A novel <i><scp>CPT</scp>1C</i> variant causes pure hereditary spastic paraplegia with benign clinical course

Hong, Daojun; Cong, Lu; Zhong, Shanshan; Liu, Ling; Xu, Yan; Zhang, Jun

doi:10.1002/acn3.717

Cited by 11 publications

(11 citation statements)

References 18 publications

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“…The energetic regulation of LE/Lys plus-end transport mediated by CPT1C seems to be of particular importance for corticospinal neurons, the ones with longer axons in the body, since individuals carrying the missense CPT1C R37C or the nonsense CPT1C Q76X mutations develop HSP (Hong et al, 2019; Rinaldi et al, 2015). Arg37 is predicted to establish an electrostatic interaction with Glu3, stabilizing the Nα state of CPT1C.…”

Section: Discussionmentioning

confidence: 99%

“…Cpt1c KO mice show motor function deficits, such as ataxia, dyscoordination, and muscle weakness (Carrasco et al, 2013), in addition to learning deficits (Carrasco et al, 2012) and impaired hypothalamic control of body energy homeostasis (Casals et al, 2016; Pozo et al, 2017; Rodríguez-Rodríguez et al, 2019). Interestingly, the unique two CPT1C mutations described in humans to date have been associated with hereditary spastic paraplegia (HSP) (Hong et al, 2019; Rinaldi et al, 2015). HSPs are a group of inherited neurological disorders characterized by slowly progressive weakness and spasticity of the muscles of the legs, caused by axonopathy of corticospinal motor neurons (Blackstone et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Sensing of nutrients by CPT1C regulates late endosome/lysosome anterograde transport and axon growth

Palomo-Guerrero

Fadó

Casas

et al. 2019

eLife

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Anterograde transport of late endosomes or lysosomes (LE/Lys) is crucial for proper axon growth. However, the role of energetic nutrients has been poorly explored. Malonyl-CoA is a precursor of fatty acids, and its intracellular levels highly fluctuate depending on glucose availability or the energy sensor AMP-activated protein kinase (AMPK). We demonstrate in HeLa cells that carnitine palmitoyltransferase 1C (CPT1C) senses malonyl-CoA and enhances LE/Lys anterograde transport by interacting with the endoplasmic reticulum protein protrudin and facilitating the transfer of Kinesin-1 from protrudin to LE/Lys. In cultured mouse cortical neurons, glucose deprivation, pharmacological activation of AMPK or inhibition of malonyl-CoA synthesis decreases LE/Lys abundance at the axon terminal, and shortens axon length in a CPT1C-dependent manner. These results identify CPT1C as a new regulator of anterograde LE/Lys transport in response to malonyl-CoA changes, and give insight into how axon growth is controlled by nutrients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Sensing of nutrients by CPT1C regulates late endosome/lysosome anterograde transport and axon growth

Palomo-Guerrero

Fadó

Casas

et al. 2019

eLife

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“…In the brain, CPT1C has been found to be critical for correct regulation of food intake and peripheral lipid metabolism in the hypothalamus ( Gao et al, 2011 , 2009 ; Ramírez et al, 2013 ; Pozo et al, 2017 ; Rodríguez-Rodríguez et al, 2019 ). In addition, its rich expression in the cerebral motor cortex and cerebellum makes it relevant in motor coordination and activity ( Carrasco et al, 2013 ), underscored by human CPT1C mutations being associated with hereditary spastic paraplegia ( Rinaldi et al, 2015 ; Hong et al, 2019 ). Finally, due to its abundance in the hippocampus and in the cerebral cortex, CPT1C also plays a pivotal role in cognition ( Carrasco et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

Sensing of nutrients by CPT1C controls SAC1 activity to regulate AMPA receptor trafficking

Casas

Fadó

Domínguez

et al. 2020

Journal of Cell Biology

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Carnitine palmitoyltransferase 1C (CPT1C) is a sensor of malonyl-CoA and is located in the ER of neurons. AMPA receptors (AMPARs) mediate fast excitatory neurotransmission in the brain and play a key role in synaptic plasticity. In the present study, we demonstrate across different metabolic stress conditions that modulate malonyl-CoA levels in cortical neurons that CPT1C regulates the trafficking of the major AMPAR subunit, GluA1, through the phosphatidyl-inositol-4-phosphate (PI(4)P) phosphatase SAC1. In normal conditions, CPT1C down-regulates SAC1 catalytic activity, allowing efficient GluA1 trafficking to the plasma membrane. However, under low malonyl-CoA levels, such as during glucose depletion, CPT1C-dependent inhibition of SAC1 is released, facilitating SAC1’s translocation to ER-TGN contact sites to decrease TGN PI(4)P pools and trigger GluA1 retention at the TGN. Results reveal that GluA1 trafficking is regulated by CPT1C sensing of malonyl-CoA and provide the first report of a SAC1 inhibitor. Moreover, they shed light on how nutrients can affect synaptic function and cognition.

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“…However, the heterozygous and homozygous variant of this SNP were also found in 300 controls (3/300 vs. 1/300), respectively. In fact, a recent study by Hong et al found a novel heterozygous variant (c.226C>T) resulting in a premature stop (p.Q76X) in exon 3 of the CPT1C, with benign clinical course (34). Therefore, whether the rs150853576 variant might be one of the "minor offenders" to contribute to cumulative risk and the occurrence of pure HSP in this pedigree, needs further functional verification.…”

Section: Discussionmentioning

confidence: 85%

A novel variant of SPAST in a pedigree with pure hereditary spastic paraplegia in Yunnan Province

Shen¹,

Zhang²,

Li³

et al. 2022

Ann Transl Med

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Background: Hereditary spastic paraplegia (HSP) is a rare group of genetically heterogeneous, neurodegenerative disorders. The aim of this study was to identify pathological candidate genes and variants in a large pedigree cohort of 11 purely HSP patients in Yunnan Province.Methods: Whole-exome sequencing (WES) was applied to 2 HSP patients and 1 control patient to screen out the candidate gene variants. Then, filtration and verification of these pathological variants were performed by Sanger sequencing.Results: After the raw data were filtered, two genes with novel variations (SPAST: c.1510 C>T, p.Gln504X, RefSeq.NM_199436; DNAJC16: c.718 C>T, p.Q240X, Ref Seq NM_015291) were identified. The accession numbers of the genes in the ClinVar database were SCV001573094 and SCV001573804, respectively. One gene with a reported single nucleotide polymorphism (CPT1C: rs150853576) was filtered as a candidate variant. Using Sanger sequencing, the novel SPAST gene (protein: Spastin) variant leading to a predicted premature termination and an 18% deletion of the SPAST/spastic paraplegia type 4 (SPG4) protein was confirmed to exist only in affected individuals. The candidate CPT1C and DNAJC16 variants were verified in almost all HSP patients, with one exception.Conclusions: Considering that the clinical symptoms and time of onset of HSP are highly heterogeneous, the SPAST as a genotype-phenotype cosegregated variant might be the causative gene of this pedigree, and the other two variants might present cumulative risks to the occurrence and progression of HSP. These three candidate genes with or without novel variants may be potential contributors to disease onset, and therefore useful diagnostic and therapeutic biomarkers. Further research is required to confirm the functions of these genes.

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A novel CPT1C variant causes pure hereditary spastic paraplegia with benign clinical course

Cited by 11 publications

References 18 publications

Sensing of nutrients by CPT1C regulates late endosome/lysosome anterograde transport and axon growth

Sensing of nutrients by CPT1C regulates late endosome/lysosome anterograde transport and axon growth

Sensing of nutrients by CPT1C controls SAC1 activity to regulate AMPA receptor trafficking

A novel variant of SPAST in a pedigree with pure hereditary spastic paraplegia in Yunnan Province

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