The study investigates the role of pathological α-synuclein in the progression of neurodegenerative diseases, specifically Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Intracerebral injections of brain homogenates from older α-synuclein transgenic (Tg) mice, which exhibit α-synuclein pathology, were found to accelerate the formation of intracellular Lewy body/Lewy neurite (LB/LN)-like inclusions and the onset of neurological symptoms in recipient mice. Pathological α-synuclein propagated along major central nervous system (CNS) pathways, leading to reduced survival with a highly reproducible interval from injection to death. Importantly, inoculation with α-synuclein amyloid fibrils assembled from recombinant human α-synuclein induced identical consequences. The findings suggest that synthetic α-synuclein fibrils are sufficient to initiate PD-like LB/LN and transmit disease in vivo, indicating a prion-like cascade in synucleinopathies where cell-to-cell transmission and propagation of misfolded α-synuclein underlie the CNS spread of LB/LN. These results open new avenues for understanding the progression of PD and developing novel therapeutics.The study investigates the role of pathological α-synuclein in the progression of neurodegenerative diseases, specifically Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Intracerebral injections of brain homogenates from older α-synuclein transgenic (Tg) mice, which exhibit α-synuclein pathology, were found to accelerate the formation of intracellular Lewy body/Lewy neurite (LB/LN)-like inclusions and the onset of neurological symptoms in recipient mice. Pathological α-synuclein propagated along major central nervous system (CNS) pathways, leading to reduced survival with a highly reproducible interval from injection to death. Importantly, inoculation with α-synuclein amyloid fibrils assembled from recombinant human α-synuclein induced identical consequences. The findings suggest that synthetic α-synuclein fibrils are sufficient to initiate PD-like LB/LN and transmit disease in vivo, indicating a prion-like cascade in synucleinopathies where cell-to-cell transmission and propagation of misfolded α-synuclein underlie the CNS spread of LB/LN. These results open new avenues for understanding the progression of PD and developing novel therapeutics.