The mitochondrial complex I inhibitor rotenone triggers a cerebral tauopathy.
Reduced activity of the mitochondrial respiratory chain--particularly complex I--may be implicated in the etiology of both Parkinson's disease and progressive supranuclear palsy, although these neurodegenerative diseases differ substantially as to their distinctive pattern of neuronal cell loss and the predominance of cerebral alpha-synuclein or tau protein pathology. To determine experimentally whether chronic generalized complex I inhibition has an effect on the distribution of alpha-synuclein or tau, we infused rats systemically with the plant-derived isoflavonoid rotenone. Rotenone-treated rats with a pronounced metabolic impairment had reduced locomotor activity, dystonic limb posture and postural instability. They lost neurons in the substantia nigra and in the striatum. Spherical deposits of alpha-synuclein were observed in a few cells, but cells with abnormal cytoplasmic accumulations of tau immunoreactivity were significantly more numerous in the striatum of severely lesioned rats. Abnormally high levels of tau immunoreactivity were found in the cytoplasm of neurons, oligodendrocytes and astrocytes. Ultrastructurally, tau-immunoreactive material consisted of straight 15-nm filaments decorated by antibodies against phosphorylated tau. Many tau+ cell bodies also stained positive for thioflavin S, nitrotyrosine and ubiquitin. Some cells with abnormal tau immunoreactivity contained activated caspase 3. Our data suggest that chronic respiratory chain dysfunction might trigger a form of neurodegeneration in which accumulation of hyperphosphorylated tau protein predominates over deposits of alpha-synuclein.
Höglinger
Günter U
GU
INSERM U679, Hôpital de la Salpêtrière, Paris, France. hoegling@med.uni-marburg.de
Lannuzel
Annie
A
Khondiker
Myriam Escobar
ME
Michel
Patrick P
PP
Duyckaerts
Charles
C
Féger
Jean
J
Champy
Pierre
P
Prigent
Annick
A
Medja
Fadia
F
Lombes
Anne
A
Oertel
Wolfgang H
WH
Ruberg
Merle
M
Hirsch
Etienne C
EC
D016229:Amyloid beta-Peptides / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000378:metabolism; D001522:Behavior, Animal; D052160:Benzothiazoles; D001835:Body Weight / Q000187:drug effects; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D003561:Cytarabine / Q000378:metabolism; D003952:Diagnostic Imaging / Q000379:methods; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D004317:Doxorubicin / Q000378:metabolism; D004421:Dystonia / Q000209:etiology / Q000503:physiopathology; D014450:Electron Transport Complex III / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D008124:Locomotion / Q000187:drug effects; D008297:Male; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008928:Mitochondria / Q000187:drug effects / Q000648:ultrastructure; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D010766:Phosphorylation; D011187:Posture; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D011917:Rats, Inbred Lew; D012402:Rotenone / Q000009:adverse effects*; D024801:Tauopathies / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D013844:Thiazoles; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D014475:Uncoupling Agents / Q000009:adverse effects*; D051844:alpha-Synuclein / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D005904:Glial Fibrillary Acidic Protein; D013844:Thiazoles; D025801:Ubiquitin; D014475:Uncoupling Agents; D051844:alpha-Synuclein; D016875:tau Proteins; D012402:Rotenone; D003561:Cytarabine; C009462:thioflavin T; C002744:3-nitrotyrosine; D014443:Tyrosine; D004317:Doxorubicin; D014446:Tyrosine 3-Monooxygenase; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D010751:Phosphopyruvate Hydratase; D014450:Electron Transport Complex III