Mechanisms of neurotoxicity and implications for neurological disorders

Abstract

Keywords: chemical contaminants, neurodegeneration, neurodevelopment, neuroinflammation, neurotoxicty.On 13 July 2012, in conjunction with the 8th FENSForum of Neuroscience in Barcelona, Dr. JordiLlorens and I organized a Satellite Event in theform of a 1-day symposium. The main focus of thesymposium was on the mechanisms of neurotox-icity potentially involved in neurodegenerative dis-eases or neurodevelopmental disorders. Aspectsincluding gene–environment interactions, specificcellular alterations and neurodevelopmental impli-cations were covered by internationally recognizedexperts in their respective field. Reviews based onsix of the oral presentations from invited speakersare included in this issue of the Journal of InternalMedicine.The review by Dr. Julie Andersen, Buck Institutefor Age Research, Novato CA, USA, discusses thepossible link between environmental stress,aging, glial cell senescence and Parkinson’s dis-ease [1]. Certain chronic environmental expo-sures have been linked to the age-relateddevelopment of Parkinson’s disease neuropathol-ogy. Neuronal damage is believed to involve theinduction of neuroinflammatory events mediatedby glial cell activation. Senescent cells accumu-late with age, and they express a senescence-associated secretory phenotype (SASP) connectedto the secretion of many inflammatory cytokines,growth factors and proteases. Andersen proposesthat senescent glia could contribute to age-related neurodegeneration by creating a chroni-cally inflamed milieu. If correct, this novelpotential link between glial senescence and Par-kinson’s disease could change the current under-standing on the role of glial cells in age-relatedneurodegenerative diseases. In particular envi-ronmental stressors associated with Parkinson’sdisease, such as paraquat and MPTP, may act inpart by eliciting senescence and SASP expressionby glial cells in the aging brain, thereby contrib-uting to the characteristic decline in neuronalintegrity that occurs in the disorder.Dr. Rosario Moratalla, Instituto Cajal, CSIC,Madrid,describesinherreviewtheroleofdopaminereceptors in the neurotoxicity of the synthetic drugmethamphetamine [2]. Despite its neurotoxiceffects including loss of dopaminergic fibres andcell bodies, methamphetamine is consumed bymillions of users. There is evidence from clinicalreports suggesting that methamphetamine abusersare predisposed to Parkinson’s disease. The mech-anism of methamphetamine neurotoxicity involvesdopamine receptors. In fact, genetic inactivation ofD1orD2receptorsubtypesprotectsagainstthelossof dopaminergic fibres in the striatum and loss ofdopaminergic neurons in the substantia nigrainduced by methamphetamine. The protectiongiven by D1 receptor inactivation is due to blockadeof hyperthermia, lower dopamine content and turn-over,andhigherlevelsofstoredvesiculardopaminein D1 receptor