Parkinson's Disease Research Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
J Parkinsons Dis. 2012;2(1):67-76. doi: 10.3233/JPD-2012-11074.
Parkinson's disease (PD) can include a progressive frontal lobe α-synucleinopathy with disability from cognitive decline and cortico-limbic dysregulation that may arise from bioenergetic impairments. We examined in PD frontal cortex regulation of mitochondrial biogenesis (mitobiogenesis) and its effects on Complex-I. We quantified expression of 33 nuclear genome (nDNA)-encoded and 7 mitochondrial genome (mtDNA)-encoded Complex-I genes, 6 Complex-I assembly factors and multiple mitobiogenesis genes. We related these findings to levels of Complex-I proteins and NADH-driven electron flow in mitochondria from these same specimens reported in earlier studies. We found widespread, decreased expression of nDNA Complex-I genes that correlated in some cases with mitochondrial Complex-I protein levels, and of ACAD9, a Complex-I assembly factor. mtDNA-transcribed Complex-I genes showed ~ constant expression within each PD sample but variable expression across PD samples that correlated with NRF1. Relationships among PGC-1α and its downstream targets NRF1 and TFAM were very similar in PD and CTL and were related to mitochondrial NADH-driven electron flow. MicroRNA arrays revealed multiple miRNA's regulated >2-fold predicted to interact with PGC-1α or its upstream regulators. Exposure of cultured human neurons to NO, rotenone and TNF-alpha partially reproduced mitobiogenesis down-regulation. In PD frontal cortex mitobiogenesis signaling relationships are maintained but down-regulated, correlate with impaired mitochondrial NADH-driven electron flow and may arise from combinations of nitrosative/oxidative stresses, inflammatory cytokines, altered levels of mitobiogenesis gene-interacting microRNA's, or other unknown mechanisms. Stimulation of mitobiogenesis in PD may inhibit rostral disease progression and appearance of secondary symptoms referable to frontal cortex.
帕金森病（PD）可能包括进行性额皮质α-突触核蛋白病，其特征为认知能力下降和皮质-边缘功能障碍，这可能源于生物能量障碍。我们研究了 PD 额叶皮质中线粒体生物发生（mitobiogenesis）的调节及其对复合物-I 的影响。我们量化了 33 个核基因组（nDNA）编码和 7 个线粒体基因组（mtDNA）编码的复合物-I 基因、6 个复合物-I 组装因子和多个 mitobiogenesis 基因的表达。我们将这些发现与之前研究中报告的来自这些相同标本的复合物-I 蛋白水平和 NADH 驱动的线粒体电子流相关联。我们发现 nDNA 复合物-I 基因的广泛、下调表达，在某些情况下与线粒体复合物-I 蛋白水平相关，以及复合物-I 组装因子 ACAD9。每个 PD 样本内的 mtDNA 转录复合物-I 基因表达相对稳定，但在 PD 样本之间的表达可变，与 NRF1 相关。PGC-1α 及其下游靶标 NRF1 和 TFAM 之间的关系在 PD 和 CTL 中非常相似，与线粒体 NADH 驱动的电子流相关。miRNA 数组揭示了多种 miRNA 的调节>2 倍，预测与 PGC-1α 或其上游调节剂相互作用。培养的人神经元暴露于 NO、鱼藤酮和 TNF-α 可部分复制 mitobiogenesis 下调。PD 额叶皮质中线粒体生物发生信号关系得以维持，但下调，与线粒体 NADH 驱动的电子流受损相关，可能源于硝化/氧化应激、炎症细胞因子、mitobiogenesis 基因相互作用的 miRNA 水平改变、或其他未知机制的组合。在 PD 中刺激 mitobiogenesis 可能抑制疾病的进展和与额叶皮质相关的二级症状的出现。
