Centro Andaluz de Biología del Desarrollo (CABD-CSIC-UPO), Universidad Pablo de Olavide, 41013, Seville, Spain.
Orphanet J Rare Dis. 2023 Apr 12;18(1):80. doi: 10.1186/s13023-023-02687-5.
Neurodegeneration with brain iron accumulation (NBIA) disorders are a group of neurodegenerative diseases that have in common the accumulation of iron in the basal nuclei of the brain which are essential components of the extrapyramidal system. Frequent symptoms are progressive spasticity, dystonia, muscle rigidity, neuropsychiatric symptoms, and retinal degeneration or optic nerve atrophy. One of the most prevalent subtypes of NBIA is Pantothenate kinase-associated neurodegeneration (PKAN). It is caused by pathogenic variants in the gene of pantothenate kinase 2 (PANK2) which encodes the enzyme responsible for the first reaction on the coenzyme A (CoA) biosynthesis pathway. Thus, deficient PANK2 activity induces CoA deficiency as well as low expression levels of 4'-phosphopantetheinyl proteins which are essential for mitochondrial metabolism.
This study is aimed at evaluating the role of alpha-lipoic acid (α-LA) in reversing the pathological alterations in fibroblasts and induced neurons derived from PKAN patients. Iron accumulation, lipid peroxidation, transcript and protein expression levels of PANK2, mitochondrial ACP (mtACP), 4''-phosphopantetheinyl and lipoylated proteins, as well as pyruvate dehydrogenase (PDH) and Complex I activity were examined.
Treatment with α-LA was able to correct all pathological alterations in responsive mutant fibroblasts with residual PANK2 enzyme expression. However, α-LA had no effect on mutant fibroblasts with truncated/incomplete protein expression. The positive effect of α-LA in particular pathogenic variants was also confirmed in induced neurons derived from mutant fibroblasts.
Our results suggest that α-LA treatment can increase the expression levels of PANK2 and reverse the mutant phenotype in PANK2 responsive pathogenic variants. The existence of residual enzyme expression in some affected individuals raises the possibility of treatment using high dose of α-LA.
神经铁沉积伴脑灰质萎缩（NBIA）是一组神经退行性疾病，其共同特征是脑基底核铁沉积，这些基底核是锥体外系的重要组成部分。常见症状包括进行性痉挛、肌张力障碍、肌肉僵硬、神经精神症状和视网膜变性或视神经萎缩。NBIA 最常见的亚型之一是泛酸激酶相关神经变性（PKAN）。它是由泛酸激酶 2（PANK2）基因的致病性变异引起的，该基因编码辅酶 A（CoA）生物合成途径中第一个反应的酶。因此，PANK2 活性缺陷会导致 CoA 缺乏以及 4'-磷酸泛酰巯基乙胺蛋白的表达水平降低，而后者对于线粒体代谢是必需的。
本研究旨在评估α-硫辛酸（α-LA）在逆转 PKAN 患者成纤维细胞和诱导神经元中病理改变的作用。检测了铁积累、脂质过氧化、PANK2、线粒体 ACP（mtACP）、4''-磷酸泛酰巯基乙胺和硫辛酰化蛋白、丙酮酸脱氢酶（PDH）和复合物 I 活性的转录和蛋白表达水平。
α-LA 处理能够纠正具有残留 PANK2 酶表达的反应性突变型成纤维细胞中的所有病理改变。然而，α-LA 对具有截断/不完整蛋白表达的突变型成纤维细胞没有影响。α-LA 在特别是致病性变异中的积极作用在源自突变型成纤维细胞的诱导神经元中也得到了证实。
我们的结果表明，α-LA 治疗可以增加 PANK2 的表达水平并逆转 PANK2 反应性致病变体中的突变表型。在一些受影响的个体中存在残留酶表达的可能性，为使用高剂量的 α-LA 治疗提供了可能性。
