Dopaminergic Loss and Inclusion Body Formation in α-Synuclein Mice: Implications for Neurodegenerative Disorders

TLDR

The study aimed to elucidate the role of α‑synuclein in neurodegenerative disorders by generating transgenic mice expressing wild‑type human α‑synuclein. Transgenic mice expressing wild‑type human α‑synuclein were created to investigate α‑synuclein’s contribution to neuronal pathology. Neuronal expression of human α‑synuclein led to progressive accumulation of α‑synuclein and ubiquitin‑positive inclusions in the neocortex, hippocampus, and substantia nigra, with electron‑dense intranuclear and cytoplasmic deposits, loss of dopaminergic terminals in the basal ganglia, motor impairments, and suggesting a causal role for wild‑type α‑synuclein in Parkinson’s disease and related conditions.

Abstract

To elucidate the role of the synaptic protein α-synuclein in neurodegenerative disorders, transgenic mice expressing wild-type human α-synuclein were generated. Neuronal expression of human α-synuclein resulted in progressive accumulation of α-synuclein—and ubiquitin-immunoreactive inclusions in neurons in the neocortex, hippocampus, and substantia nigra. Ultrastructural analysis revealed both electron-dense intranuclear deposits and cytoplasmic inclusions. These alterations were associated with loss of dopaminergic terminals in the basal ganglia and with motor impairments. These results suggest that accumulation of wild-type α-synuclein may play a causal role in Parkinson's disease and related conditions.