Centro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), and Centro de Investigación Biomédica en Red: Enfermedades Raras, Instituto de Salud Carlos III, 41013, Sevilla, Spain.
Orphanet J Rare Dis. 2022 Aug 9;17(1):311. doi: 10.1186/s13023-022-02465-9.
Neurodegeneration with brain iron accumulation (NBIA) is a group of rare neurogenetic disorders frequently associated with iron accumulation in the basal nuclei of the brain characterized by progressive spasticity, dystonia, muscle rigidity, neuropsychiatric symptoms, and retinal degeneration or optic nerve atrophy. Pantothenate kinase-associated neurodegeneration (PKAN) is one of the most widespread NBIA subtypes. It is caused by mutations in the gene of pantothenate kinase 2 (PANK2) that result in dysfunction in PANK2 enzyme activity, with consequent deficiency of coenzyme A (CoA) biosynthesis, as well as low levels of essential metabolic intermediates such as 4'-phosphopantetheine, a necessary cofactor for essential cytosolic and mitochondrial proteins.
In this manuscript, we examined the therapeutic effectiveness of pantothenate, panthetine, antioxidants (vitamin E and omega 3) and mitochondrial function boosting supplements (L-carnitine and thiamine) in mutant PANK2 cells with residual expression levels.
Commercial supplements, pantothenate, pantethine, vitamin E, omega 3, carnitine and thiamine were able to eliminate iron accumulation, increase PANK2, mtACP, and NFS1 expression levels and improve pathological alterations in mutant cells with residual PANK2 expression levels.
Our results suggest that several commercial compounds are indeed able to significantly correct the mutant phenotype in cellular models of PKAN. These compounds alone or in combinations are of common use in clinical practice and may be useful for the treatment of PKAN patients with residual enzyme expression levels.
神经铁沉积伴脑铁沉积（NBIA）是一组罕见的神经遗传疾病，常伴有脑基底核铁沉积，其特征为进行性痉挛、肌张力障碍、肌肉僵硬、神经精神症状以及视网膜变性或视神经萎缩。泛酸激酶相关神经变性（PKAN）是最广泛的 NBIA 亚型之一。它是由泛酸激酶 2（PANK2）基因突变引起的，导致 PANK2 酶活性功能障碍，继而辅酶 A（CoA）生物合成不足，以及必需代谢中间产物水平降低，如 4'-磷酸泛酰巯基乙胺，这是必需胞质和线粒体蛋白的必要辅因子。
在本手稿中，我们研究了泛酸、泛硫乙胺、抗氧化剂（维生素 E 和 omega 3）和线粒体功能增强补充剂（左旋肉碱和硫胺素）在具有残留表达水平的突变 PANK2 细胞中的治疗效果。
商业补充剂、泛酸、泛硫乙胺、维生素 E、omega 3、肉碱和硫胺素能够消除铁沉积，增加 PANK2、mtACP 和 NFS1 的表达水平，并改善具有残留 PANK2 表达水平的突变细胞的病理改变。
我们的结果表明，几种商业化合物确实能够显著纠正 PKAN 细胞模型中的突变表型。这些化合物单独或联合使用在临床实践中很常见，可能对具有残留酶表达水平的 PKAN 患者的治疗有用。
