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The mitochondrial complex I inhibitor rotenone triggers a cerebral tauopathy
Author(s) -
Höglinger Günter U.,
Lannuzel Annie,
Khondiker Myriam Escobar,
Michel Patrick P.,
Duyckaerts Charles,
Féger Jean,
Champy Pierre,
Prigent Annick,
Medja Fadia,
Lombes Anne,
Oertel Wolfgang H.,
Ruberg Merle,
Hirsch Etienne C.
Publication year - 2005
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2005.03493.x
Subject(s) - rotenone , substantia nigra , neurodegeneration , tauopathy , striatum , parkinson's disease , respiratory chain , biology , neuroscience , mitochondrial respiratory chain , mitochondrion , pathology , microbiology and biotechnology , dopamine , medicine , dopaminergic , disease
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 α‐synuclein or tau protein pathology. To determine experimentally whether chronic generalized complex I inhibition has an effect on the distribution of α‐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 α‐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 α‐synuclein.