Atypical parkinsonism in the Caribbean island of Guadeloupe: Etiological role of the mitochondrial complex I inhibitor annonacin

Abstract

On the French West Indian island of Guadeloupe, atypical parkinsonian patients represent two-thirds of all cases of parkinsonism, which is exceptionally frequent compared to epidemiological data from European countries where atypical parkinsonism accounts for only approximately 5% of all cases. The clinical entity was a unique combination of levodopa-resistant parkinsonism, tremor, myoclonus, hallucinations, REM sleep behavior disorder and fronto-subcortical dementia. Based on the presence or the absence of supranuclear gaze palsy, two subgroups of patients were distinguished. In patients with oculomotor signs that came to autopsy, neuronal loss was found to predominate in the substantia nigra and the striatum but other brain areas were also affected, including the frontal cortex. In addition, tau-containing lesions were detected throughout the brain. Epidemiological data suggested a close association of the disease with the regular consumption of soursop, a tropical annonaceous plant. Experimental studies performed in midbrain cell cultures identified annonacin, a selective mitochondrial complex I inhibitor contained in the fruit and leaves of soursop, as a probable etiological factor. Consistent with this view, chronic administration of annonacin to rats through Alzet osmotic minipumps showed that annonacin was able to reproduce the brain lesions characteristic of the human disease.

Food derived respiratory complex I inhibitors modify the effect of Leber hereditary optic neuropathy mutations

“…The quantities of acetogenins in annonaceous fruits are such that a cumulative dose sufficient to cause neurodegeneration in rats can be attained in humans by regular consumption within a year (Hollerhage et al, 2009). In Guadeloupe (French West Indies) there is an unusually high incidence of atypical parkinsonism, which has been linked to regular consumption of these plants, in particular soursop (Lannuzel et al, 2003(Lannuzel et al, , 2007(Lannuzel et al, , 2008. The thiophene-3-carboxamide analog of annonaceous acetogenins JCI-20679 inhibited the oxygen consumption of human non-small cell lung carcinoma NCI-H23 cells with a half maximal inhibitory concentration (IC 50 ) of 170 nM (Akatsuka et al, 2016).…”

Specific needs of dopamine neurons for stimulation in order to survive: implication for Parkinson disease

“…This mouse model was developed because genes that cause familial Parkinsonism are linked to mitochondrial function, and a mitochondrial complex I deficiency was observed in PD SN (31). As already mentioned, DA neurons are also particularly vulnerable to toxins that impair mitochondrial function (32). Patch‐clamp recordings in Mitopark mice revealed that the patterns of activity of DA neurons were profoundly altered long before the onset of degeneration (33).…”

Coexistence of parkinsonism, dementia and upper motor neuron syndrome in four Czech patients

“…In such a case, the phenotype of the disease would be the same as those described in the four presented cases. The possibility that the environmental factor might play a role in the pathophysiology of the rare disease should be also considered [23]. However, further hypotheses would be a pure speculation, at least until we have the brain specimen.…”