Rinsho Shinkeigaku (Clinical Neurology)

Symposium 14

Neurodegeration based on polyglutamine aggregation

Nobuyuki Nukina, M.D.

RIKEN Lab for Structural Neuropathology

One of the major hypotheses about polyQ toxicity is the sequestration of functionally important proteins into the aggregates. We established and carried out a direct, systematic proteomic analysis of aggregate-interacting proteins (AIPs). This analysis, as well as other studies in our lab, has revealed the following AIPs in addition to our previously reported chaperones: ubiquitin binding proteins such as ubiquilins and Tollip and p62, TLS and transcription factor NF-Y. Although transcriptional dysregulation has been reported in polyQ disease, the precise mechanism has not been clarified. We identified NF-Y as an AIP and found the reduction of NF-Y binding to the promoter region of HSP70, one of the NF-Y targets. Because suppressive roles of HSP70 on the HD pathological process have been shown in several HD models, NF-Y could be an important target of expanded polyQ. We further screened transcription factors, which reduced in HD model mouse, using Protein DNA array and found the decrease of POU domain factor. Based on this result, we confirmed Brn2 is decreased in HD model mouse, which showed the dysfunction of hypothalamus. We proposed the mechanism of hypothalamic dysregulation, suggesting the region specific abnormality could be induced by the imbalance of cellular compensatory mechanism.
Full Text of this Article in Japanese PDF (159K)

(CLINICA NEUROL, 51: 976|978, 2011)
key words: Polyglutamine disease, aggregate, ubiquitin binding protein, transcription factor, RNA binding protein

(Received: 19-May-11)