Potential of Cellular and Animal Models Based on a Prion-Like Propagation of α-Synuclein for Assessing Antiparkinson Agents.

Abstract

The pathological hallmark of Parkinson's disease (PD) is the loss of dopaminergic neurons in the substantia nigra pars compacta and the presence of Lewy bodies (LBs). LBs are intracellular inclusions typically found in these neurons and in noradrenergic neurons of the locus coeruleus in patients with PD. However, LBs can be found more widely in neurons of the olfactory bulb, cerebral cortex, and spinal cord. Additionally, LBs appear in neurons of the cardiac, cutaneous, and intestinal autonomic nervous systems. LBs are composed of fibrillar aggregates of α-synuclein (α-syn). The widespread distribution of LBs indicates that α-syn aggregation occurs in neurons in various areas, supporting the concept that PD is not only a simple movement disorder but also a complex one with nonmotor impairments. However, it is unclear how α-syn pathology spreads in the nervous system. Postmortem analyses of patients with PD who received transplants of fetal mesencephalic dopaminergic neurons revealed LB formation in surviving grafts, providing a crucial clue regarding the host-to-graft disease propagation. Recent experiments demonstrated that fibrillar α-syn is transferred from neurons to neurons in cellular and animal models, suggesting that fibrillar α-syn is repeatedly generated in cells by triggering the continuous conversion of normal soluble species into fibrillar ones. These findings suggest a "prion-like" mechanism for α-syn propagation in the pathogenesis of PD. This review summarizes the experimental findings on the prion-like propagation of α-syn and discusses the potential of cellular and animal models for testing the protective effects of chemical agents against neurodegeneration in PD.