Determinants of seeding and spreading of α-synuclein pathology in the brain.
Determinants of seeding and spreading of α-synuclein pathology in the brain.
复制标题
DOI：
10.1126/sciadv.abc2487
复制
发表时间：
2020-11
期刊：
影响因子：
13.6
通讯作者：
Surmeier DJ
中科院分区：
文献类型：
--
作者：
Henrich MT;Geibl FF;Lakshminarasimhan H;Stegmann A;Giasson BI;Mao X;Dawson VL;Dawson TM;Oertel WH;Surmeier DJ
大脑中α-突触核蛋白病理学的摄取和传播受神经元表型和连接组学的控制。在帕金森病 (PD) 中，假设纤维形式的 α-突触核蛋白通过突触耦合网络传播，导致路易病理 (LP) 和神经变性。为了更严格地表征扩散的决定因素，将预先形成的 α-突触核蛋白原纤维注射到小鼠桥脚核 (PPN) 中，这是一个在 PD 患者中表现出 LP 的大脑区域，并且与顺行和逆行连接组图确定的情况相比，正在发展的 α-突触核蛋白病理分布。在 PPN 中，α-突触核蛋白病理学具有细胞特异性，在 PD 易损胆碱能神经元中很强，但在邻近的非胆碱能神经元中则不然。虽然几乎所有投射到 PPN 胆碱能的神经元都表现出 α-突触核蛋白病理学，但传播病理学的动力学、程度和持久性与这些连接的强度无关。因此，神经元表型控制着病理性α-突触核蛋白的体细胞树突摄取，虽然传入连接组限制了病理学的后续传播，但其大小和持久性并不是耦合强度的严格函数。
The uptake and spread of a-synuclein pathology in the brain are governed by neuronal phenotype and connectomics. In Parkinson’s disease (PD), fibrillar forms of α-synuclein are hypothesized to propagate through synaptically coupled networks, causing Lewy pathology (LP) and neurodegeneration. To more rigorously characterize the determinants of spreading, preformed α-synuclein fibrils were injected into the mouse pedunculopontine nucleus (PPN), a brain region that manifests LP in PD patients and the distribution of developing α-synuclein pathology compared to that ascertained by anterograde and retrograde connectomic mapping. Within the PPN, α-synuclein pathology was cell-specific, being robust in PD-vulnerable cholinergic neurons but not in neighboring noncholinergic neurons. While nearly all neurons projecting to PPN cholinergics manifested α-synuclein pathology, the kinetics, magnitude, and persistence of the propagated pathology were unrelated to the strength of those connections. Thus, neuronal phenotype governs the somatodendritic uptake of pathological α-synuclein, and while the afferent connectome restricts the subsequent spreading of pathology, its magnitude and persistence is not a strict function of the strength of coupling.
登录
查看更多内容
影响因子：
14.5
作者：
GAI, WP;HALLIDAY, GM;BLESSING, WW
通讯作者：
BLESSING, WW
影响因子：
14.5
作者：
Chu, Yaping;Muller, Scott;Kordower, Jeffrey H.
通讯作者：
Kordower, Jeffrey H.
DOI：
10.1126/science.aat8407
发表时间：
2018-11-02
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kam TI;Mao X;Park H;Chou SC;Karuppagounder SS;Umanah GE;Yun SP;Brahmachari S;Panicker N;Chen R;Andrabi SA;Qi C;Poirier GG;Pletnikova O;Troncoso JC;Bekris LM;Leverenz JB;Pantelyat A;Ko HS;Rosenthal LS;Dawson TM;Dawson VL
通讯作者：
Dawson VL
影响因子：
15.9
作者：
Karachi, Carine;Grabli, David;Francois, Chantal
通讯作者：
Francois, Chantal
影响因子：
5.3
作者：
Burre, Jacqueline;Sharma, Manu;Suedhof, Thomas C.
通讯作者：
Suedhof, Thomas C.