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**Chapter 7**

**Abstract**

Molecular Mechanisms of

Polyglutamine Pathology

Huntington's Disease

*Nagehan Ersoy Tunalı*

expansion, neuronal death

**1. PolyQ diseases**

and Lessons Learned from

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.

**1.1 Clinical and neuropathological characteristics of PolyQ diseases**

Despite a wide spectrum of clinical presentations, all polyQ diseases are characterized by late onset and progressive neurodegeneration, involving selective neuron death. Clinical symptoms generally begin in midlife, although they can also manifest earlier. In all cases, age of onset is inversely related to the CAG repeat size in respective genes. Larger CAG repeat tracts were found to be associated with earlier disease onset, severe phenotype and rapid progression [1]. The expanded repeat tracts are prone to changes in length during intergenerational transmission. This results in earlier disease onset in the later generations, known as anticipation.

**Keywords:** polyglutamine diseases, trinucleotide repeats, Huntington's disease, CAG

#### **Chapter 7**
