![]() ![]() Therefore, the intracerebral growth of a-syn pathologies is considered to be the underlying mechanism for disease progression, and the localization and abundance of a-syn deposits tend to correlate with the clinical symptoms. As the disease progresses, the pathology spreads to other brain areas, over the course of 5–10 years. Studies on PD brains reveal that a-syn pathologies spread to the brainstem from the olfactory bulb and the enteric vagus nerve during the first several years of the disease. However, the reason for the a-syn deposits to result in distinct disease phenotypes remains unclear. These a-syn deposits are also observed in dementia with Lewy body and in multiple system atrophy. The protein alpha-synuclein (a-syn), a major component of LBs and Lewy neurites, is deposited in a phosphorylated form. The primary manifestations of PD consist of movement disturbances, such as bradykinesia, tremor, and rigidity, while the main cellular pathological features include neuronal degeneration along with inclusions called Lewy bodies (LBs), and neuronal loss in the substantia nigra (SN). Parkinson’s disease (PD) is one of the most common neurodegenerative disorders. ![]() ![]() This study offers a novel concept regarding a-syn propagation, based on the Braak hypothesis, and also cautions that experimental transmission systems may be examining a unique type of transmission, which differs from the clinical disease state. In addition, we found that botulinum toxin B blocked the transsynaptic transmission of a-syn seeds by specifically inactivating the synaptic vesicle fusion machinery. These results suggest that a-syn seeds are rapidly disseminated through neuronal circuits immediately after seed injection, in a prion-like seeding experiment in vivo, although it is believed that clinical a-syn pathologies take years to spread throughout the brain. In contrast, mice that underwent callosotomy 24 h after a-syn PFFs injection showed a-syn pathology similar to that seen in mice without callosotomy. In mice that underwent callosotomy before the injection, the propagation of a-syn pathology to the contralateral hemisphere was clearly reduced. We injected a-syn preformed fibrils (PFFs), which are seeds for the propagation of a-syn deposits, either before or after callosotomy, to disconnect bilateral hemispheric connections. Here, we investigated the speed of a-syn transmission, which has not been a focus of previous a-syn transmission experiments, and whether a-syn pathologies spread in a neural circuit–dependent manner in the mouse brain. However, the precise mechanisms and the processes underlying the spread of these fibril seeds have not been clarified in vivo. Accumulating evidence suggests that the lesions of Parkinson’s disease (PD) expand due to transneuronal spreading of fibrils composed of misfolded alpha-synuclein (a-syn), over the course of 5–10 years. ![]()
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