Huntingtin protein: A new option for fixing the Huntington's disease countdown clock

Caterino, Marco; Squillaro, Tiziana; Montesarchio, Daniela; Giordano, Antonio; Giancola, Concetta; Melone, Mariarosa Anna Beatrice

doi:10.1016/j.neuropharm.2018.03.009

Cited by 20 publications

(24 citation statements)

References 199 publications

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“…The N17 sequence functions as a nuclear export signal and its PTMs are thought to modulate subcellular localization and the clearance of mHTT. The PRD has a function in HTT aggregation, protein-protein recognition, and mHTT turnover [69]. Based on structural studies, N17 is predominantly disordered in solution but adopts an α-helical conformation in amyloid fibrils [70,71].…”

Section: Ptms In Abnormal Htt Protein Aggregationmentioning

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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Section: Ptms In Abnormal Htt Protein Aggregationmentioning

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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“…HD is a neurodegenerative disorder that is caused by a mutation in a single gene and is autosomal dominantly inherited. In HD there is a repeat expansion of the amino acid sequence for glutamine (CAG) within exon 1 of the Huntingtin (Htt) gene; CAG repeats of approximately 40 or more causes HD, with repeats of more than 60 causing juvenileonset HD (70, 438). This expansion, while ubiquitously expressed, primarily causes the death of MSNs in the striatum, but cells in the cerebral cortex, hippocampus, and hypothalamus are also affected (94).…”

Section: D Models To Study Neurodegenerative Diseasesmentioning

confidence: 99%

Studying Human Neurological Disorders Using Induced Pluripotent Stem Cells: From 2D Monolayer to 3D Organoid and Blood Brain Barrier Models

Logan

Arzua

Canfield

et al. 2019

Comprehensive Physiology

145

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Neurological disorders have emerged as a predominant healthcare concern in recent years due to their severe consequences on quality of life and prevalence throughout the world. Understanding the underlying mechanisms of these diseases and the interactions between different brain cell types is essential for the development of new therapeutics. Induced pluripotent stem cells (iPSCs) are invaluable tools for neurological disease modeling, as they have unlimited self-renewal and differentiation capacity. Mounting evidence shows: 1) various brain cells can be generated from iPSCs in 2-dimensional (2D) monolayer cultures; 2) further advances in 3D culture systems have led to the differentiation of iPSCs into organoids with multiple brain cell types and specific brain regions. These 3D organoids have gained widespread attention as in vitro tools to recapitulate complex features of the brain, and 3) Complex interactions between iPSC-derived brain cell types can recapitulate physiological and pathological conditions of blood-brain barrier (BBB). As iPSCs can be generated from diverse patient populations, researchers have effectively applied 2D, 3D and BBB models to recapitulate genetically complex neurological disorders and reveal novel insights into molecular and genetic mechanisms of neurological disorders. In this review, we describe recent progress in the generation of 2D, 3D and BBB models from iPSCs and further discuss their limitations, advantages, and future ventures. This review also covers the current status of applications of 2D, 3D and BBB models in drug screening, precision medicine, and modeling a wide range of neurological diseases (e.g., neurodegenerative diseases, neurodevelopmental disorders, brain injury, and neuropsychiatric disorders).

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“…The HEAT sequences are resistant to the proteolytic cleavage providing a scaffold function to the protein. Exon 1 corresponds to 90 AA of HTT and comprises a N-terminal 17 amino-acid (N17) segment with α-helical structure, the PolyQ tract and a 51-residue proline-rich domain (PRD) [ 25 ].…”

Section: Wild-type Huntingtin: Structure and Functionsmentioning

confidence: 99%

Huntington disease: Advances in the understanding of its mechanisms

Gatto

Rojas

Persi

et al. 2020

Clinical Parkinsonism & Related Disorders

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Huntington disease (HD) is a devastating monogenic autosomal dominant disorder. HD is caused by a CAG expansion in exon 1 of the gene coding for huntingtin, placed in the short arm of chromosome 4. Despite its well-defined genetic origin, the molecular and cellular mechanisms underlying the disease are unclear and complex. Here, we review some of the currently known functions of the wild-type huntingtin protein and discuss the deleterious effects that arise from the expansion of the CAG repeats, which are translated into an abnormally long polyglutamine tract. Also, we present a modern view on the molecular biology of HD as a representative of the group of polyglutamine diseases, with an emphasis on conformational changes of mutant huntingtin, disturbances in its cellular processing, and proteolytic stress in degenerating neurons. The main pathogenetic mechanisms of neurodegeneration in HD are discussed in detail, such as autophagy, impaired mitochondrial biogenesis, lysosomal dysfunction, organelle and protein transport, inflammation, oxidative stress, and transcription factor modulation. However, other unraveling mechanisms are still unknown. This practical and brief review summarizes some of the currently known functions of the wild-type huntingtin protein and the recent findings related to the mechanisms involved in HD pathogenesis.

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Huntingtin protein: A new option for fixing the Huntington's disease countdown clock

Cited by 20 publications

References 199 publications

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

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

Studying Human Neurological Disorders Using Induced Pluripotent Stem Cells: From 2D Monolayer to 3D Organoid and Blood Brain Barrier Models

Huntington disease: Advances in the understanding of its mechanisms

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