PolyQ length-dependent metabolic alterations and DNA damage drive human astrocyte dysfunction in Huntington's disease.

Huntington's Disease (HD) is a neurodegenerative disease caused by a polyglutamine (polyQ) expansion in the Huntingtin gene. Astrocyte dysfunction is known to contribute to HD pathology, however our understanding of the molecular pathways involved is limited. Transcriptomic analysis of patient-derived PSC (pluripotent stem cells) astrocyte lines revealed that astrocytes with similar polyQ lengths shared a large number of differentially expressed genes (DEGs).

Cerebral Organoids and Antisense Oligonucleotide Therapeutics: Challenges and Opportunities.

The advent of stem cell-derived cerebral organoids has already advanced our understanding of disease mechanisms in neurological diseases. Despite this, many remain without effective treatments, resulting in significant personal and societal health burden. Antisense oligonucleotides (ASOs) are one of the most widely used approaches for targeting RNA and modifying gene expression, with significant advancements in clinical trials for epilepsy, neuromuscular disorders and other neurological conditions.

Glial Dysfunction and Its Contribution to the Pathogenesis of the Neuronal Ceroid Lipofuscinoses.

While significant efforts have been made in developing pre-clinical treatments for the neuronal ceroid lipofuscinoses (NCLs), many challenges still remain to bring children with NCLs a cure. Devising effective therapeutic strategies for the NCLs will require a better understanding of pathophysiology, but little is known about the mechanisms by which loss of lysosomal proteins causes such devastating neurodegeneration. Research into glial cells including astrocytes, microglia, and oligodendrocytes have revealed many of their critical functions in brain homeostasis and potential contributions to neurodegenerative diseases.

Dystrophin deficiency affects human astrocyte properties and response to damage.

In addition to progressive muscular degeneration due to dystrophin mutations, 1/3 of Duchenne muscular dystrophy (DMD) patients present cognitive deficits. However, there is currently an incomplete understanding about the function of the multiple dystrophin isoforms in human brains. Here, we tested the hypothesis that dystrophin deficiency affects glial function in DMD and could therefore contribute to neural impairment.

Mislocalization of Nucleocytoplasmic Transport Proteins in Human Huntington's Disease PSC-Derived Striatal Neurons.

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene (). Disease progression is characterized by the loss of vulnerable neuronal populations within the striatum. A consistent phenotype across HD models is disruption of nucleocytoplasmic transport and nuclear pore complex (NPC) function.

Pathomechanisms in the neuronal ceroid lipofuscinoses.

The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative lysosomal storage disorders (LSDs), traditionally grouped together based on shared clinical symptoms. The recent emergence of new forms of NCL along with an improved understanding of endo-lysosomal system function have necessitated the reassessment of their classification and pathogenesis. Novel clinical findings, as well as observations in various animal models of NCL, have revealed significant pathological changes in regions outside the brain, as well as progression of disease along connected anatomical pathways.

Compromised astrocyte function and survival negatively impact neurons in infantile neuronal ceroid lipofuscinosis.

The neuronal ceroid lipofuscinoses (NCLs) are the most common cause of childhood dementia and are invariably fatal. Early localized glial activation occurs in these disorders, and accurately predicts where neuronal loss is most pronounced. Recent evidence suggests that glial dysfunction may contribute to neuron loss, and we have now explored this possibility in infantile NCL (INCL, CLN1 disease).

Identification of rare nonsynonymous variants in SYNE1/CPG2 in bipolar affective disorder.

Background: Bipolar affective disorder (BPD) is a severe mood disorder with a prevalence of ∼1.5% in the population. The pathogenesis of BPD is poorly understood; however, a strong heritable component has been identified.

The effects of measures of language experience and language ability on segmental accuracy in bilingual children.

Purpose: The present study investigated the effects of selected measures of language experience (parent-reported estimates of frequency of output and language use) and language ability (parent-reported language proficiency and mean length of utterance in words) on the segmental accuracy of Spanish- and English-speaking bilingual children.

Method: The phonological skills of 50 typically developing bilingual Spanish-English children (mean age = 5;9 [years;months]) were examined. Independent variables included parent estimates of language use, language proficiency, and frequency of language output (5 groups), as well as a direct language measure (mean length of utterance in words) to predict the dependent segmental accuracy measures (percentage of consonants and vowels correct).