Acceleration of Parkinson pathogenesis by chronic low-dose rate gamma exposure - OSTINATO

As is known from radiotherapy patients, high-dose ionizing radiation in particular to children has the potential to increase the risk of premature dementia or other neurodegenerative diseases (ND) (Kempf et al 2012). The evidence for such a link in low-dose exposed cohorts is less clear, probably because of inadequate diagnostic tools. Our hypotheses was that low dose (rate) radiation to the brain, in particular early in life, may cause an accelerated development of ND conditions such as dementia or Parkinson Disease (PD). A known risk-factor for ND is oxidative stress to the neuronal tissues, and this is known to be the major type of DNA damage at chronic low-dose rate ionising radiation. We therefore evaluated the impact of a defective repair system for ROS induced DNA damage (the Ogg1-knockout mouse model) towards the progression of neurological deficiencies in a PD mouse model (PitxEYL/EYL) after pre- and postnatal chronic irradiation using the recently EU/RCN-funded unique FIGARO facility. We found that after the very low doses/dose rates used the appearance of PD-symptoms were changed only minimally and temporarily. The Ogg1-deficiency did not significantly aggravated the effects. Profiling of mature microRNA in forebrain showed significant changes in exposed animals, especially in Ogg1-deficient mice. We also showed that T-cell repertoire were not changes and that reproductive capacity remained unchanged in the first litters after exposure. The project contributes with novel information regarding in utero and neonatal exposure to low dose (rate) ionising radiation.

As is known from radiotherapy patients, high-dose ionizing radiation in particular to children has the potential to increase the risk of premature dementia or other neurodegenerative diseases (ND) (Kempf et al 2012). The evidence for such a link in low-d ose exposed cohorts is less clear, probably because of inadequate diagnostic tools. We reason that low radiation doses to the brain, in particular early in life, may cause an accelerated development of ND conditions such as dementia or Parkinson Disease (PD). A known risk-factor for ND is oxidative stress to the neuronal tissues, and this is known to be the preferential mode of damage at chronic low-dose rate ionising radiation. We therefore propose to evaluate the impact of a defective repair system for ROS induced DNA damage (Ogg1 k.o.) towards the progression of neurological deficiencies in a PD mouse model (PitxEYL/EYL) after pre- and postnatal chronic irradiation using the recently EU/RCN-funded unique FIGARO facility. To make maximum usage of the F IGARO facility, we will also store other tissues relevant for non-cancer diseases (heart, muscle, liver, blood, eyes) in a central repository to be used by other DoReMi partners.