Pathological α-Synuclein Transmission Initiates Parkinson-like Neurodegeneration in Nontransgenic Mice

Abstract

Synthetic Parkinson's Parkinson's disease (PD) and related α-synucleinopathies are defined by the accumulation of α-synuclein (α-Syn)–containing intraneuronal inclusions—Lewy bodies (LBs) and Lewy neurites (LNs)—in association with the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and other brain regions. However, a cause-and-effect relationship between LB/LN formation and neurodegeneration remains unclear. Indeed, whether LB/LNs are toxic or represent a neuroprotective response has been contentious. Luk et al. (p. 949 ) injected α-Syn fibrils generated from recombinant mouse α-Syn protein into the dorsal striatum of wild-type mice and found that misfolded α-Syn caused the formation of PD-like LB/LNs and subsequent cell-to-cell transmission of pathologic α-Syn to anatomically interconnected regions, including the SNpc. Furthermore, the formation of LB/LNs and their accumulation in SNpc resulted in the progressive loss of these dopaminergic neurons, reduced dopamine innervations to the dorsal striatum, and culminated in motor deficits similar to PD. Thus, a synthetic misfolded wild-type protein (that is, α-Syn) was able to elicit and transmit disease pathology and neurodegeneration in healthy nontransgenic mice.