Mutant huntingtin aggregates impair mitochondrial movement and trafficking in cortical neurons.
Huntington's disease (HD) is a neurodegenerative disorder caused by a polyglutamine repeat in the huntingtin gene (Htt). Mitochondrial defects and protein aggregates are characteristic of affected neurons. Recent studies suggest that these aggregates impair cellular transport mechanisms by interacting with cytoskeletal components and molecular motors. Here, we investigated whether mutant Htt alters mitochondrial trafficking and morphology in primary cortical neurons. We demonstrate that full-length mutant Htt was more effective than N-terminal mutant Htt in blocking mitochondrial movement, an effect that correlated with its heightened expression in the cytosolic compartment. Aggregates impaired the passage of mitochondria along neuronal processes, causing mitochondria to accumulate adjacent to aggregates and become immobilized. Furthermore, mitochondrial trafficking was reduced specifically at sites of aggregates while remaining unaltered in regions lacking aggregates. We conclude that in cortical neurons, an early event in HD pathophysiology is the aberrant mobility and trafficking of mitochondria caused by cytosolic Htt aggregates.
Department of Pharmacology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Diane T W
DT
Chang
Gordon L
GL
Rintoul
Sruthi
S
Pandipati
Ian J
IJ
Reynolds
D000818:Animals; D002021:Buffers; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D003595:Cytoplasmic Streaming / Q000235:genetics; D003599:Cytoskeleton / Q000378:metabolism / Q000473:pathology; D003600:Cytosol / Q000378:metabolism / Q000473:pathology; D018698:Glutamic Acid / Q000378:metabolism / Q000633:toxicity; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002479:Inclusion Bodies / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009498:Neurotoxins / Q000378:metabolism / Q000633:toxicity; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection
D002021:Buffers; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D009687:Nuclear Proteins; D018698:Glutamic Acid; D002118:Calcium