Abstract
The presence of expanded poly-glutamine (polyQ) repeats in proteins is directly linked to the pathogenesis of several neurodegenerative diseases, including Huntington’s disease. However, the molecular and structural basis underlying the increased toxicity of aggregates formed by proteins containing expanded polyQ repeats remain poorly understood, in part due to the size and morphological heterogeneity of the aggregates they form in vitro. To address this knowledge gap and technical limitations, we investigated the structural, mechanical and morphological properties of fibrillar aggregates at the single molecule and nanometer scale using the first exon of the Huntingtin protein as a model system (Exon1). Our findings demonstrate a direct correlation of the morphological and mechanical properties of Exon1 aggregates with their structural organization at the single aggregate and nanometric scale and provide novel insights into the molecular and structural basis of Huntingtin Exon1 aggregation and toxicity.
Highlights
The presence of expanded poly-glutamine repeats in proteins is directly linked to the pathogenesis of several neurodegenerative diseases, including Huntington’s disease
There is consensus that huntingtin protein (Htt) aggregation plays an important role in the pathogenesis of Huntington’s disease (HD), the nature of the toxic species remains elusive
Numerous recent HD studies support a discrepancy between Htt aggregation and toxicity showing that inclusion formation in striatal neurons by mutant Htt can be protective or that Exon[1] with polyQ repeats below the pathogenic threshold can still aggregate in vitro and form bona fide amyloid-like fibrils[12,51,52,53]
Summary
The presence of expanded poly-glutamine (polyQ) repeats in proteins is directly linked to the pathogenesis of several neurodegenerative diseases, including Huntington’s disease. The molecular and structural basis underlying the increased toxicity of aggregates formed by proteins containing expanded polyQ repeats remain poorly understood, in part due to the size and morphological heterogeneity of the aggregates they form in vitro. To address this knowledge gap and technical limitations, we investigated the structural, mechanical and morphological properties of fibrillar aggregates at the single molecule and nanometer scale using the first exon of the Huntingtin protein as a model system (Exon[1]). From bulk techniques, single molecule techniques, such as Atomic Force Microscopy (AFM), possess increased robustness in measuring the properties of heterogeneous populations by allowing direct measurements and correlation of the biophysical properties of protein aggregates at the nanoscale and single molecule level
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