A novel &lt;i&gt;PGK1&lt;/i&gt; mutation associated with neurological dysfunction and the absence of episodes of hemolytic anemia or myoglobinuria

Matsumaru, Shigeto; Oguni, Hirokazu; Ogura, Hiromi; Shimojima, Keiko; Nagata, Satoru; Kanno, Hitoshi; Yamamoto, Toshiyuki

doi:10.5582/irdr.2017.01020

Cited by 15 publications

(9 citation statements)

References 32 publications

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“…It is caused by mutated Pgk1, the folding and stability of which are altered (Chiarelli et al, 2012; Pey et al, 2014). Pgk1 deficiency is accompanied by suffering from muscle lesions, motor neuron defect, neurological dysfunction and myopathy (Valentini et al, 2013; Matsumaru et al, 2017), as well as susceptibility to Parkinson’s disease (Sakaue et al, 2017). Therefore, it can be reasonably speculated that the abnormal secretion of Pgk1 may affect neuronal development, which supports our finding that Pgk1 secreted from muscle cells plays a novel role in NOM and neuronal development.…”

Section: Discussionmentioning

confidence: 99%

Extracellular Pgk1 enhances neurite outgrowth of motoneurons through Nogo66/NgR-independent targeting of NogoA

Lin

Lee

et al. 2019

eLife

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NogoA inhibits neurite outgrowth of motoneurons (NOM) through interaction with its receptors, Nogo66/NgR. Inhibition of Nogo receptors rescues NOM, but not to the extent exhibited by NogoA-knockout mice, suggesting the presence of other pathways. We found that NogoA-overexpressing muscle cells reduced phosphoglycerate kinase 1 (Pgk1) secretion, resulting in inhibiting NOM. Apart from its glycolytic role and independent of the Nogo66 pathway, extracellular Pgk1 stimulated NOM by triggering a reduction of p-Cofilin-S3, a growth cone collapse marker, through decreasing a novel Rac1-GTP/p-Pak1-T423/p-P38-T180/p-MK2-T334/p-Limk1-S323/p-Cofilin-S3 molecular pathway. Not only did supplementary Pgk1 enhance NOM in defective cells, but injection of Pgk1 rescued denervation in muscle-specific NogoA-overexpression of zebrafish and an Amyotrophic Lateral Sclerosis mouse model, SOD1 G93A. Thus, Pgk1 secreted from muscle is detrimental to motoneuron neurite outgrowth and maintenance.

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Section: Discussionmentioning

confidence: 99%

Extracellular Pgk1 enhances neurite outgrowth of motoneurons through Nogo66/NgR-independent targeting of NogoA

Lin

Lee

et al. 2019

eLife

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“…In the glycolytic pathway, phosphoglycerate kinase (PGK) is a major enzyme that catalyzes the first ATP-generating step in which a phosphate group in 1,3-biphosphoglycerate is transferred to ADP, producing 3-phosphoglycerate and one molecule of ATP. Deficiency of PGK activity caused by genetic mutations (e.g., c.649G > A) that results in impaired ATP production had been established as a major cause of medical conditions such as hemolytic anemia, myopathy, and neurological deficits ( Matsumaru et al, 2017 ). Multiple studies have reported that patients suffering from these disorders exhibited PD-like symptoms, pointing to the role of PGK deficiency in the development of idiopathic PD ( Sotiriou et al, 2010 ; Sakaue et al, 2017 ; Cai et al, 2019 ; Le Bras, 2019 ; Shimizu et al, 2020 ).…”

Section: Glycolytic Dysfunction In Other Neurodegenerative Diseasesmentioning

confidence: 99%

Glycolytic Metabolism, Brain Resilience, and Alzheimer’s Disease

2021

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Alzheimer’s disease (AD) is the most common form of age-related dementia. Despite decades of research, the etiology and pathogenesis of AD are not well understood. Brain glucose hypometabolism has long been recognized as a prominent anomaly that occurs in the preclinical stage of AD. Recent studies suggest that glycolytic metabolism, the cytoplasmic pathway of the breakdown of glucose, may play a critical role in the development of AD. Glycolysis is essential for a variety of neural activities in the brain, including energy production, synaptic transmission, and redox homeostasis. Decreased glycolytic flux has been shown to correlate with the severity of amyloid and tau pathology in both preclinical and clinical AD patients. Moreover, increased glucose accumulation found in the brains of AD patients supports the hypothesis that glycolytic deficit may be a contributor to the development of this phenotype. Brain hyperglycemia also provides a plausible explanation for the well-documented link between AD and diabetes. Humans possess three primary variants of the apolipoprotein E (ApoE) gene – ApoE∗ϵ2, ApoE∗ϵ3, and ApoE∗ϵ4 – that confer differential susceptibility to AD. Recent findings indicate that neuronal glycolysis is significantly affected by human ApoE isoforms and glycolytic robustness may serve as a major mechanism that renders an ApoE2-bearing brain more resistant against the neurodegenerative risks for AD. In addition to AD, glycolytic dysfunction has been observed in other neurodegenerative diseases, including Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis, strengthening the concept of glycolytic dysfunction as a common pathway leading to neurodegeneration. Taken together, these advances highlight a promising translational opportunity that involves targeting glycolysis to bolster brain metabolic resilience and by such to alter the course of brain aging or disease development to prevent or reduce the risks for not only AD but also other neurodegenerative diseases.

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“…Because of normal kidney function in our patient, we speculate that the mild increase in bilirubin is protective to delay the appearance of kidney damage, although it is difficult to know in our patient whether it is associated with the onset of LPIN1 -associated RM. Moreover, it should be noted that our case is easily confused with phosphoglycerate kinase (PGK) deficiency, which is a rare cause of congenital hemolytic anemia accompanied by hyperbilirubinaemia, muscle weakness, myalgia and myoglobinuria [ 33 ]. Although our case has similar clinical features with PGK deficiency, it has been ruled out by genetic testing.…”

Section: Discussionmentioning

confidence: 99%

Acute recurrent rhabdomyolysis in a Chinese boy associated with a novel compound heterozygous LPIN1 variant: a case report

Tong

2021

BMC Neurol

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Background LPIN1-related acute recurrent rhabdomyolysis (RM), first reported in 2008, is an autosomal recessive inherited metabolic disease. In recent years, LPIN1 gene variants have been identified as one of the main causes of severe RM in children in Western countries. The disease is extremely rare in China, and we report a case of acute recurrent RM caused by a novel compound heterozygous LPIN1 variant. Case presentation A 15-year-old Chinese boy presented with myalgia after strenuous exercise, accompanied by transient increases in serum creatine kinase and myoglobin and persistent hyperuricaemia and hyperbilirubinaemia. Genetic analysis using high-throughput genomic sequencing and Sanger sequencing revealed that there was a compound heterozygous variant in the LPIN1 gene of the proband: the paternal c.2047A > G(p.I683V) was an unreported missense variant, and the maternal c.2107_2108 insAGG(p.Q703delin sQE) was an unreported in-frame variant. Conclusions In children with RM, LPIN1 variants should always be considered in the differential diagnosis. The clinical features of our case are atypical, which highlights the importance of an accurate diagnosis by genetic testing. If detected early, the condition may be controlled, and the prognosis may be improved.

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A novel <i>PGK1</i> mutation associated with neurological dysfunction and the absence of episodes of hemolytic anemia or myoglobinuria

Cited by 15 publications

References 32 publications

Extracellular Pgk1 enhances neurite outgrowth of motoneurons through Nogo66/NgR-independent targeting of NogoA

Extracellular Pgk1 enhances neurite outgrowth of motoneurons through Nogo66/NgR-independent targeting of NogoA

Glycolytic Metabolism, Brain Resilience, and Alzheimer’s Disease

Acute recurrent rhabdomyolysis in a Chinese boy associated with a novel compound heterozygous LPIN1 variant: a case report

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