Molecular Mechanisms of Polyglutamine Pathology and Lessons Learned from Huntington’s Disease

Identification of polymorphic repeating units on DNA as a cause of many neurological disorders has introduced a new concept in molecular biology: Dynamic mutations. Many of the identified dynamic mutations involve expansion of trinucleotide repeats within disease genes. Nine neurodegenerative disorders are currently known to be caused by expanding CAG trinucleotide repeats. These are Huntington’s Disease (HD), Dentato-Rubral Pallidoluysian Atrophy (DRPLA), Spinal and Bulbar Muscular Atrophy (SBMA), and Spinocerebellar Ataxia (SCA) Type 1, 2, 3, 6, 7 and 17. All are inherited in an autosomal dominant fashion except for SBMA, which is X-linked recessive. In all polyQ diseases, the disease mutation involves an increase in the number of CAG repeats within the coding regions of the respective genes. Since CAG triplets encode glutamine in the proteins, diseases caused by CAG repeat expansions are known as “Polyglutamine (polyQ) Diseases”. PolyQ diseases share certain clinical, neuropathological and molecular findings. The most widely studied polyQ disease is HD. In HD and other polyQ diseases, conformational change in the mutant protein causes abnormal folding and proteolysis of the protein, leading to the formation of a toxic polyQ fragment, which aggregates and causes neuronal dysfunction and selective neuronal death in the brain

NR1 Receptor Gene Variation is a Modifier of Age at Onset in Turkish Huntington’s Disease Patients

The length of the CAG repeat tract is the major determinant of age of onset (AO) of Huntington’s Disease (HD) However, there remains a significant variance in AO when the expanded repeat size is ruled out. The search for genetic modifiers has revealed various candidate loci; however, many reports have been contradictory. The N-methyl-d-aspartate receptors (NMDAR) have been proposed as an important putative modifier. We aimed to determine whether polymorphisms in NMDAR-coding genes have an effect on the AO. We analyzed the association between GRIN1 (rs6293), GRIN2A (rs1969060), and GRIN2B (rs1806201, rs890) polymorphisms and AO of Turkish HD patients. According to our findings, expanded CAG repeat size explains 41.8% of the variance in AO. Upon classification of genotypes into CAG repeat length intervals, rs6293 can be considered as an AO modifier for Turkish HD patients with 50 or higher CAG repeats. In addition to that, we found a significant association of this polymorphism to HD, with the GG genotype constituting a risk factor. Candidate genetic modifiers should be tested in different populations since their effects may exist only in groups of specific ethnic origins. Defining such modifiers will help in complete understanding of HD pathogenesis and in designing therapeutic targets

Huntington's Disease - Molecular Pathogenesis and Current Models

Huntington's disease is a progressive neurodegenerative disorder of the brain. It is one of the quite devastating and currently incurable human conditions. Degeneration of specific types of neurons in the brain results in a triad of clinical features: serious behavioral disturbances, uncontrolled movements of body parts, and deterioration of intellectual capabilities. The underlying complex mechanisms and molecular players of the cellular cascades still need to be deciphered in detail despite considerable advances. Once solved, the related molecular mechanisms will not only enlighten the HD story but will also shed light on other polyglutamine diseases and similar brain disorders. This book, Huntington's Disease-Molecular Pathogenesis and Current Models, is planned to cover recent scientific achievements in understanding the cellular mechanisms of HD. The chapters provide comprehensive description of the key issues in HD research. In this regard, this book will serve as a source for clinicians and researchers in the field and also for life science readers in increasing their understanding and awareness of the clinical correlates, genetic aspects, neuropathological findings, and potential therapeutic interventions related to HD