Oxidative stress and mitochondrial dynamics malfunction are linked in Pelizaeus‐Merzbacher disease

Abstract

Pelizaeus-Merzbacher disease (PMD) is a fatal hypomyelinating disorder characterized by early impairment of motor development, nystagmus, choreoathetotic movements, ataxia and progressive spasticity. PMD is caused by variations in the proteolipid protein gene PLP1, which encodes the two major myelin proteins of the central nervous system, PLP and its spliced isoform DM20, in oligodendrocytes. Large duplications including the entire PLP1 gene are the most frequent causative mutation leading to the classical form of PMD. The Plp1 overexpressing mouse model (PLP-tg ) develops a phenotype very similar to human PMD, with early and severe motor dysfunction and a dramatic decrease in lifespan. The sequence of cellular events that cause neurodegeneration and ultimately death is poorly understood. In this work, we analyzed patient-derived fibroblasts and spinal cords of the PLP-tg mouse model, and identified redox imbalance, with altered antioxidant defense and oxidative damage to several enzymes involved in ATP production, such as glycolytic enzymes, creatine kinase and mitochondrial proteins from the Krebs cycle and oxidative phosphorylation. We also evidenced malfunction of the mitochondria compartment with increased ROS production and depolarization in PMD patient's fibroblasts, which was prevented by the antioxidant N-acetyl-cysteine. Finally, we uncovered an impairment of mitochondrial dynamics in patient's fibroblasts which may help explain the ultrastructural abnormalities of mitochondria morphology detected in spinal cords from PLP-tg mice. Altogether, these results underscore the link between redox and metabolic homeostasis in myelin diseases, provide insight into the pathophysiology of PMD, and may bear implications for tailored pharmacological intervention.

Expanding the phenotypic spectrum of Allan–Herndon–Dudley syndrome in patients with SLC16A2 mutations

“…Failure to thrive, which is classically associated with feeding difficulties and dysthyroidism, could also be related to abnormal myelination. Absence of weight gain is the hallmark of early‐onset hypomyelinating leukodystrophies and is related to severe energy impairment in the brain . Microcephaly, usually acquired and moderate, was more frequent in our series than in patients with AHDS reported in the literature and Schwartz et al.…”

“…Absence of weight gain is the hallmark of early-onset hypomyelinating leukodystrophies and is related to severe energy impairment in the brain. 51 Microcephaly, usually acquired and moderate, was more frequent in our series than in patients with AHDS reported in the literature and Schwartz et al's cohort. 4,8,16,21,27,33,42,45 Dysmorphic features in our cohort were linked to severe hypotonia and correspond to those described in the literature; they consist of a narrow face, high-arched palate, kyphoscoliosis, cryptorchidism, pectus excavatum, and flat feet with valgus.…”

Ketogenic diet ameliorates axonal defects and promotes myelination in Pelizaeus–Merzbacher disease

“…In addition, we observed in Plp1tgB mice that many axons contained enlarged mitochondrial profiles (Fig. 3 b), as observed before in other models of PMD [ 28 , 45 , 53 ]. Such morphological alterations can reflect increased activity and/or functional deficits in mitochondria which could both occur in PMD (see below).…”

“…In PMD oligodendrocytes, overexpressed PLP accumulates together with cholesterol which impairs the intracellular transport of proteins and lipids to the growing myelin sheath [ 31 , 57 , 62 ]. In combination with the progressive loss of mutant oligodendrocytes, this leads to dysmyelination and demyelination in PMD [ 11 , 53 , 59 ]. The MRI pattern of diffuse hypomyelination in PMD caused by PLP1 duplication is hence considered consequence of arrested brain maturation and lacks focal or inflammatory demyelination [ 9 , 66 , 71 ].…”

Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy

“…Accumulation of DhCer is involved in many stress signals such as cell cycle regulation, autophagy induction, apoptosis, and ROS generation (35,36), the latter being substantiated by our results. Redox imbalance is intertwined with energy homeostasis in diseases of myelin (23,37), and may play a role in the cachexia observed in the large majority of our patients. Moreover, suppressing DEGS1 led to cell cycle arrest, cell growth inhibition, and apoptosis in cell culture models (16,38), which may explain the decrease of myelinating MBP + oligodendrocyte numbers and perhaps contribute to the general developmental delay and impressive failure to thrive in our patients.…”