Nuclear accumulation of truncated atrophin-1 fragments in a transgenic mouse model of DRPLA.

Abstract

Dentatorubral and pallidoluysian atrophy (DRPLA) is a member of a family of progressive neurodegenerative diseases caused by polyglutamine repeat expansion. Transgenic mice expressing full-length human atrophin-1 with 65 consecutive glutamines exhibit ataxia, tremors, abnormal movements, seizures, and premature death. These mice accumulate atrophin-1 immunoreactivity and inclusion bodies in the nuclei of multiple populations of neurons. Subcellular fractionation revealed 120 kDa nuclear fragments of mutant atrophin-1, whose abundance increased with age and phenotypic severity. Brains of DRPLA patients contained apparently identical 120 kDa nuclear fragments. By contrast, mice overexpressing atrophin-1 with 26 glutamines were phenotypically normal and did not accumulate the 120 kDa fragments. We conclude that the evolution of neuropathology in DRPLA involves proteolytic processing of mutant atrophin-1 and nuclear accumulation of truncated fragments.

• Authors: G Schilling, J D Wood, K Duan, H H Slunt, V Gonzales, M Yamada, J K Cooper, R L Margolis, N A Jenkins, N G Copeland, H Takahashi, S Tsuji, D L Price, D R Borchelt, C A Ross
• Journal: Neuron (Neuron) Vol. 24 Issue 1 Pg. 275-86 (Sep 1999) ISSN: 0896-6273 [Print] United States
• PMID: 10677044 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Nerve Tissue Proteins
• Peptide Fragments
• atrophin-1

Topics

• Adolescent
• Animals
• Ataxia
• Brain (pathology)
• Cell Nucleus (metabolism)
• Child
• Chorea
• Disease Models, Animal
• Female
• Humans
• Male
• Mice
• Mice, Transgenic
• Multiple System Atrophy (genetics, metabolism, pathology)
• Nerve Tissue Proteins (genetics, metabolism)
• Neurodegenerative Diseases (genetics, metabolism)
• Peptide Fragments (metabolism)
• Repetitive Sequences, Nucleic Acid
• Tremor