RESUMEN
The complexity of affected brain regions and cell types is a challenge for Huntington's disease (HD) treatment. Here we use single nucleus RNA sequencing to investigate molecular pathology in the cortex and striatum from R6/2 mice and human HD post-mortem tissue. We identify cell type-specific and -agnostic signatures suggesting oligodendrocytes (OLs) and oligodendrocyte precursors (OPCs) are arrested in intermediate maturation states. OL-lineage regulators OLIG1 and OLIG2 are negatively correlated with CAG length in human OPCs, and ATACseq analysis of HD mouse NeuN-negative cells shows decreased accessibility regulated by OL maturation genes. The data implicates glucose and lipid metabolism in abnormal cell maturation and identify PRKCE and Thiamine Pyrophosphokinase 1 (TPK1) as central genes. Thiamine/biotin treatment of R6/1 HD mice to compensate for TPK1 dysregulation restores OL maturation and rescues neuronal pathology. Our insights into HD OL pathology spans multiple brain regions and link OL maturation deficits to abnormal thiamine metabolism.
Asunto(s)
Biotina , Enfermedad de Huntington , Oligodendroglía , Tiamina , Animales , Humanos , Ratones , Biotina/metabolismo , Biotina/farmacología , Suplementos Dietéticos , Modelos Animales de Enfermedad , Enfermedad de Huntington/metabolismo , Ratones Transgénicos , Proteínas del Tejido Nervioso/metabolismo , Oligodendroglía/metabolismo , Núcleo Solitario/metabolismo , Tiamina/metabolismo , Tiamina/farmacologíaRESUMEN
In familial and sporadic multiple system atrophy (MSA) patients, deficiency of coenzyme Q10 (CoQ10) has been associated with mutations in COQ2, which encodes the second enzyme in the CoQ10 biosynthetic pathway. Cerebellar ataxia is the most common presentation of CoQ10 deficiency, suggesting that the cerebellum might be selectively vulnerable to low levels of CoQ10 To investigate whether CoQ10 deficiency represents a common feature in the brains of MSA patients independent of the presence of COQ2 mutations, we studied CoQ10 levels in postmortem brains of 12 MSA, 9 Parkinson disease (PD), 9 essential tremor (ET) patients, and 12 controls. We also assessed mitochondrial respiratory chain enzyme activities, oxidative stress, mitochondrial mass, and levels of enzymes involved in CoQ biosynthesis. Our studies revealed CoQ10 deficiency in MSA cerebellum, which was associated with impaired CoQ biosynthesis and increased oxidative stress in the absence of COQ2 mutations. The levels of CoQ10 in the cerebella of ET and PD patients were comparable or higher than in controls. These findings suggest that CoQ10 deficiency may contribute to the pathogenesis of MSA. Because no disease modifying therapies are currently available, increasing CoQ10 levels by supplementation or upregulation of its biosynthesis may represent a novel treatment strategy for MSA patients.
Asunto(s)
Ataxia/metabolismo , Cerebelo/metabolismo , Enfermedades Mitocondriales/metabolismo , Atrofia de Múltiples Sistemas/metabolismo , Debilidad Muscular/metabolismo , Ubiquinona/análogos & derivados , Ubiquinona/deficiencia , Anciano , Anciano de 80 o más Años , Ataxia/complicaciones , Ataxia/patología , Estudios de Casos y Controles , Cerebelo/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Mitocondriales/complicaciones , Enfermedades Mitocondriales/patología , Atrofia de Múltiples Sistemas/complicaciones , Atrofia de Múltiples Sistemas/patología , Debilidad Muscular/complicaciones , Debilidad Muscular/patología , Estrés Oxidativo/fisiología , Ubiquinona/metabolismoRESUMEN
Parkinson's disease (PD) is characterized by a loss of ventral midbrain dopaminergic neurons, which can be modeled by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Inflammatory oxidants have emerged as key contributors to PD- and MPTP-related neurodegeneration. Here, we show that myeloperoxidase (MPO), a key oxidant-producing enzyme during inflammation, is upregulated in the ventral midbrain of human PD and MPTP mice. We also show that ventral midbrain dopaminergic neurons of mutant mice deficient in MPO are more resistant to MPTP-induced cytotoxicity than their wild-type littermates. Supporting the oxidative damaging role of MPO in this PD model are the demonstrations that MPO-specific biomarkers 3-chlorotyrosine and hypochlorous acid-modified proteins increase in the brains of MPTP-injected mice. This study demonstrates that MPO participates in the MPTP neurotoxic process and suggests that inhibitors of MPO may provide a protective benefit in PD.