Intracerebral inoculation of pathological α-synuclein initiates a rapidly progressive neurodegenerative α-synucleinopathy in mice. This study demonstrates that injecting brain homogenates from older α-synuclein transgenic (Tg) mice into young asymptomatic Tg mice accelerates the formation of intracellular Lewy body (LB)/Lewy neurite (LN)-like inclusions and the onset of neurological symptoms. Pathological α-synuclein spreads along major central nervous system (CNS) pathways, leading to widespread pathology and reduced survival. Importantly, α-synuclein amyloid fibrils assembled from recombinant human α-synuclein also induce identical consequences. The study shows that synthetic α-synuclein fibrils are sufficient to initiate PD-like LBs/LNs and transmit disease in vivo, suggesting a prion-like cascade in synucleinopathies. These findings indicate that cell-to-cell transmission and propagation of misfolded α-synuclein underlie the spread of LBs/LNs in the CNS. The results open new avenues for understanding the progression of Parkinson's disease (PD) and developing novel therapeutics. The study also highlights the role of α-synuclein in neurodegenerative diseases, showing that pathological α-synuclein can spread through interconnected neuronal populations, leading to progressive neurodegeneration. The findings support the idea that α-synuclein pathology can spread to multiple CNS regions, including cortical, midbrain, and brainstem neurons. The study provides evidence that synthetic α-synuclein fibrils can induce DLB/PD-like α-synucleinopathy in vivo, suggesting that the transmission of misfolded proteins is a common process in neurodegenerative diseases. The results have implications for developing disease-modifying therapies for DLB/PD and other neurodegenerative diseases linked to the accumulation of misfolded protein aggregates.Intracerebral inoculation of pathological α-synuclein initiates a rapidly progressive neurodegenerative α-synucleinopathy in mice. This study demonstrates that injecting brain homogenates from older α-synuclein transgenic (Tg) mice into young asymptomatic Tg mice accelerates the formation of intracellular Lewy body (LB)/Lewy neurite (LN)-like inclusions and the onset of neurological symptoms. Pathological α-synuclein spreads along major central nervous system (CNS) pathways, leading to widespread pathology and reduced survival. Importantly, α-synuclein amyloid fibrils assembled from recombinant human α-synuclein also induce identical consequences. The study shows that synthetic α-synuclein fibrils are sufficient to initiate PD-like LBs/LNs and transmit disease in vivo, suggesting a prion-like cascade in synucleinopathies. These findings indicate that cell-to-cell transmission and propagation of misfolded α-synuclein underlie the spread of LBs/LNs in the CNS. The results open new avenues for understanding the progression of Parkinson's disease (PD) and developing novel therapeutics. The study also highlights the role of α-synuclein in neurodegenerative diseases, showing that pathological α-synuclein can spread through interconnected neuronal populations, leading to progressive neurodegeneration. The findings support the idea that α-synuclein pathology can spread to multiple CNS regions, including cortical, midbrain, and brainstem neurons. The study provides evidence that synthetic α-synuclein fibrils can induce DLB/PD-like α-synucleinopathy in vivo, suggesting that the transmission of misfolded proteins is a common process in neurodegenerative diseases. The results have implications for developing disease-modifying therapies for DLB/PD and other neurodegenerative diseases linked to the accumulation of misfolded protein aggregates.