PIAS2-mediated blockade of IFN-β signaling: a basis for sporadic Parkinson disease dementia.
PIAS2-mediated blockade of IFN-β signaling: a basis for sporadic Parkinson disease dementia.
复制标题
DOI：
10.1038/s41380-021-01207-w
复制
发表时间：
2021-10
影响因子：
11
通讯作者：
Issazadeh-Navikas S
中科院分区：
文献类型：
--
作者：
Magalhaes J;Tresse E;Ejlerskov P;Hu E;Liu Y;Marin A;Montalant A;Satriano L;Rundsten CF;Carlsen EMM;Rydbirk R;Sharifi-Zarchi A;Andersen JB;Aznar S;Brudek T;Khodosevich K;Prinz M;Perrier JM;Sharma M;Gasser T;Issazadeh-Navikas S
家族性帕金森病（PD）与罕见的基因突变有关，但大多数散发性PD患者的病因在很大程度上尚不清楚，其进展为痴呆（sPDD）的基础也很难描述。我们已经确定，IFNβ或IFNα/β受体IFNAR 1的缺失导致类似PDD的病理和行为变化，促使我们假设IFNβ-IFNAR信号通路中的失调基因使人易患sPD。通过转录组学分析，我们发现了神经元IFNβ-IFNAR信号传导缺陷，特别是与sPDD相关的PIAS 2升高。通过对GWAS的荟萃分析，我们确定了sPD患者中IFNβ-IFNAR相关基因的序列变异。此外，sPDD患者在神经元中表达更高水平的PIAS 2 mRNA和蛋白。为了确定其在脑中的功能，我们在神经元启动子下单独或与人α-突触核蛋白一起在小鼠脑中过表达PIAS 2，这导致运动和认知障碍，并与神经元内磷酸化（p）α-突触核蛋白积累和多巴胺能神经元损失相关。神经元PIAS 2的异位表达通过使ERK 1/2-P53信号失活而阻断线粒体自噬，增加衰老线粒体和氧化应激的积累，如过量的oxDJ 1和8 OHdG所证明的。相反，PIAS 2敲低在恢复线粒体稳态、氧化应激和pERK 1/2-pP 53信号传导方面挽救了Ifnb-/-小鼠中PDD的临床病理学表现。JAK-STAT 2-PIAS 2信号传导的调节对于神经突生长和神经元存活和兴奋性至关重要，因此可能预防认知障碍。我们的研究结果为sPD和痴呆的进展提供了见解，并对新的治疗方法产生了影响。
Familial Parkinson disease (PD) is associated with rare genetic mutations, but the etiology in most patients with sporadic (s)PD is largely unknown, and the basis for its progression to dementia (sPDD) is poorly characterized. We have identified that loss of IFNβ or IFNAR1, the receptor for IFNα/β, causes pathological and behavioral changes resembling PDD, prompting us to hypothesize that dysregulated genes in IFNβ-IFNAR signaling pathway predispose one to sPD. By transcriptomic analysis, we found defective neuronal IFNβ-IFNAR signaling, including particularly elevated PIAS2 associated with sPDD. With meta-analysis of GWASs, we identified sequence variants in IFNβ-IFNAR-related genes in sPD patients. Furthermore, sPDD patients expressed higher levels of PIAS2 mRNA and protein in neurons. To determine its function in brain, we overexpressed PIAS2 under a neuronal promoter, alone or with human α-synuclein, in the brains of mice, which caused motor and cognitive impairments and correlated with intraneuronal phosphorylated (p)α-synuclein accumulation and dopaminergic neuron loss. Ectopic expression of neuronal PIAS2 blocked mitophagy, increased the accumulation of senescent mitochondrial and oxidative stress, as evidenced by excessive oxDJ1 and 8OHdG, by inactivating ERK1/2-P53 signaling. Conversely, PIAS2 knockdown rescued the clinicopathological manifestations of PDD in Ifnb–/– mice on restoring mitochondrial homeostasis, oxidative stress, and pERK1/2-pP53 signaling. The regulation of JAK-STAT2-PIAS2 signaling was crucial for neurite outgrowth and neuronal survival and excitability and thus might prevent cognitive impairments. Our findings provide insights into the progression of sPD and dementia and have implications for new therapeutic approaches.
登录
查看更多内容
影响因子：
5.4
作者：
Klein, Christine;Westenberger, Ana
通讯作者：
Westenberger, Ana
DOI：
10.1016/s0925-4439(97)00070-7
发表时间：
1997-11-28
影响因子：
6.2
作者：
Cassarino, DS;Fall, CP;Bennett, JP
通讯作者：
Bennett, JP
影响因子：
14.8
作者：
Brewer, Gregory J.;Torricelli, John R.
通讯作者：
Torricelli, John R.
影响因子：
2.6
作者：
Garcia-Ptacek, Sara;Kramberger, Milica G.
通讯作者：
Kramberger, Milica G.
影响因子：
7.3
作者：
BROWN, NA;KEMP, JA;SEABROOK, GR
通讯作者：
SEABROOK, GR