Pathological Mechanisms in Polyglutamine Expansion Diseases

Since 1991, 9 monogenic neurodegenerative diseases have been shown to be caused by moderate expansion of a CAG repeat coding for a polyglutamine stretch in specific target proteins. These disorders include Huntington’s disease (HD), spinobulbar muscular atrophy (SBMA) and various spinocerebellar ataxias (SCAs), and their pathogenic mechanism has been the object of intense recent studies. While it is clear that the mutations confer a gain of toxic property to the target proteins, correlated with appearance of a common pathologic epitope and of self aggregation properties, much remains to be learned concerning how these elongated polyglutamines cause neuronal dysfunction and death, and what features can account for the selectivity with which various neuronal populations are affected. Important observations have recently been made, notably by use of cellular or transgenic animal models, that give new insight in the mechanisms of polyglutamine diseases and raise hopes for therapies.