Crosslinking of alpha-synuclein by advanced glycation endproducts - an early pathophysiological step in Lewy body formation?

An excess of reactive carbonyl compounds (carbonyl stress) and their reacti on products, advanced glycation endproducts (AGEs), are thought to play a d ecisive role in the pathogenesis of neurodegenerative disorders and Parkins on's disease (PD) in particular. Accumulation of AGEs in various intracellu lar pathological hallmarks of PD. such as Lewy bodies, densely crosslinked intracellular protein deposits formed from neurofilament components and alp ha -synuclein, have already been described in patients in advanced stages o f the disease. There is, however, no indication of the involvement of AGE-i nduced crosslinking of alpha -synuclein in very early stages of the disease . In this study, we observed that AGEs and alpha -synuclein are similarly d istributed in very early Lewy bodies in the human brain in cases with incid ental Lewy body disease. These cases might be viewed as pre-Parkinson patie nts, i.e. patients who came for autopsy before the possible development of clinical signs of PD. AGEs are both markers of transition metal induced oxi dative stress as well as, inducers of protein crosslinking and free radical formation by chemical and cellular processes. Thus, it is likely that AGE promoted formation of Lewy bodies reflects very early causative changes rat her than late epiphenomenons of PD. (C) 2000 Elsevier Science B.V. All righ ts reserved.