Dement Neurocogn Disord.  2012 Mar;11(1):1-12. 10.12779/dnd.2012.11.1.1.

Unstable Repeat Expansion in Neurodegenerative Dementias: Mechanisms of Disease

Affiliations
  • 1Inam Neuroscience Research Center, Department of Neurology, Sanbon Medical Center, College of Medicine, Wonkwang University, Gunpo, Korea. hyundyang@gmail.com

Abstract

The majority of neurodegenerative dementias are thought to result primarily from the misfolding, aggregation and accumulation of proteins which interfere with protein homeostasis in the brain. Some of them are caused by the expansion of unstable nucleotide repeats, which include Huntington's disease as a prototype. Other neurodevelopmental or neurodegenerative disorders, such as fragile X syndrome, some spinocerebellar ataxias and myotonic dystrophies exhibit cognitive or behavioral deficits as parts of their clinical manifestations. Unstable repeat expansions include trinucleotide, tetranucleotide, and pentanucleotide. Recently hexanucleotide repeat expansion in frontotemporal dementia and amyotrophic lateral sclerosis was identified. The pathogenic mechanisms for these repeat disorders include either loss of protein function or gain of function at the protein or RNA levels. The aim of this article is to review proposed mechanisms by which unstable repeat expansions give rise to degeneration of brain with the hope of understanding the diseases and providing insights into the areas of therapeutic intervention. We will review these potential mechanisms in the context of fragile X syndrome, Huntington's disease, spinocerebellar ataxias, myotonic dystrophy, and frontotemporal dementia and amyotrophic lateral sclerosis. We will also discuss the potential targets for therapeutic intervention.

Keyword

Dementia; Unstable repeat expansion

MeSH Terms

Amyotrophic Lateral Sclerosis
Brain
Dementia
Fragile X Syndrome
Frontotemporal Dementia
Homeostasis
Huntington Disease
Myotonic Dystrophy
Neurodegenerative Diseases
Proteins
RNA
Spinocerebellar Ataxias
Proteins
RNA
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