Dysfunction of cAMP-Protein Kinase A-Calcium Signaling Axis in Striatal Medium Spiny Neurons: A Role in Schizophrenia and Huntington's Disease Neuropathology.
Dysfunction of cAMP-Protein Kinase A-Calcium Signaling Axis in Striatal Medium Spiny Neurons: A Role in Schizophrenia and Huntington's Disease Neuropathology.
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DOI：
10.1016/j.bpsgos.2022.03.010
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发表时间：
2023-07
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影响因子：
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在亨廷顿病中，纹状体中棘神经元(MSN)优先丢失。基因组研究还表明MSN在精神分裂症中有直接作用，精神分裂症是一种已知涉及皮质神经元功能障碍的精神疾病。目前尚不清楚这两种疾病是否具有相似的MSN发病机制，或者神经元缺陷是否可归因于细胞类型依赖的生物学途径。转录因子BCL11B在所有MSN和深层皮质神经元中都有表达，最近被认为是亨廷顿病选择性神经退行性变的驱动因素，并被确定为精神分裂症的候选危险基因。以缺乏BCL11B的人干细胞来源的神经元为模型，在这些疾病的背景下，我们研究了MSN和皮质神经元的细胞病理学。对差异表达的转录本和已发表的全基因组关联研究数据集的综合分析确定了特定细胞类型的疾病相关表型。我们发现BCL11B在两种类型的神经元中都在钙稳态中发挥作用，而线粒体功能缺陷和PKA(蛋白激酶A)依赖的钙瞬变仅在MSN中被检测到。此外，BCL11B缺陷的MSN对谷氨酸的反应异常，未能整合多巴胺能和谷氨酸能刺激，这是体内纹状体神经元的一个关键特征。基因浓缩分析表明，在BCL11B调控的通路中，紊乱风险基因过度表达，主要与cAMP-PKA-钙信号轴和突触信号有关。我们的研究表明，亨廷顿病和精神分裂症可能具有共同的神经元病理生理学，在纹状体和皮质神经元中都发现了细胞内钙稳态的失调。相反，PKA信号的减少和多巴胺/谷氨酸受体信号的异常在很大程度上是MSN特有的。
Striatal medium spiny neurons (MSNs) are preferentially lost in Huntington’s disease. Genomic studies also implicate a direct role for MSNs in schizophrenia, a psychiatric disorder known to involve cortical neuron dysfunction. It remains unknown whether the two diseases share similar MSN pathogenesis or if neuronal deficits can be attributed to cell type–dependent biological pathways. Transcription factor BCL11B, which is expressed by all MSNs and deep layer cortical neurons, was recently proposed to drive selective neurodegeneration in Huntington’s disease and identified as a candidate risk gene in schizophrenia. Using human stem cell–derived neurons lacking BCL11B as a model, we investigated cellular pathology in MSNs and cortical neurons in the context of these disorders. Integrative analyses between differentially expressed transcripts and published genome-wide association study datasets identified cell type–specific disease-related phenotypes. We uncover a role for BCL11B in calcium homeostasis in both neuronal types, while deficits in mitochondrial function and PKA (protein kinase A)–dependent calcium transients are detected only in MSNs. Moreover, BCL11B-deficient MSNs display abnormal responses to glutamate and fail to integrate dopaminergic and glutamatergic stimulation, a key feature of striatal neurons in vivo. Gene enrichment analysis reveals overrepresentation of disorder risk genes among BCL11B-regulated pathways, primarily relating to cAMP-PKA-calcium signaling axis and synaptic signaling. Our study indicates that Huntington’s disease and schizophrenia are likely to share neuronal pathophysiology where dysregulation of intracellular calcium homeostasis is found in both striatal and cortical neurons. In contrast, reduction in PKA signaling and abnormal dopamine/glutamate receptor signaling is largely specific to MSNs.
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DOI：
10.1016/j.bbrc.2004.08.035
发表时间：
2004-10-01
影响因子：
3.1
作者：
Bezprozvanny, I;Hayden, MR
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影响因子：
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作者：
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影响因子：
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影响因子：
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影响因子：
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