Wang Chung Han

INTRODUCTION

• Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder resulting from a CAG expansion in the huntingtin gene.

• The earliest signs of pathology in HD are in the striatum, a subcortical structure involved in the control of movement and action selection.

parallel projection systems

direct pathway indirect pathway

promotes action suppresses action

• In recent years, this loss has been attributed to impaired expression and release of brain-derived neurotrophic factor (BDNF) by corticostriatal terminals.

• The BACHD mouse is a transgenic model of HD in which the

full-length human mutant huntingtin (mHtt) gene has been inserted using a bacterial artificial chromosome (BAC).

• These mice display progressive motor and physiological deficits that are pronounced by 6 months of age.

• This also was true in the Q175 knockin mouse model of HD, which displays a similar progressive motor and physiological phenotype.

BDNF signal pathway

Nature Reviews Neuroscience 10, 850-860 (December 2009)

BACHD mice normal

Q175 miceimpaired

BDNF Expression and Delivery to the Striatum Was Normal in HD Mice

No change in TrkBR expression in symptomatic (5–6 months old) BACHD mice

Signaling Downstream of TrkBRs Is Attenuated in the BACHD Striatum