Huntingtin aggregate-associated axonal degeneration is an early pathological event in Huntington's disease mice

• Type of Material: Article
• Authors: He Li, Emory University; Shihua Li, Emory University; Xiao-Jiang Li, Emory University; Zhao-Xue Yu, Emory University; Peggy Shebourne, University of Glasgow
• Language: English
• Date: 2001-11-01
• Publisher: Lippincott, Williams & Wilkins
• Publication Version: Final Published Version
• Copyright Statement: Copyright © 2001 Society for Neuroscience
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1523/JNEUROSCI.21-21-08473.2001
• Title of Journal or Parent Work: Journal of Neuroscience Nursing
• ISSN: 0888-0395
• Volume: 21
• Issue: 21
• Start Page: 8473
• End Page: 8481
• Grant/Funding Information: H.L. is a recipient of the postdoctoral fellowship of the Hereditary Disease Foundation and is partly supported by the National Natural Science Foundation of China.; This work was supported by grants from the National Institutes of Health (AG19206) and the Hereditary Disease Foundation.
• Keywords: TRANSGENIC MICE; STRIATAL PROJECTION NEURONS; MUTANT HUNTINGTIN; BEHAVIORAL ABNORMALITIES; Science & Technology; NEURONAL INTRANUCLEAR INCLUSIONS; axon; SYNAPTIC PLASTICITY; NUCLEAR-LOCALIZATION; transport; polyglutamine; BASAL GANGLIA; PREFERENTIAL LOSS; Life Sciences & Biomedicine; MOUSE MODEL; Neurosciences; Neurosciences & Neurology; mitochondria; Huntingtin; degeneration
• Research Categories: Biology, Animal Physiology; Biology, Neuroscience

Abstract

Huntington′s disease (HD) is characterized by the selective loss of striatal projection neurons. In early stages of HD, neurodegeneration preferentially occurs in the lateral globus pallidus (LGP) and substantia nigra (SN), two regions in which the axons of striatal neurons terminate. Here we report that in mice expressing full-length mutant huntingtin and modeling early stages of HD, neuropil aggregates form preferentially in the LGP and SN. The progressive formation of these neuropil aggregates follows intranuclear accumulation of mutant huntingtin and becomes prominent from 11 to 27 months after birth, Neuropil aggregates, but no intranuclear inclusions, were observed in the LGP and SN, suggesting that huntingtin aggregates are formed in the axons of striatal projection neurons. In the LGP and SN, we observed degenerated axons in which huntingtin aggregates were associated with dark, swollen organelles that resemble degenerated mitochondria. Neuritic aggregates also form in cultured striatal neurons expressing mutant huntingtin, block protein transport in neurites, and cause neuritic degeneration before nuclear DNA fragmentation occurs. These findings suggest that the early neuropathology of HD originates from axonal dysfunction and degeneration associated with huntingtin aggregates.