Oral subchronic exposure to the mycotoxin ochratoxin A induces key pathological features of Parkinson's disease in mice six months after the end of the treatment

• Published in: Food and chemical toxicology Vol. 152; p. 112164
• Main Authors: Izco, María, Vettorazzi, Ariane, Forcen, Raquel, Blesa, Javier, de Toro, Maria, Alvarez-Herrera, Natalia, Cooper, J Mark, Gonzalez-Peñas, Elena, Lopez de Cerain, Adela, Alvarez-Erviti, Lydia
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.06.2021
• Subjects: Administration, Oral; Alpha-synuclein; alpha-Synuclein - chemistry; alpha-Synuclein - metabolism; Animals; Chaperone-mediated autophagy; Dopaminergic Neurons - drug effects; Gut-brain axis; Intestinal Mucosa - drug effects; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; LAMP-2A; Lysosomal-Associated Membrane Protein 2 - metabolism; Male; Mesencephalon - drug effects; Mesencephalon - metabolism; Mesencephalon - pathology; Mice; Mice, Inbred BALB C; MicroRNAs - metabolism; Mycotoxins - administration & dosage; Mycotoxins - toxicity; Ochratoxin A; Ochratoxins - administration & dosage; Ochratoxins - toxicity; Parkinson Disease - etiology; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson's disease; Pars Compacta - drug effects; Pars Compacta - metabolism; Pars Compacta - pathology; Phosphorylation - drug effects; Time Factors; LAMP-2A; Parkinson's disease; Chaperone-mediated autophagy; Ochratoxin A; Gut-brain axis; Alpha-synuclein
• ISSN: 0278-6915; 1873-6351
• DOI: 10.1016/j.fct.2021.112164

Some epidemiological studies with different levels of evidence have pointed to a higher risk of Parkinson's disease (PD) after exposure to environmental toxicants. A practically unexplored potential etiological factor is a group of naturally-occurring fungal secondary metabolites called mycotoxins. The mycotoxin ochratoxin A (OTA) has been reported to be neurotoxic in mice. To further identify if OTA exposure could have a role in PD pathology, Balb/c mice were orally treated with OTA (0.21, 0.5 mg/kg bw) four weeks and left for six months under normal diet. Effects of OTA on the onset, progression of alpha-synuclein pathology and development of motor deficits were evaluated. Immunohistochemical and biochemical analyses showed that oral subchronic OTA treatment induced loss of striatal dopaminergic innervation and dopaminergic cell dysfunction responsible for motor impairments. Phosphorylated alpha-synuclein levels were increased in gut and brain. LAMP-2A protein was decreased in tissues showing alpha-synuclein pathology. Cell cultures exposed to OTA exhibited decreased LAMP-2A protein, impairment of chaperone-mediated autophagy and decreased alpha-synuclein turnover which was linked to miRNAs deregulation, all reminiscent of PD. These results support the hypothesis that oral exposure to low OTA doses in mice can lead to biochemical and pathological changes reported in PD. •Ochratoxin A altered motor function and dopaminergic system 6 months after exposure.•Phosphorylated alpha-synuclein levels were increased in gut and brain of mice.•LAMP-2A protein was decreased in tissues showing alpha-synuclein pathology.•LAMP-2A and alpha-synuclein turnover decreased in vitro due to miRNA dysregulation.•All these features have been previously described in Parkinson's Disease.