α-Synucleinopathy and selective dopaminergic neuron loss in a rat lentiviral-based model of Parkinson's disease

TLDR

Parkinson’s disease is marked by progressive loss of substantia nigra dopaminergic neurons and Lewy body formation, with α‑synuclein mutations (A30P, A53T) linked to familial forms and α‑syn constituting the main component of Lewy bodies in sporadic cases. The study aimed to create a lentiviral rat model of Parkinson’s disease by injecting vectors encoding human or rat α‑synuclein into the substantia nigra, to investigate α‑syn‑induced cell death mechanisms and enable therapeutic screening. The model was established by stereotaxic injection of lentiviral vectors encoding human or rat α‑synuclein into the substantia nigra of rats. Animals expressing human α‑synuclein, wild‑type or mutant, showed selective loss of nigral dopaminergic neurons and striatal denervation, with abundant α‑syn inclusions and neuritic pathology, recapitulating key PD features, whereas rat α‑syn induced aggregation without cell loss, indicating inclusions alone are insufficient to cause degeneration.

Abstract

Parkinson's disease (PD) is characterized by the progressive loss of substantia nigra dopaminergic neurons and the presence of cytoplasmic inclusions named Lewy bodies. Two missense mutations of the α-synuclein (α-syn; A30P and A53T) have been described in several families with an autosomal dominant form of PD. α-Syn also constitutes one of the main components of Lewy bodies in sporadic cases of PD. To develop an animal model of PD, lentiviral vectors expressing different human or rat forms of α-syn were injected into the substantia nigra of rats. In contrast to transgenic mice models, a selective loss of nigral dopaminergic neurons associated with a dopaminergic denervation of the striatum was observed in animals expressing either wild-type or mutant forms of human α-syn. This neuronal degeneration correlates with the appearance of abundant α-syn-positive inclusions and extensive neuritic pathology detected with both α-syn and silver staining. Lentiviral-mediated expression of wild-type or mutated forms of human α-syn recapitulates the essential neuropathological features of PD. Rat α-syn similarly leads to protein aggregation but without cell loss, suggesting that inclusions are not the primary cause of cell degeneration in PD. Viral-mediated genetic models may contribute to elucidate the mechanism of α-syn-induced cell death and allow the screening of candidate therapeutic molecules.