Neuroinflammation in Huntington's disease

Abstract

Huntington's disease (HD) is a progressive, eventually terminal, neurodegenerative disease caused by autosomal-dominant mutations in the huntingtin gene (HTT). The early symptoms of HD typically include subtle changes in mood and/or cognition, as well as poor coordination and unsteady gait. These symptoms progressively worsen until coordinated movement is virtually impossible and mental abilities have declined to a state of dementia. There is no cure and patients generally succumb to comorbid complications within 20 years of onset. The mutation is an expansion of the CAG triplet repeat stretch in the HTT gene, resulting in an expanded poly-glutamine (polyQ) stretch in the huntingtin protein (HTT). The length of this CAG repeat correlates strongly with the age of onset as well as the rate of disease progression. The ability to identify at-risk individuals by genetic testing enabled researchers to conduct clinical studies and learn about early events in the development of HD. One of the earliest pathological changes observed in the CNS of HD patients is the appearance of neuroinflammation, preceding overt neurodegeneration or protein aggregation. Here we will review the data implicating neuroinflammation in all stages of HD, from initiation to progression. We will also explore the most recent advances in our understanding of neuroinflammation in HD including a potential role for the peripheral immune system. We will also discuss how these various biologies may lead the way to discovery of novel, innovative, and urgently needed therapies.