HUNTINGTIN PROTEIN COLOCALIZES WITH LESIONS OF NEURODEGENERATIVE DISEASES - AN INVESTIGATION IN HUNTINGTONS, ALZHEIMERS, AND PICKS DISEASES

Huntington's disease (HD) is an autosomal dominant neurodegenerative d isease associated with a CAG trinucleotide repeat expansion in a large gene on chromosome 4. The gene encodes the protein huntingtin with a polyglutamine tract encoded by the CAG repeat at the N-terminus. The n umber of CAG repeats in HD are significantly increased (36 to 120+) co mpared with the normal population (8-39). The pathological mechanism a ssociated with the expanded CAG repeat in HD is not clear but there is evidence that polyglutamine is directly neurotoxic. We have immunoloc alized huntingtin with an in-house, well-characterised, polyclonal ant ibody in HD, Alzheimer's disease (AD), and Picks disease (PiD) brains. Control brain tissue sections were from head injured and cerebral isc haemia cases. In HD, huntingtin was immunopositive in the surviving bu t damaged neurons and reactive astrocytes of the caudate and putamen. However, in AD and]PiD the immunostaining was largely restricted to th e characteristic intracellular inclusion bodies associated with the di sease process in each case. In AD, huntingtin was localized only in th e intracellular neurofibrillary tangles and dystrophic neurites within the neuritic amyloid plaques but not with the amyloid. In PiD, strong ly positive huntingtin immunostaining was present within cytoplasmic P ick bodies. Our findings suggest huntingtin selectively accumulates in association with abnormal intracytoplasmic and cytoskeletal filaments of neurons and glia in neurodegenerative diseases such as HD, AD, and PiD. Cells in the CNS appear sensitive to damage by the aggregated, t oxic levels of huntingtin and evidence of its interaction with neurofi laments could provide information about its potential role in the aeti ology of HD. (C) 1998 Academic Press.