Experimental Models for Identifying Modifiers of Polyglutamine-Induced Aggregation and Neurodegeneration

Abstract

Huntington's disease (HD) typifies a class of inherited neurodegenerative disorders in which a CAG expansion in a single gene leads to an extended polyglutamine tract and misfolding of the expressed protein, driving cumulative neural dysfunction and degeneration. HD is invariably fatal with symptoms that include progressive neuropsychiatric and cognitive impairments, and eventual motor disability. No curative therapies yet exist for HD and related polyglutamine diseases; therefore, substantial efforts have been made in the drug discovery field to identify potential drug and drug target candidates for disease-modifying treatment. In this context, we review here a range of early-stage screening approaches based in in vitro, cellular, and invertebrate models to identify pharmacological and genetic modifiers of polyglutamine aggregation and induced neurodegeneration. In addition, emerging technologies, including high-content analysis, threedimensional culture models, and induced pluripotent stem cells are increasingly being incorporated into drug discovery screening pipelines for protein misfolding disorders. Together, these diverse screening strategies are generating novel and exciting new probes for understanding the disease process and for furthering development of therapeutic candidates for eventual testing in the clinical setting.

Polyglutamine (PolyQ) Diseases: Navigating the Landscape of Neurodegeneration

“…Biomarkers related to energy metabolism, mitochondrial function, or metabolite levels in the brain or peripheral tissues could provide insights into disease mechanisms and progression. , Genetic modifiers : Variants in other genes can modulate the age of onset, severity, or progression of polyQ diseases. Identifying genetic modifiers through genome-wide association studies (GWAS) or whole-genome sequencing could help stratify patients based on disease risk and prognosis. ,, …”

“…Genetic modifiers : Variants in other genes can modulate the age of onset, severity, or progression of polyQ diseases. Identifying genetic modifiers through genome-wide association studies (GWAS) or whole-genome sequencing could help stratify patients based on disease risk and prognosis. ,, …”

iPSC-based drug screening for Huntington׳s disease

“…Many screens including high throughput screening (HTS) and high content screening (HCS) have already been conducted in HD invertebrate models, primary cells, or immortalized cell lines with chemical or genetic modifiers (32). However, lower organisms like yeast, worms, and fruit flies have limitations and may not accurately reflect the pathogenesis of HD in humans.…”

“…When screening for potential therapeutic compounds, it would be advisable to screen for aggregation formation, mHTT, HTT post-translational modifications and toxic fragment levels. Since mHTT protein is the cause of HD pathology, screening for compounds capable of decreasing mHTT levels has been reported (32). Time-resolved fluorescence resonance energy transfer (FRET) assays that detect HTT levels were developed to screen small molecule libraries in the HN10 neuronal cell line in a high throughput format (51, 52).…”