Aggregate formation and the impairment of long-term synaptic facilitation by ectopic expression of mutant huntingtin in Aplysia neurons.
Huntington's disease (HD) is caused by an expansion of a polyglutamine (polyQ) tract within huntingtin (htt) protein. To examine the cytotoxic effects of polyQ-expanded htt, we overexpressed an enhanced green fluorescent protein (EGFP)-tagged N-terminal fragment of htt with 150 glutamine residues (Nhtt150Q-EGFP) in Aplysia neurons. A combined confocal and electron microscopic study showed that Aplysia neurons expressing Nhtt150Q-EGFP displayed numerous abnormal aggregates (diameter 0.5-5 microm) of filamentous structures, which were formed rapidly (approximately 2 h) but which were sustained for at least 18 days in the cytoplasm. Furthermore, the overexpression of Nhtt150Q-EGFP in sensory cells impaired 5-hydroxytryptamine (5-HT)-induced long-term synaptic facilitation in sensori-motor synapses without affecting basal synaptic strength or short-term facilitation. This study demonstrates the stability of polyQ-based aggregates and their specific effects on long-term synaptic plasticity.
Lee
Jin-A
JA
National Research Laboratory, Institute of Molecular Biology and Genetics, School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, Korea.
Lim
Chae-Seok
CS
Lee
Seung-Hee
SH
Kim
Hyoung
H
Nukina
Nobuyuki
N
Kaang
Bong-Kiun
BK
D000818:Animals; D001048:Aplysia; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism / Q000648:ultrastructure; D006816:Huntington Disease / Q000235:genetics; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008164:Luminescent Proteins / Q000235:genetics; D046911:Macromolecular Substances; D008845:Microinjections; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D010446:Peptide Fragments / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D012701:Serotonin / Q000494:pharmacology; D013569:Synapses / Q000378:metabolism*; D019680:Trinucleotide Repeat Expansion
D008164:Luminescent Proteins; D046911:Macromolecular Substances; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D012701:Serotonin