The pathobiology of perturbed mutant huntingtin protein–protein interactions in Huntington's disease

Wanker, Erich E.; Ast, Anne; Schindler, Franziska; Trepte, Philipp; Schnoegl, Sigrid

doi:10.1111/jnc.14853

Cited by 86 publications

(67 citation statements)

References 136 publications

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“…HTT plays an important role in neuronal transport. The interaction of HTT with dynein and HAP1, proteins that regulate the transport of organelles, have been reported, which, when the complex is disturbed, lead to dysfunction of the axonal transport (for a review see [285,286]).…”

Section: Neuronal Cytoskeleton Abnormalities Generate Neurodegenerationmentioning

confidence: 99%

Much More Than a Scaffold: Cytoskeletal Proteins in Neurological Disorders

Muñoz-Lasso

Romá‐Mateo

Pallardó

et al. 2020

Cells

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Recent observations related to the structure of the cytoskeleton in neurons and novel cytoskeletal abnormalities involved in the pathophysiology of some neurological diseases are changing our view on the function of the cytoskeletal proteins in the nervous system. These efforts allow a better understanding of the molecular mechanisms underlying neurological diseases and allow us to see beyond our current knowledge for the development of new treatments. The neuronal cytoskeleton can be described as an organelle formed by the three-dimensional lattice of the three main families of filaments: actin filaments, microtubules, and neurofilaments. This organelle organizes well-defined structures within neurons (cell bodies and axons), which allow their proper development and function through life. Here, we will provide an overview of both the basic and novel concepts related to those cytoskeletal proteins, which are emerging as potential targets in the study of the pathophysiological mechanisms underlying neurological disorders.

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Section: Neuronal Cytoskeleton Abnormalities Generate Neurodegenerationmentioning

confidence: 99%

Much More Than a Scaffold: Cytoskeletal Proteins in Neurological Disorders

Muñoz-Lasso

Romá‐Mateo

Pallardó

et al. 2020

Cells

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“…Enhanced proteolysis in HD-affected neuronal cells leads to the release of N-terminal fragments with expanded polyQ sequences. The polyQ expansion leads to misfolding and self-assembly into amyloid-like fibrillary aggregates [140][141][142], which form intranuclear inclusions in neurons. According to recent studies, cytotoxicity is attributed mostly to polyQ-expanded mHTTex1 fibrils, rather than oligomers or misfolded monomers [143].…”

Section: Disrupted Proteolytic Pathways: Ptms In Abnormal Htt Proteinmentioning

confidence: 99%

How Do Post-Translational Modifications Influence the Pathomechanistic Landscape of Huntington’s Disease? A Comprehensive Review

Lontay

Kiss

Virág

et al. 2020

IJMS

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Huntington’s disease (HD) is an autosomal dominant inherited neurodegenerative disorder characterized by the loss of motor control and cognitive ability, which eventually leads to death. The mutant huntingtin protein (HTT) exhibits an expansion of a polyglutamine repeat. The mechanism of pathogenesis is still not fully characterized; however, evidence suggests that post-translational modifications (PTMs) of HTT and upstream and downstream proteins of neuronal signaling pathways are involved. The determination and characterization of PTMs are essential to understand the mechanisms at work in HD, to define possible therapeutic targets better, and to challenge the scientific community to develop new approaches and methods. The discovery and characterization of a panoply of PTMs in HTT aggregation and cellular events in HD will bring us closer to understanding how the expression of mutant polyglutamine-containing HTT affects cellular homeostasis that leads to the perturbation of cell functions, neurotoxicity, and finally, cell death. Hence, here we review the current knowledge on recently identified PTMs of HD-related proteins and their pathophysiological relevance in the formation of abnormal protein aggregates, proteolytic dysfunction, and alterations of mitochondrial and metabolic pathways, neuroinflammatory regulation, excitotoxicity, and abnormal regulation of gene expression.

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“…Symptoms of the disease develop when the polyQ expansion exceeds a critical length of ~ 37 glutamines. Although the genetics of HD are well studied, the exact biological functions of huntingtin remain speculative and the exact mechanism of pathogenic peptide aggregation remains a controversial topic (5).…”

mentioning

confidence: 99%

Membrane interactions accelerate the self-aggregation of huntingtin exon 1 fragments in a polyglutamine length-dependent manner

Marquette

Bechinger

2020

Preprint

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The accumulation of aggregated protein is a typical hallmark of many human neurodegenerative disorders including Huntington's disease. Misfolding of the amyloidogenic proteins gives rise to self-assembled complexes and fibers. The huntingtin protein is characterized by a segment of consecutive glutamines, which when exceeding a certain number of residues results in the occurrence of the disease.Furthermore, it has also been demonstrated that the 17-residue amino-terminal domain of the protein (htt17), located upstream of this polyglutamine tract, strongly correlates with aggregate formation and pathology. Here we demonstrate that membrane interactions strongly accelerate the oligomerization and β-amyloid fibril formation of htt17-polyglutamine segments. By using a combination of biophysical approaches the kinetics of fibre formation has been quantitatively investigated and found to be strongly dependent to the presence of lipids, the length of the polyQ expansion and the polypeptide-to-lipid ratio. Finally, the implications for therapeutic approaches are discussed. Statement of significance:The quantitative analysis of the aggregation kinetics of amino-terminal fragments of huntingtin demonstrate the importance of the 17residue amino-terminal membrane anchor and a resulting dominant effect of membranes in promoting the aggregation of polyglutamines. Other parameters further modulating the association kinetics are the length of the polyglutamine stretch and the peptide concentration. The findings can have important impact on finding new therapies to treat Huntington's and other polyglutamine related diseases.

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The pathobiology of perturbed mutant huntingtin protein–protein interactions in Huntington's disease

Cited by 86 publications

References 136 publications

Much More Than a Scaffold: Cytoskeletal Proteins in Neurological Disorders

Much More Than a Scaffold: Cytoskeletal Proteins in Neurological Disorders

How Do Post-Translational Modifications Influence the Pathomechanistic Landscape of Huntington’s Disease? A Comprehensive Review

Membrane interactions accelerate the self-aggregation of huntingtin exon 1 fragments in a polyglutamine length-dependent manner

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