TMEM63C mutations cause mitochondrial morphology defects and underlie hereditary spastic paraplegia
Luis Carlos Tábara,Fatema Al-Salmi,Reza Maroofian,Amna Al-Futaisi,Fathiya Al-Murshedi,Joanna S. Kennedy,Jacob J. Day,Thomas Courtin,Aisha Al-Khayat,H Galedari,Neda Mazaheri,Margherita Protasoni,Mark H. Johnson,Joseph S Leslie,Claire G. Salter,Lettie E. Rawlins,James Fasham,Almundher Al-Maawali,Nikol Voutsina,Perrine Charles,L. Harrold,Boris Keren,Edmund R.S. Kunji,Barbara Vona,Gholamreza Jelodar,Alireza Sedaghat,Gholamreza Shariati,Henry Houlden,Andrew H. Crosby,Julien Prudent,Emma L. Baple +30 more
TLDR
Findings identify autosomal recessive TMEM63C variants as a cause of pure and complex HSP and add to the growing evidence of a fundamental pathomolecular role of perturbed mitochondrial-endoplasmic reticulum dynamics in motor neurone degenerative diseases.Abstract:
Abstract The hereditary spastic paraplegias (HSP) are among the most genetically diverse of all Mendelian disorders. They comprise a large group of neurodegenerative diseases that may be divided into ‘pure HSP’ in forms of the disease primarily entailing progressive lower-limb weakness and spasticity, and ‘complex HSP’ when these features are accompanied by other neurological (or non-neurological) clinical signs. Here, we identified biallelic variants in the transmembrane protein 63C (TMEM63C) gene, encoding a predicted osmosensitive calcium-permeable cation channel, in individuals with hereditary spastic paraplegias associated with mild intellectual disability in some, but not all cases. Biochemical and microscopy analyses revealed that TMEM63C is an endoplasmic reticulum-localized protein, which is particularly enriched at mitochondria–endoplasmic reticulum contact sites. Functional in cellula studies indicate a role for TMEM63C in regulating both endoplasmic reticulum and mitochondrial morphologies. Together, these findings identify autosomal recessive TMEM63C variants as a cause of pure and complex HSP and add to the growing evidence of a fundamental pathomolecular role of perturbed mitochondrial-endoplasmic reticulum dynamics in motor neurone degenerative diseases.read more
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Multi-omics approach reveals dysregulated genes during hESCs neuronal differentiation exposure to paracetamol
Mari Spildrejorde,Athina Samara,Ankush Sharma,Magnus Leithaug,Martin Falck,Stefania Modafferi,Arvind Y. M. Sundaram,Ganesh Acharya,Hedvig Nordeng,Ragnhild Eskeland,Kristina Gervin,Robert Lyle +11 more
TL;DR: In this article , the effects of prenatal paracetamol exposure on brain development were investigated using a multi-omics approach, using human embryonic stem cells undergoing in vitro neuronal differentiation to daily media changes with the concentrations corresponding to maternal therapeutic doses.
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Mitochondria-endoplasmic reticulum contacts in sepsis-induced myocardial dysfunction
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Copy number variations in SPAST and ATL1 are rare among Brazilians
Helena Fussiger,Bruna Letícia da Silva Pereira,Janice Pacheco Dias Padilha,Karina Carvalho Donis,Marina Siebert,Ana Carolina Brusius-Facchin,Guilherme Baldo,Jonas Alex Morales Saute +7 more
TL;DR: In this paper , the frequency of copy number variations (CNV) in SPAST and ATL1 was assessed and the most frequent autosomal dominant subtypes of hereditary spastic paraplegias (HSP) were identified.
Multi-omics analysis of paracetamol exposure identifies dysregulated genes involved in neurotoxicity and neuronal differentiation of human embryonic stem cells
Mari Spildrejorde,Athina Samara,Ankush Sharma,Magnus Leithaug,Martin,Falck,Stefania Modafferi,Arvind Y. M. Sundaram,Ganesh Acharya,Hedvig,Nordeng,Ragnhild Eskeland,Kristina Gervin,Robert Lyle +13 more
TL;DR: In this article , an integrated multi-omics approach was used to investigate epigenetic and transcriptomic effects of paracetamol on the early stages of human brain development, and they found differentially methylated and or expressed genes involved in signal transduction, neurotransmitter secretion and cell fate determination trajectories.
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