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Involvement of the cerebral cortex in Parkinson disease linked with G2019S LRRK2 mutation without cognitive impairment

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Abstract

Previous studies have shown altered synuclein, increased oxidative stress damage and increased oxidative stress responses in patients with sporadic Parkinson’s disease (PD) without cognitive impairment. Yet no information exists about possible molecular alterations in the cerebral cortex in familial PD. The present study shows abnormal α-synuclein solubility and aggregation, and aggregated nitrated α-synuclein, in the cerebral cortex (area 8) in cases with long-lasting PD linked with the G2019S LRRK2 mutation, one of them with a few Lewy bodies (LBs) and the other two without LBs in the cerebral cortex. Increased expression of the oxidative stress marker malondialdehyde-lysine (MDAL), together with increased oxidative stress responses, AGE receptors (RAGE) and superoxide dismutase 2, occurred in the frontal cortex in the three LRRK2 cases compared with three controls processed in parallel. Bi-dimensional gel electrophoresis, western blotting, in-gel digestion and mass spectrometry disclosed glial fibrillary acidic protein as a target of MDAL adducts. Tubulin β4 and enolase 2 were also identified as targets of oxidative damage. These results demonstrate biochemical abnormalities of α-synuclein, and increased oxidative stress damage and oxidative stress responses in the frontal cortex in PD linked with G2019S LRRK2 mutation not related with the presence of cortical LBs and in the absence of apparent cognitive deficits. These findings show that the cerebral cortex in familial PD linked with G2019S LRRK2 is affected in a similar way than that seen in sporadic PD without cognitive impairment.

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Acknowledgments

This work was funded by grants from the Spanish Ministry of Health, Instituto de Salud Carlos III PI08/0582, and supported by the European Commission under the Sixth Framework Programme BrainNet Europe II, LSHM-CT-2004-503039 and INDABIP FP6-2005-IFESCIHEALTH-7 Molecular Diagnostics. Thanks to T. Yohannan for editorial help.

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There is no conflict of interest including any financial, personal or other relationships with other people or organizations within the 3 years from the beginning of the work.

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    Anna Gomez & Isidre Ferrer

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Gomez, A., Ferrer, I. Involvement of the cerebral cortex in Parkinson disease linked with G2019S LRRK2 mutation without cognitive impairment. Acta Neuropathol 120, 155–167 (2010). https://doi.org/10.1007/s00401-010-0669-y

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