Abstract
Huntington’s disease arises from CAG codon-repeat expansions in the Htt gene, which leads to a Htt gene product with an expanded polyglutamine (polyQ) sequence. The length of the polyQ expansion correlates with an increased tendency to form aggregates and clustering into micrometer-plus sized inclusion bodies in neurons and other cell types. Yet after nearly 20 years since the genetic basis for HD was identified, our knowledge of how polyQ-expanded Htt fragment aggregation relates to disease mechanisms remains fragmentary and controversial. Challenges remain in defining the aggregation process at the molecular level and how this process is influenced by, or influences cellular activities. Insight is further confounded by the term “aggregation” being used to describe a composite of distinct processes that may have opposing consequences to cell health and survival. This review discusses these issues in light of a historic summary of Htt aggregation in the cellular milieu and the intrinsic attributes of polyQ-expanded Htt that lead to aggregation. Finally, discussion centers on strategies forward to improve our knowledge for how aggregation relates to cellular dysfunction.
Keywords: Huntington’s disease (HD), huntingtin, polyglutamine (polyQ), misfolding, aggregation
Current Topics in Medicinal Chemistry
Title:Putting Huntingtin “Aggregation” in View with Windows into the Cellular Milieu
Volume: 12 Issue: 22
Author(s): Danny M. Hatters
Affiliation:
Keywords: Huntington’s disease (HD), huntingtin, polyglutamine (polyQ), misfolding, aggregation
Abstract: Huntington’s disease arises from CAG codon-repeat expansions in the Htt gene, which leads to a Htt gene product with an expanded polyglutamine (polyQ) sequence. The length of the polyQ expansion correlates with an increased tendency to form aggregates and clustering into micrometer-plus sized inclusion bodies in neurons and other cell types. Yet after nearly 20 years since the genetic basis for HD was identified, our knowledge of how polyQ-expanded Htt fragment aggregation relates to disease mechanisms remains fragmentary and controversial. Challenges remain in defining the aggregation process at the molecular level and how this process is influenced by, or influences cellular activities. Insight is further confounded by the term “aggregation” being used to describe a composite of distinct processes that may have opposing consequences to cell health and survival. This review discusses these issues in light of a historic summary of Htt aggregation in the cellular milieu and the intrinsic attributes of polyQ-expanded Htt that lead to aggregation. Finally, discussion centers on strategies forward to improve our knowledge for how aggregation relates to cellular dysfunction.
Export Options
About this article
Cite this article as:
M. Hatters Danny, Putting Huntingtin “Aggregation” in View with Windows into the Cellular Milieu, Current Topics in Medicinal Chemistry 2012; 12 (22) . https://dx.doi.org/10.2174/1568026611212220013
DOI https://dx.doi.org/10.2174/1568026611212220013 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
AlphaFold in Medicinal Chemistry: Opportunities and Challenges
AlphaFold, a groundbreaking AI tool for protein structure prediction, is revolutionizing drug discovery. Its near-atomic accuracy unlocks new avenues for designing targeted drugs and performing efficient virtual screening. However, AlphaFold's static predictions lack the dynamic nature of proteins, crucial for understanding drug action. This is especially true for multi-domain proteins, ...read more
Artificial intelligence for Natural Products Discovery and Development
Our approach involves using computational methods to predict the potential therapeutic benefits of natural products by considering factors such as drug structure, targets, and interactions. We also employ multitarget analysis to understand the role of drug targets in disease pathways. We advocate for the use of artificial intelligence in predicting ...read more
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Hereditary Rickets. How Genetic Alterations Explain the Biochemical and Clinical Phenotypes
Endocrine, Metabolic & Immune Disorders - Drug Targets Efficacy and Toxicity of Clioquinol Treatment and A-beta42 Inoculation in the APP/PSI Mouse Model of Alzheimer's Disease
Current Alzheimer Research Recent Developments in the Regulation of Monoamine Oxidase Form and Function: Is the Current Model Restricting Our Understanding of the Breadth of Contribution of Monoamine Oxidase to Brain [dys]Function?
Current Topics in Medicinal Chemistry Advances in the Understanding of the Gabaergic Neurobiology of FMR1 Expanded Alleles Leading to Targeted Treatments for Fragile X Spectrum Disorder
Current Pharmaceutical Design Antiinflammatory Activity of Melatonin in Central Nervous System
Current Neuropharmacology Evaluation of [11C]S14506 and [18F]S14506 in Rat and Monkey as Agonist PET Radioligands for Brain 5-HT1A Receptors
Current Radiopharmaceuticals Bipolar Affective Disorder, Epilepsy and Migraine – Does Possible Shared Pathogenesis Explain their Association?
Current Psychopharmacology Detection and Therapeutic Implications of c-Met Mutations in Small Cell Lung Cancer and Neuroendocrine Tumors
Current Pharmaceutical Design The Influence of Thyroid Hormone on Ca<sup>2+</sup> Signaling Pathways During Embryonal Development
Current Topics in Medicinal Chemistry Ubiquitin-Protein Ligases - Novel Therapeutic Targets?
Current Protein & Peptide Science Pathological Brain Image Segmentation and Classification: A Survey
Current Medical Imaging Genetics of Schizophrenia and other Psychotic Disorders
Current Psychiatry Reviews Mesenchymal Stem Cells as Mediators of Neural Differentiation
Current Stem Cell Research & Therapy Somatic Genome Variations in Health and Disease
Current Genomics Channel-Like Functions of the 18-kDa Translocator Protein (TSPO): Regulation of Apoptosis and Steroidogenesis as Part of the Host-Defense Response
Current Pharmaceutical Design Chemistry and Pharmacological Properties of Some Natural and Synthetic Antioxidants for Heavy Metal Toxicity
Current Medicinal Chemistry Functional Cross-Talk between Adenosine and Metabotropic Glutamate Receptors
Current Neuropharmacology Relationship Between Na<sup>+</sup>, K<sup>+</sup>-ATPase and NMDA Receptor at Central Synapses
Current Protein & Peptide Science Molecular Targeting Agents in Renal Cell Carcinoma: Present Strategies and Future Perspectives
Current Pharmaceutical Design An Updated Meta-Analysis of the Efficacy and Safety of Acupuncture Treatment for Vascular Cognitive Impairment Without Dementia
Current Neurovascular Research