title: Mitochondrial toxins in Basal Ganglia disorders: from animal models to therapeutic strategies.
abstract: Current knowledge of the pathogenesis of basal ganglia disorders, such as Huntington's disease (HD) and Parkinson's disease (PD) appoints a central role to a dysfunction in mitochondrial metabolism. The development of animal models, based upon the use of mitochondrial toxins has been successfully introduced to reproduce human disease, leading to important acquisitions. Most notably, experimental evidence supports the existence, within basal ganglia, of a peculiar regional vulnerability to distinct mitochondrial toxins. MPTP and rotenone, both selective inhibitors of mitochondrial complex I have been extensively used to mimic PD. Accordingly, in human PD, a specific dysfunction of complex I activity was found in vulnerable dopaminergic neurons of the substantia nigra. Conversely, in HD a selective impairment of mitochondrial succinate dehydrogenase, key enzyme in complex II activity was found in medium spiny neurons of the caudate-putamen. The relevance of such finding is further demonstrated by the evidence that toxins able to primarily target mitochondrial complex II, such as malonic acid and 3-nitropropionic acid (3-NP), strikingly reproduce the main phenotypic and pathological features of HD.Despite the advances obtained from these experimental models, a deeper understanding of the molecular and cellular mechanisms underlying such neuronal vulnerability is lacking.The present review provides a brief survey of currently utilized animal models of mitochondrial intoxication, in attempt to address the cellular mechanisms triggered by energy metabolism failure and to identify potential therapeutic targets.
authors.affiliation: Fondazione Santa Lucia, I.R.C.C.S. - C.E.R.C., European Brain Research Institute, Roma, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Bonsi
authors.forename: D
authors.initials: D
authors.lastname: Cuomo
authors.forename: G
authors.initials: G
authors.lastname: Martella
authors.forename: G
authors.initials: G
authors.lastname: Sciamanna
authors.forename: M
authors.initials: M
authors.lastname: Tolu
authors.forename: P
authors.initials: P
authors.lastname: Calabresi
authors.forename: G
authors.initials: G
authors.lastname: Bernardi
authors.forename: A
authors.initials: A
authors.lastname: Pisani