期刊
MOLECULAR THERAPY
卷 29, 期 9, 页码 2821-2840出版社
CELL PRESS
DOI: 10.1016/j.ymthe.2021.04.035
关键词
-
资金
- Finnish Parkinson's Foundation
- Finnish Cultural Foundation
- Ella and Georg Ehrnrooth Foundation
- National Council for Scientific and Technological Development (CNPq)
- Fundacao de Amparo a Pesquisa do Rio de Janeiro (FAPERJ)
- Deutscher Akademischer Austauschdienst (DAAD)
- Jane and Aatos Erkko Foundation
- Finnish Parkinson Foundation
- Academy of Finland [126744, 309708, 314233, 293392, 319195, 296409, 1310891, 256398, 250275, 309489]
- Paivikki and Sakari Sohlberg Foundation
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [EXC 2067/1390729940]
- Instrumentarium Science Foundation
- Sigrid Juselius Foundation
- Capes-Print
- CNPq
- FAPERJ
- Michael J. Fox Foundation for Parkinson's Research
- Academy of Finland (AKA) [314233, 126744, 309708, 314233, 296409, 309708, 296409, 126744] Funding Source: Academy of Finland (AKA)
CDNF interacts with alpha-synuclein to reduce its aggregation and internalization, while inducing the formation of insoluble phosphorylated alpha-synuclein. However, the beneficial effects of CDNF on rodent behavior do not seem to be related to the number of phosphorylated alpha-synuclein inclusions formed. Further study is needed to understand its effects on aggregation mechanism in vivo.
A molecular hallmark in Parkinson's disease (PD) pathogenesis are a-synuclein aggregates. Cerebral dopamine neurotrophic factor (CDNF) is an atypical growth factor that is mostly resident in the endoplasmic reticulum but exerts its effects both intracellularly and extracellularly. One of the beneficial effects of CDNF can be protecting neurons from the toxic effects of alpha-synuclein. Here, we investigated the effects of CDNF on alpha-synuclein aggregation in vitro and in vivo. We found that CDNF directly interacts with alpha-synuclein with a KD = 23 +/- 6 nM and reduces its auto-association. Using nuclear magnetic resonance (NMR) spectroscopy, we identified interaction sites on the CDNF protein. Remarkably, CDNF reduces the neuronal internalization of alpha-synuclein fibrils and induces the formation of insoluble phosphorylated alpha-synuclein inclusions. Intra-striatal CDNF administration alleviates motor deficits in rodents challenged with a-synuclein fibrils, though it did not reduce the number of phosphorylated alpha-synuclein inclusions in the substantia nigra. CDNF's beneficial effects on rodent behavior appear not to be related to the number of inclusions formed in the current context, and further study of its effects on the aggregation mechanism in vivo are needed. Nonetheless, the interaction of CDNF with a-synuclein, modifying its aggregation, spreading, and associated behavioral alterations, provides novel insights into the potential of CDNF as a therapeutic strategy in PD and other synucleinopathies.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据