; 95% CI, -25.86 to -5.02; η2p = 0.16) associations were found in girls not boys (EF-frontal: B [SE] = 6.51 [5.88]; 95% CI, -5.26 to 18.27; η2p = 0.02; EF-parietal: B [SE] = 4.18 [5.48]; 95% CI, -6.78 to 15.15; η2p = 0.01). Conclusions and Relevance: This cohort study of toddlers at HL and LL of autism suggests that there is an association between sex and EF and that brain-behavior associations in EF may be altered in children at HL of autism. Furthermore, EF deficits may aggregate in families, particularly in girls.

Mitochondrial dysfunction and oxidative stress contribute to the pathogenesis of spinocerebellar ataxia type 12 (SCA12).

Spinal cerebellar ataxia type 12 (SCA12) has been attributed to the elevated expression of ppp2r2b. To better elucidate the pathomechanism of the neuronal disorder and to search for a pharmacological treatment, Drosophila models of SCA12 were generated by overexpression of a human ppp2r2b and its Drosophila homolog tws. Ectopic expression of ppp2r2b or tws caused various pathological features, including neurodegeneration, apoptosis, and shortened life span. More detailed analysis revealed that elevated ppp2r2b and tws induced fission of mitochondria accompanied by increases in cytosolic reactive oxygen species (ROS), cytochrome c, and caspase 3 activity. Transmission electron microscopy revealed that fragmented mitochondria with disrupted cristae were engulfed by autophagosomes in photoreceptor neurons of flies overexpressing tws. Additionally, transgenic flies were more susceptible to oxidative injury induced by paraquat. By contrast, ectopic Drosophila Sod2 expression and antioxidant treatment reduced ROS and caspase 3 activity and extended the life span of the SCA12 fly model. In summary, our study demonstrates that oxidative stress induced by mitochondrial dysfunction plays a causal role in SCA12, and reduction of ROS is a potential therapeutic intervention for this neuropathy.

Visuomotor adaptation and its relationship with motor ability in children with and without autism spectrum disorder.

The high prevalence rates of motor impairments among individuals with autism spectrum disorder (ASD) lead to increased attention to motor learning. The current study examined the visuomotor adaptability in children with and without ASD using a computerized visuomotor adaptation task in which the real-time visual feedback of hand movement was rotated. The relationships between visuomotor adaptability and clinical symptomology were also investigated. Results revealed that the children with ASD showed a slower rate of improvement and smaller after-effects than their peers on the measures of motor planning. Additionally, autistic characteristics significantly moderated the association between individuals' adaptability and fine motor skills. The findings contribute to the growing evidence of compromised visuomotor adaptability, which suggested the importance of addressing these clinical features of ASD.

Pigment dispersing factor: an output regulator of the circadian clock in the German cockroach.

Pigment-dispersing factor (PDF) is a neuropeptide that is synthesized specifically and constantly in the circadian clock cells of many insects. The functions of PDF have not been fully determined, but it might serve as the output and coupling signal of circadian locomotor rhythms. In this experiment, we explore the functions of PDF in the German cockroach with RNA interference technique. Since the 2nd day after pdf double-strand RNA (dsRNA) injection, the amount of pdf mRNA decreased significantly, and this knockdown effect could persist at least 56 days. With immunostaining technique, the clock cells of pdf dsRNA-injected cockroaches could not be stained by anti-PDF antibody. In the behavioral study, pdf dsRNA injection caused rhythmic males to become arrhythmic in light-dark cycles or in constant darkness. In addition, due to the nocturnal nature of the German cockroaches, the locomotor activity increased after lights-off or entering subjective night. However, this activity peak gradually disappeared after pdf dsRNA injection. Based on these 2 lines of evidences, PDF serves as an output regulator of locomotor circadian rhythm in the German cockroach.

Pentachlorophenol contaminated groundwater bioremediation using immobilized Sphingomonas cells inoculation in the bioreactor system.

Pentachlorophenol (PCP) has been used as a wood preservative for more than 100 years. The extensive use of PCP has widely contaminated soil and groundwater. PCP is toxic to living organisms. The main objective of this research was to inoculate the pure PCP-degrading bacterium strain Sphingomonas chlorophenolica PCP-1, isolated from PCP-contaminated soils, into PCP-contaminated groundwater for remediation purposes. The factors that influenced the bioremediation were explored with batch experiments using the inoculated immobilized and suspended cells as inoculation. A biological treatment system inoculated with immobilized cells was set up to estimate the microbial capability to degrade PCP. The results indicated that the suspended and immobilized cells could be inoculated into PCP-contaminated groundwater without adding other supplementary nitrogen and phosphate sources in batch conditions. Moreover, PCP decomposition was accompanied with released Cl- and decreasing pH value. The optimum HRT in the bioreactor system was 12.6h. PCP removal in the bioreactor remained stable and PCP removal efficiency was higher than 92% at this phase. Furthermore, PCP concentration in the biotreatment system effluent remained undetectable. It is possible to bioremediate PCP-contaminated groundwater using immobilized S. chlorophenolica PCP-1 cells in a bioreactor system. The proposed biological treatment system could be maintained for at least for 2 months.

Chinese Herbal Medicine Glycyrrhiza inflataReduces Aß Aggregation and Exerts Neuroprotection through Anti-Oxidation and Anti-Inflammation.

Amyloid [Formula: see text] (A[Formula: see text]) plays a major role in the pathogenesis of Alzheimer's disease (AD). The accumulation of misfolded A[Formula: see text] causes oxidative and inflammatory damage leading to apoptotic cell death. Chinese herbal medicine (CHM) has been widely used in clinical practice to treat neurodegenerative diseases associated with oxidative stress and neuroinflammation. This study examined the neuroprotection effects of CHM extract Glycyrrhiza inflata (G. inflata) and its active constituents, licochalcone A and liquiritigenin in AD. We examined A[Formula: see text] aggregation inhibition, anti-oxidation and neuroprotection in Tet-On A[Formula: see text]-GFP 293/SH-SY5Y cells and anti-inflammatory potential in lipopolysaccharide (LPS)-stimulated RAW 264.7 and LPS and interferon (IFN)-[Formula: see text] (LPS/IFN-[Formula: see text])-activated BV-2 cells. In addition, we applied conditioned media (CM) of BV-2 cells primed with LPS/IFN-[Formula: see text] to A[Formula: see text]-GFP SH-SY5Y cells to uncover the neuroprotective mechanisms. Our results showed that G. inflata extract and its two constituents displayed potentials of A[Formula: see text] aggregation inhibition and radical-scavenging in biochemical assays, A[Formula: see text] misfolding inhibition and reactive oxygen species (ROS) reduction in A[Formula: see text]-GFP 293 cells, as well as neurite outgrowth promotion, acetylcholinesterase inhibition and SOD2 up-regulation in A[Formula: see text]-GFP SH-SY5Y cells. Meanwhile, both G. inflata extract and its constituents suppressed NO, TNF-[Formula: see text], IL-1[Formula: see text], PGE2 and/or Iba1 productions in inflammation-stimulated RAW 264.7 or BV-2 cells. G. inflata extract and its constituents further protected A[Formula: see text]-GFP SH-SY5Y cells from BV-2 CM-induced cell death by ameliorating reduced BCL2 and attenuating increased IGFBP2, cleaved CASP3, BAD and BAX. Collectively, G. inflata extract, licochalcone A and liquiritigenin display neuroprotection through exerting anti-oxidative and anti-inflammatory activities to suppress neuronal apoptosis.

Isolation of the epsilon-caprolactam denitrifying bacteria from a wastewater treatment system manufactured with acrylonitrile-butadiene-styrene resin.

epsilon-Caprolactam has high COD and toxicity, so its discharge to natural water and soil systems may lead to an adverse environmental effect on water quality, endangering public health and welfare. This investigation attempts to isolate epsilon-caprolactam denitrifying bacteria from a wastewater treatment system manufactured with acrylonitrile-butadiene-styrene (ABS) resin. The goal is to elucidate the effectiveness of isolated pure strain and ABS mixed strains in treating epsilon-caprolactam from synthetic wastewater. The results reveal that Paracoccus versutus MDC-3 was isolated from the wastewater treatment system manufactured with ABS resin. The ABS mixed strains and P. versutus MDC-3 can consume up to 1539mg/l epsilon-caprolactam to denitrify from synthetic wastewater. Complete epsilon-caprolactam removal depended on the supply of sufficient electron acceptors (nitrate). Strain P. versutus MDC-3, Hyphomicrobium sp. HM, Methylosinus pucelana and Magnetospirillum sp. CC-26 are related closely, according to the phylogenetic analyses of 16S rDNA sequences.

Inter-limb transfer of kinematic adaptation in individuals with motor difficulties.

A previous study suggested that adults with greater motor difficulties demonstrated less adaptation under a regular error feedback schedule (gain=1:1) but reached a similar level of adaptation compared to controls when feedback was enhanced (gain=1:2). In light of these findings, the present study examined inter-limb transfer after adults adapted to visuomotor distortions with their dominant hand on either regular or enhanced feedback schedules. Results revealed that successful transfer related to the magnitude of adaptation with their dominant hand regardless of the individuals' motor abilities on the regular feedback schedule. When the feedback was enhanced, the transfer was not related to either the adaptation of the dominant hand or individuals' motor abilities. We argue that a stable internal model is essential for inter-limb transfer in kinematic adaptation.

Visuomotor adaptability in older adults with mild cognitive decline.

The current study examined the augmentation of error feedback on visuomotor adaptability in older adults with varying degrees of cognitive decline (assessed by the Montreal Cognitive Assessment; MoCA). Twenty-three participants performed a center-out computerized visuomotor adaptation task when the visual feedback of their hand movement error was presented in a regular (ratio=1:1) or enhanced (ratio=1:2) error feedback schedule. Results showed that older adults with lower scores on the MoCA had less adaptability than those with higher MoCA scores during the regular feedback schedule. However, participants demonstrated similar adaptability during the enhanced feedback schedule, regardless of their cognitive ability. Furthermore, individuals with lower MoCA scores showed larger after-effects in spatial control during the enhanced schedule compared to the regular schedule, whereas individuals with higher MoCA scores displayed the opposite pattern. Additional neuro-cognitive assessments revealed that spatial working memory and processing speed were positively related to motor adaptability during the regular scheduled but negatively related to adaptability during the enhanced schedule. We argue that individuals with mild cognitive decline employed different adaptation strategies when encountering enhanced visual feedback, suggesting older adults with mild cognitive impairment (MCI) may benefit from enhanced visual error feedback during sensorimotor adaptation.

Isolation and physiological characterization of the pentachlorophenol degrading bacterium Sphingomonas chlorophenolica.

Many chlorophenols tend to persist in the environment, and they may become public health hazards. Among chlorophenols, pentachlorophenol (PCP) is a priority pollutant that has been used widely as a general biocide in commercial wood treatment. Owing to the rapid industrial growth, serious soil and water pollutions by chlorophenols has been reported in Taiwan. In this study, 10 indigenous PCP-degrading bacterial strains were isolated from a PCP-degrading mixed culture, and the potential of both the pure and mixed cultures for PCP degradation compared. Moreover, the physiological characteristics and optimum growth conditions of the PCP-degrading bacteria were investigated. One of the isolated bacterial strains with good potential for PCP degradation was characterized and identified as Sphingomonas chlorophenolica by 16S rDNA gene analysis. The result of the optimum growth temperatures revealed that this organism was a mesophile. The optimum pH for PCP removal by S. chlorophenolica was between 6.9 and 7.6. Increase in concentration of PCP has a negative effect on the biodegradation potential of S. chlorophenolica and PCP concentration above 600 mg l(-1) was inhibitory to its growth. The results of this study indicate that this S. chlorophenolica strain has a better potential for PCP degradation compared to the enriched mixed culture. The physiological characterization of the isolates also indicates the possible application of this strain for bioremediation of sites contaminated with PCP.

Error Argumentation Enhance Adaptability in Adults With Low Motor Ability.

The authors focused on young adults with varying degrees of motor difficulties and examined their adaptability in a visuomotor adaptation task where the visual feedback of participants' movement error was presented with either 1:1 ratio (i.e., regular feedback schedule) or 1:2 ratio (i.e., enhanced feedback schedule). Within-subject design was used with two feedback schedules counter-balanced and separated for 10 days. Results revealed that participants with greater motor difficulties showed less adaptability than those with normal motor abilities in the regular feedback schedule; however, all participants demonstrated similar level of adaptability in the enhanced feedback schedule. The results suggest that error argumentation enhances adaptability in adults with low motor ability.

Medicinal herbs Oenanthe javanica (Blume) DC., Casuarina equisetifolia L. and Sorghum bicolor (L.) Moench protect human cells from MPP+ damage via inducing FBXO7 expression.

BACKGROUND: The F-box protein 7 (FBXO7) mutations have been identified in families with early-onset parkinsonism and pyramidal tract signs, and designated as PARK15. In addition, FBXO7 mutations were found in typical and young onset Parkinson's disease (PD). Evidence has also shown that FBXO7 plays an important role in the development of dopaminergic neurons and increased stability and overexpression of FBXO7 may be beneficial to PD. PURPOSE: We screened extracts of medicinal herbs to enhance FBXO7 expression for neuroprotection in MPP+-treated cells. METHODS: Promoter reporter assay in HEK-293 cells was used to examine the cis/trans elements controlling FBXO7 expression and to screen extracts of medicinal herbs enhancing FBXO7 expression. MTT assay was performed to assess cell viability of MPP+-treated HEK-293/SH-SY5Y cells. In addition, proteasome activity, mitochondrial membrane potential and FBXO7/TRAF2/GATA2 protein expression were evaluated. RESULTS: We demonstrated that -202--57 region of the FBXO7 promoter is likely to contain sequences that are bound by positive trans protein factors to activate FBXO7 expression and GATA2 is the main trans protein factor enhancing FBXO7 expression. Extracts of medicinal herbs Oenanthe javanica (Blume) DC. (Umbelliferae), Casuarina equisetifolia L. (Casuarinaceae), and Sorghum bicolor (L.) Moench (Gramineae) improved cell viability of both MPP+-treated HEK-293 and SH-SY5Y cells, rescued proteasome activity in MPP+-treated HEK-293 cells, and restored mitochondrial membrane potential in MPP+-treated SH-SY5Y cells. These protection effects of herbal extracts are acting through enhancing FBXO7 and decreasing TRAF2 expression, which is probably mediated by GATA2 induction. CONCLUSION: Collectively, our study provides new targets, FBXO7 and its regulator GATA2, for the development of potential treatments of PD.

Novel Lactulose and Melibiose Targeting Autophagy to Reduce PolyQ Aggregation in Cell Models of Spinocerebellar Ataxia 3.

Trehalose, a chemical chaperone and mTOR-independent autophagy enhancer, has shown promise in models of Huntington's disease, Parkinson's disease and tauopathies. In this study, two trehalase analogs, lactulose and melibiose, were examined for their potentials in spinocerebellar ataxia treatment. Using a SCA3 ATXN3/Q75-GFP cell model, we found that the ATXN3/Q75 aggregation was significantly prohibited by lactulose and melibiose because of their abilities to up-regulate autophagy. Meanwhile, lactulose and melibiose reduced reactive oxygen species production in ATXN3/Q75 cells. Both of them further inhibited the ATXN3/Q75 aggregation in neuronally differentiated SH-SY5Y cells. These findings suggest the therapeutic applications of novel trehalose analogs in polyglutamine aggregation-associated neurodegenerative diseases.

The potential of synthetic indolylquinoline derivatives for Aß aggregation reduction by chemical chaperone activity.

Alzheimer's disease (AD) is the most prevalent form of dementia associated with progressive cognitive decline and memory loss. Extracellular ß-amyloid (Aß) is a major constituent of senile plaques, one of the pathological hallmarks of AD. Aß deposition causes neuronal death via a number of possible mechanisms such as increasing oxidative stress. Therefore therapeutic approaches to identify novel Aß aggregate reducers could be effective for AD treatment. Using a Trx-His-Aß biochemical assay, we screened 11 synthetic indolylquinoline compounds, and found NC009-1, -2, -6 and -7 displaying potential to reduce Aß aggregation. Treating Tet-On Aß-GFP 293 cells with these compounds reduced Aß aggregation and reactive oxygen species. These compounds also promoted neurite outgrowth in Tet-On Aß-GFP SH-SY5Y cells. Furthermore, treatment with above compounds improved neuronal cell viability, neurite outgrowth, and synaptophysin expression level in mouse hippocampal primary culture under oligomeric Aß-induced cytotoxicity. Moreover, the tested NC009-1 significantly ameliorated Aß-induced inhibition of hippocampal long-term potentiation in mouse hippocampal slices. Our results demonstrate how synthetic indolylquinoline compounds are likely to work as chemical chaperones in Aß-aggregation reduction and neuroprotection, providing insight into the possible applications of indolylquinoline compounds in AD treatment.