Transglutaminase aggregates huntingtin into nonamyloidogenic polymers, andits enzymatic activity increases in Huntington's disease brain nuclei

The protein huntingtin (htt), aggregated in neuronal nuclear inclusions, is pathognomonic of Huntington's disease (HD), Constructs, translated in I vi tro from the N terminus of htt, containing either polyQ23 from a normal ind ividual, or polyQ41 or polyQ67 from an HD patient, were all soluble. Transg lutaminase (TGase) crosslinked these proteins, and the aggregations did not have the staining properties of amyloid, More TGase-catalyzed aggregates f ormed when the polyglutamine domain of htt exceeded the pathologic threshol d of polyQ36. Furthermore, shorter htt constructs, containing 135 aa or few er, formed more aggregates than did larger htt constructs. TGase activity i n the HD brain was increased compared with the control, with notable increa ses in cell nuclei, The increased TGase activity was brain specific. In lym phoblastoid cells from HD patients, TGase activity Has decreased. TGase-med iated crosslinking of htt may be involved in the formation of the nonamyloi dogenic nuclear inclusions found in the HD brain, The staining properties o f nuclear inclusions in the HD brain revealed that they were not amyloid.