Fourth International Symposium on Neuroacanthocytosis

Abstracts from the Fourth International Symposium on Neuroacanthocytosis

July 1-2, 2008
London and Oxford

Chairs: Prof. Kailash Bhatia, MD, FRCP, Institute of Neurology, University College London; Prof. Anthony P. Monaco, MD, PhD, Wellcome Trust Centre for Human Genetics, University of Oxford

Organizers: Antonio Velayos-Baeza, PhD; Susanne Schneider, MD; Glenn Irvine

4-6 Pathogenesis of Huntington's disease-like 2 (HDL2)
D. D. Rudnicki, W. Chung, A. Seixas, C. A. Ross, and R. L. Margolis
Dept. of Psychiatry, Johns Hopkins University, Baltimore, Maryland, USA

Huntington's disease-like 2 (HDL2) is an autosomal dominant, progressive, adult onset neurodegenerative disorder characterized clinically by chorea, dystonia, rigidity, bradykinesia, psychiatric syndromes, dementia, and an inevitable decline to death. Pathologically, HDL2 resembles Huntington's disease (HD), with cortical and basal ganglia degeneration and a loss of medium sized neurons in the striatum in a dorsal to ventral gradient. Staining with anti-ubiquitin and 1C2 reveals intranuclear protein inclusions in multiple brain regions. Some individuals with HDL2 appear to have acanthocytes, suggesting a potential relationship between HDL2 and neuroacanthocytosis syndromes. At least 25 HDL2 pedigrees have been identified; all pedigrees of known ethnicity are of definite or probable African origin. HDL2 is caused by a CAG/CTG expansion mutation on chromosome 16q24.3. We previously found that, in addition to protein aggregates, HDL2 brain contains RNA foci that are detectable with both a CAG riboprobe and with riboprobes specific to JPH3 transcripts. Similar to foci detected in myotonic dystrophy 1 (DM1), the foci co-localize with muscleblind-like 1 protein (MBNL1), and nuclear MBNL1 in HDL2 cortical neurons is decreased relative to controls. In cell experiments, expression of a JPH3 transcript with an expanded CUG repeat resulted in the formation of RNA foci that co-localized with MBNL1 and in cell toxicity. The toxicity was rescued by co-expression of MBNL1. These results imply that RNA toxicity may contribute to the pathogenesis of HDL2.