Gene expression in a mouse model of Pantothenate Kinase-Associated Neurodegeneration
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ABSTRACT:
PROVIDER: PRJNA541011 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9008330_1.fastq.gz | Fastqsanger.gz | |||
| SRR9008330_2.fastq.gz | Fastqsanger.gz | |||
| SRR9008340_1.fastq.gz | Fastqsanger.gz | |||
| SRR9008340_2.fastq.gz | Fastqsanger.gz | |||
| SRR9008331_1.fastq.gz | Fastqsanger.gz |
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Project description:Pantothenate kinase 4 controls skeletal muscle substrate metabolism
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Project description:A mouse model lacking systemic expression of Pank1 together with neuronal deletion of Pank2 was generated and revealed a developmental requirement for CoA that, when deficient, resulted in abnormal motor behavior preceding early death. Neuronal Pank2 expression in Pank1-/-Syn-Pank2-/- double knockout mice (dKO) decreased starting at P9-11 and brain CoA levels did not increase subsequently, in contrast to wild-type matched control animals. The Pank1-/-Syn-Pank2-/- dKO mice developed a forelimb deformity and abnormal gait behavior, similar to PKAN patients, and lost weight when brain CoA became depressed relative to wild-type levels. Comparative gene expression analysis revealed significant alteration of a relatively small selection of genes, including reduction of gene transcripts affecting heme and hemoglobin synthesis together with upregulation of gene transcripts related to the response to oxygen/glucose deprivation.
2020-01-28 | GSE130705 | GEO
Project description:Pantothenate kinase-associated neurodegeneration (PKAN), a progressive neurodegenerative disorder, is associated with impairment of pantothenate kinase function. Pantothenate kinase is the first enzyme required for de novo synthesis of CoA, an essential metabolic cofactor. The pathophysiology of PKAN is not understood, and there is no cure to halt or reverse the symptoms of this devastating disease. Recently, we and others presented a PKAN Drosophila model, and we demonstrated that impaired function of pantothenate kinase induces a neurodegenerative phenotype and a reduced lifespan. We have explored this Drosophila model further and have demonstrated that impairment of pantothenate kinase is associated with decreased levels of CoA, mitochondrial dysfunction, and increased protein oxidation. Furthermore, we searched for compounds that can rescue pertinent phenotypes of the Drosophila PKAN model and identified pantethine. Pantethine feeding restores CoA levels, improves mitochondrial function, rescues brain degeneration, enhances locomotor abilities, and increases lifespan. We show evidence for the presence of a de novo CoA biosynthesis pathway in which pantethine is used as a precursor compound. Importantly, this pathway is effective in the presence of disrupted pantothenate kinase function. Our data suggest that pantethine may serve as a starting point to develop a possible treatment for PKAN.
| S-EPMC2872433 | biostudies-literature
Project description:Neurodegeneration with brain iron accumulation (NBIA) includes a rare and heterogeneous group of disorders characterized by iron deposition in the basal ganglia. Pantothenate kinase-associated neurodegeneration (PKAN) is the most common NBIA and has 2 main presentations: typical and atypical, the latter rarely presents with tremor. Our reported patients underwent full neurologic examination, standard brain magnetic imaging, and genetic testing for PKAN. Three patients who had "tremor-dominant" PKAN with a relatively benign course were reported, including 1 with dystonic tremor and 2 with parkinsonian tremor. All 3 patients had homozygous mutations in the PANK2 gene and typical eye of the tiger sign on brain imaging. PKAN (and NBIA in general) may be a potential cause of tremor, thus emphasizing the need to consider this diagnosis even in patients with a clinical diagnosis of essential, dystonic, or parkinsonian tremor.
| S-EPMC6353413 | biostudies-literature
Project description:Metabolic flexibility in skeletal muscle is essential for maintaining healthy glucose and lipid metabolism, and its dysfunction is closely linked to metabolic diseases. Exercise enhances metabolic flexibility, making it an important tool for discovering mechanisms that promote metabolic health. Here we show that pantothenate kinase 4 (PanK4) is a new conserved exercise target with high abundance in muscle. Muscle-specific deletion of PanK4 impairs fatty acid oxidation which is related to higher intramuscular acetyl-CoA and malonyl levels. These elevated acetyl-CoA levels persist regardless of feeding state and are associated with whole-body glucose intolerance, reduced insulin-stimulated glucose uptake in glycolytic muscle, and impaired glucose uptake during exercise. Conversely, increasing PanK4 levels in glycolytic muscle lowers acetyl-CoA and enhances glucose uptake. Our findings highlight PanK4 as an important regulator of acetyl-CoA levels, playing a key role in both muscle lipid and glucose metabolism.
2024-10-24 | GSE273694 | GEO
Project description:Neurodegeneration with brain iron accumulation is a broad term that describes a heterogeneous group of progressive and invalidating neurologic disorders in which iron deposits in certain brain areas, mainly the basal ganglia. The predominant clinical symptoms include spasticity, progressive dystonia, Parkinson's disease-like symptoms, neuropsychiatric alterations, and retinal degeneration. Among the neurodegeneration with brain iron accumulation disorders, the most frequent subtype is pantothenate kinase-associated neurodegeneration (PKAN) caused by defects in the gene encoding the enzyme pantothenate kinase 2 (PANK2) which catalyzed the first reaction of the coenzyme A biosynthesis pathway. Currently there is no effective treatment to prevent the inexorable course of these disorders. The aim of this review is to open up a discussion on the utility of using cellular models derived from patients as a valuable tool for the development of precision medicine in PKAN. Recently, we have described that dermal fibroblasts obtained from PKAN patients can manifest the main pathological changes of the disease such as intracellular iron accumulation accompanied by large amounts of lipofuscin granules, mitochondrial dysfunction and a pronounced increase of markers of oxidative stress. In addition, PKAN fibroblasts showed a morphological senescence-like phenotype. Interestingly, pantothenate supplementation, the substrate of the PANK2 enzyme, corrected all pathophysiological alterations in responder PKAN fibroblasts with low/residual PANK2 enzyme expression. However, pantothenate treatment had no favourable effect on PKAN fibroblasts harbouring mutations associated with the expression of a truncated/incomplete protein. The correction of pathological alterations by pantothenate in individual mutations was also verified in induced neurons obtained by direct reprograming of PKAN fibroblasts. Our observations indicate that pantothenate supplementation can increase/stabilize the expression levels of PANK2 in specific mutations. Fibroblasts and induced neurons derived from patients can provide a useful tool for recognizing PKAN patients who can respond to pantothenate treatment. The presence of low but significant PANK2 expression which can be increased in particular mutations gives valuable information which can support the treatment with high dose of pantothenate. The evaluation of personalized treatments in vitro of fibroblasts and neuronal cells derived from PKAN patients with a wide range of pharmacological options currently available, and monitoring its effect on the pathophysiological changes, can help for a better therapeutic strategy. In addition, these cell models will be also useful for testing the efficacy of new therapeutic options developed in the future.
| S-EPMC6425824 | biostudies-literature
Project description:Pantothenate kinase (PANK) is a metabolic enzyme that regulates cellular coenzyme A (CoA) levels. There are three human PANK genes, and inactivating mutations in PANK2 lead to pantothenate kinase associated neurodegeneration (PKAN). Here we performed a library screen followed by chemical optimization to produce PZ-2891, an allosteric PANK activator that crosses the blood brain barrier. PZ-2891 occupies the pantothenate pocket and engages the dimer interface to form a PANK•ATP•Mg2+•PZ-2891 complex. The binding of PZ-2891 to one protomer locks the opposite protomer in a catalytically active conformation that is refractory to acetyl-CoA inhibition. Oral administration of PZ-2891 increases CoA levels in mouse liver and brain. A knockout mouse model of brain CoA deficiency exhibited weight loss, severe locomotor impairment and early death. Knockout mice on PZ-2891 therapy gain weight, and have improved locomotor activity and life span establishing pantazines as novel therapeutics for the treatment of PKAN.
| S-EPMC6199309 | biostudies-literature
Project description:AimsMutations in the pantothenate kinase 2 gene (PANK2) are responsible for the most common type of neurodegeneration with brain iron accumulation (NBIA), known as pantothenate kinase-associated neurodegeneration (PKAN). Historically, NBIA is considered a synucleinopathy with numerous reports of NBIA cases with Lewy bodies and Lewy neurites and some cases reporting additional abnormal tau accumulation. However, clinicopathological correlations in genetically proven PKAN cases are rare. We describe the clinical, genetic and neuropathological features of three unrelated PKAN cases.MethodsAll three cases were genetically screened for the PANK2 gene mutations using standard Sanger polymerase chain reaction sequencing. A detailed neuropathological assessment of the three cases was performed using histochemical and immunohistochemical preparations.ResultsAll cases had classical axonal swellings and Perls' positive iron deposition in the basal ganglia. In contrast to neuroaxonal dystrophies due to mutation of the phospholipase A2, group VI (PLA2G6) gene, in which Lewy body pathology is widespread, no α-synuclein accumulation was detected in any of our PKAN cases. In one case (20-year-old male) there was significant tau pathology comprising neurofibrillary tangles and neuropil threads, with very subtle tau pathology in another case.ConclusionsThese findings indicate that PKAN is not a synucleinopathy and, hence the cellular pathways implicated in this disease are unlikely to be relevant for the pathomechanism of Lewy body disorders.
| S-EPMC3712463 | biostudies-literature
Project description:Pantothenate kinase-associated neurodegeneration (PKAN) is an autosomal recessive disorder of coenzyme A homeostasis caused by defects in the mitochondrial pantothenate kinase 2. Patients with PKAN present with a progressive neurological decline and brain iron accumulation, but general energy balance and nutrition status among these patients has not been reported. To determine if defects in PANK2 change basic energy metabolism in humans, we measured body composition, resting energy expenditure, dietary intake, and blood metabolites among 16 subjects with PKAN. Subjects had a broad range of disease severity but, despite the essential role of coenzyme A in energy metabolism, the subjects had remarkably normal body composition, dietary intake and energy metabolism compared to population normal values. We did observe increased resting energy expenditure associated with disease severity, suggesting increased energy needs later in the disease process, and elevated urinary mevalonate levels.
| S-EPMC6059611 | biostudies-literature
Project description:Pantothenate Kinase-associated Neurodegeneration (PKAN) belongs to a wide spectrum of diseases characterized by brain iron accumulation and extrapyramidal motor signs. PKAN is caused by mutations in PANK2, encoding the mitochondrial pantothenate kinase 2, which is the first enzyme of the biosynthesis of Coenzyme A. We established and characterized glutamatergic neurons starting from previously developed PKAN Induced Pluripotent Stem Cells (iPSCs). Results obtained by inductively coupled plasma mass spectrometry indicated a higher amount of total cellular iron in PKAN glutamatergic neurons with respect to controls. PKAN glutamatergic neurons, analyzed by electron microscopy, exhibited electron dense aggregates in mitochondria that were identified as granules containing calcium phosphate. Calcium homeostasis resulted compromised in neurons, as verified by monitoring the activity of calcium-dependent enzyme calpain1, calcium imaging and voltage dependent calcium currents. Notably, the presence of calcification in the internal globus pallidus was confirmed in seven out of 15 genetically defined PKAN patients for whom brain CT scan was available. Moreover, we observed a higher prevalence of brain calcification in females. Our data prove that high amount of iron coexists with an impairment of cytosolic calcium in PKAN glutamatergic neurons, indicating both, iron and calcium dys-homeostasis, as actors in pathogenesis of the disease.
| S-EPMC7279353 | biostudies-literature