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OBJECTIVE: Mounting evidence suggests that [alpha]-synuclein, a major protein component of Lewy bodies (LB), may be responsible for initiating and spreading the pathological process in Parkinson disease (PD). Supporting this concept, intracerebral inoculation of synthetic recombinant [alpha]-synuclein fibrils can trigger [alpha]-synuclein pathology in mice. However, it remains uncertain whether the pathogenic effects of recombinant synthetic [alpha]-synuclein may apply to PD-linked pathological [alpha]-synuclein and occur in species closer to humans. METHODS: Nigral LB-enriched fractions containing pathological [alpha]-synuclein were purified from postmortem PD brains by sucrose gradient fractionation and subsequently inoculated into the substantia nigra or striatum of wild-type mice and macaque monkeys. Control animals received non-LB fractions containing soluble [alpha]-synuclein derived from the same nigral PD tissue. RESULTS: In both mice and monkeys, intranigral or intrastriatal inoculations of PD-derived LB extracts resulted in progressive nigrostriatal neurodegeneration starting at striatal dopaminergic terminals. No neurodegeneration was observed in animals receiving non-LB fractions from the same patients. In LB-injected animals, exogenous human [alpha]-synuclein was quickly internalized within host neurons and triggered the pathological conversion of endogenous [alpha]-synuclein. At the onset of LB-induced degeneration, host pathological [alpha]-synuclein diffusely accumulated within nigral neurons and anatomically interconnected regions, both anterogradely and retrogradely. LB-induced pathogenic effects required both human [alpha]-synuclein present in LB extracts and host expression of [alpha]-synuclein. INTERPRETATION: [alpha]-Synuclein species contained in PD-derived LB are pathogenic and have the capacity to initiate a PD-like pathological process, including intracellular and presynaptic accumulations of pathological [alpha]-synuclein in different brain areas and slowly progressive axon-initiated dopaminergic nigrostriatal neurodegeneration. ANN NEUROL 2014;75:351-362. [ABSTRACT FROM AUTHOR]

The pathophysiology of Parkinson's disease is reviewed in light of recent advances in the understanding of the functional organization of the basal ganglia (BG). Current emphasis is placed on the parallel interactions between corticostriatal and corticosubthalamic afferents on the one hand, and internal feedback circuits modulating BG output through the globus pallidus pars interna and substantia nigra pars reticulata on the other. In the normal BG network, the globus pallidus pars externa emerges as a main regulatory station of output activity. In the parkinsonian state, dopamine depletion shifts the BG toward inhibiting cortically generated movements by increasing the gain in the globus pallidus pars externa-subthalamic nucleus-globus pallidus pars interna network and reducing activity in 'direct' cortico-putaminal-globus pallidus pars interna projections. Standard pharmacological treatments do not mimic the normal physiology of the dopaminergic system and, therefore, fail to restore a functional balance between corticostriatal afferents in the so-called direct and indirect pathways, leading to the development of motor complications. This review emphasizes the concept that the BG can no longer be understood as a 'go-through' station in the control of movement, behavior, and emotions. The growing understanding of the complexity of the normal BG and the changes induced by DA depletion should guide the development of more efficacious therapies for Parkinson's disease. Ann Neurol 2008;64 (suppl):S30-S46 [ABSTRACT FROM AUTHOR]