Original Paper

Acta Neuropathologica

, Volume 120, Issue 2, pp 155-167

First online:

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

  • Anna GomezAffiliated withServei Anatomia Patològica, Institut de Neuropatologia, CIBERNED, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona
  • , Isidre FerrerAffiliated withServei Anatomia Patològica, Institut de Neuropatologia, CIBERNED, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona Email author 

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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.

Keywords

Parkinson disease LRRK2 α-Synuclein Oxidative stress Glial fibrillary acidic protein Superoxide dismutase