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Publications

Alterations of the Oxidative Phosphorylation Complexes in Rhabdomyosarcomas

Authors

Kofler B, Feichtinger RG, Vidali S, Hauser-Kronberger C, Ridzewski R, Hahn H.

Journal

PEDIATRIC BLOOD & CANCER Volume: 63 Supplement: 3 Pages: S261-S261


Feasibility of ketogenic diet to treat renal cell carcinoma in vivo

Authors

Vidali S, Aminzadeh S, Feichtinger RG, Vatrinet R, Locker F, Rutherford T, O’Donnel M, Stöger-Kleiber A, Sperl W, Porcelli AM, Kofler B.

Journal

Conference: Biochimica et Biophysica Acta (BBA) - Bioenergetics Volume: 1857 Pages: e116


 

Thyroid hormones enhance mitochondrial activity and biogenesis in human epidermis.

 

Authors

Vidali S, Chéret J, Giesen M, Haeger S, Alam M, Watson RE, Langton AK, Klinger M, Knuever J, Funk W, Kofler B, Paus R.

Journal

J Invest Dermatol. Volume: 136 Issue: 9 Supplement: 2 Pages: S172-S172

 


 

Thyroid Hormones Enhance Mitochondrial Function in Human Epidermis.

 

Authors

Vidali S, Chéret J, Giesen M, Haeger S, Alam M, Watson RE, Langton AK, Klinger M, Knuever J, Funk W, Kofler B, Paus R.

Journal

J Invest Dermatol. 2016 Oct;136(10):2003-12. DOI: 10.1016/j.jid.2016.05.118

 


 

Effects of alpha-melanocyte-stimulating hormone on mitochondrial energy metabolism in rats of different age-groups.

 

Authors

Feichtinger RG, Pétervári E, Zopf M, Vidali S, Aminzadeh-Gohari S, Mayr JA, Kofler B, Balaskó M.

Journal

Neuropeptides. 2016 Aug 26. pii: S0143-4179(16)30089-0. DOI: 10.1016/j.npep.2016.08.009

 


 

Dysregulation of Parkin-mediated mitophagy in thyroid Hürthle cell tumors.

 

Authors

Lee J, Ham S, Lee MH, Kim SJ, Park JH, Lee SE, Chang JY, Joung KH, Kim TY, Kim JM, Sul HJ, Kweon GR, Jo YS, Kim KS, Shong YK, Gasparre G, Chung JK, Porcelli AM, Shong M.

 

Journal

Carcinogenesis. 2015 Nov;36(11):1407-18. DOI: 10.1093/carcin/bgv122

 


 

HmtDB 2016: data update, a better performing query system and human mitochondrial DNA haplogroup predictor.

 

Authors

Clima R, Preste R, Calabrese C, Diroma MA, Santorsola M, Scioscia G, Simone D, Shen L, Gasparre G, Attimonelli M.

 

Journal

Nucleic Acids Res. 2017 Jan 4;45(D1):D698-D706. DOI: 10.1093/nar/gkw1066

 


 

The α-ketoglutarate dehydrogenase complex in cancer metabolic plasticity.

 

Authors

Vatrinet R, Leone G, De Luise M, Girolimetti G, Vidone M, Gasparre G, Porcelli AM.

 

Journal

Cancer Metab. 2017 Feb 2;5:3. doi: 10.1186/s40170-017-0165-0. eCollection 2017.

 


 

Pathological ribonuclease H1 causes R-loop depletion and aberrant DNA segregation in mitochondria.

 

Authors

Akman G, Desai R, Bailey LJ, Yasukawa T, Dalla Rosa I, Durigon R, Holmes JB, Moss CF, Mennuni M, Houlden H, Crouch RJ, Hanna MG, Pitceathly RD, Spinazzola A, Holt IJ.

 

Journal

Proc Natl Acad Sci U S A. 2016 Jul 26;113(30):E4276-85. doi: 10.1073/pnas.1600537113. Epub 2016 Jul 8.

 


 

Multiplexed high-content analysis of mitochondrial morphofunction using live-cell microscopy.

 

Authors

Iannetti EF, Smeitink JAM, Beyrath J, Willems PHGM, Koopman WJH.

 

Journal

Nature Protocols 11, 1693–1710 | doi:10.1038/nprot.2016.094. Published online

 


 

Mutations in Complex I Assembly Factor TMEM126B Result in Muscle Weakness and Isolated Complex I Deficiency.

 

Authors

Sánchez-Caballero L, Ruzzenente B, Bianchi L, Assouline Z, Barcia G, Metodiev MD, Rio M, Funalot B, van den Brand MA, Guerrero-Castillo S, Molenaar JP, Koolen D, Brandt U, Rodenburg RJ, Nijtmans LG, Rötig A.

 

Journal

Am J Hum Genet. 2016 Jun 29. pii: S0002-9297(16)30157-4. doi: 10.1016/j.ajhg.2016.05.022.

 


 

 

Unraveling the complexity of mitochondrial complex I assembly: A dynamic process.

 

Authors

Sánchez-Caballero L, Guerrero-Castillo S, Nijtmans L.

 

Journal

Biochim Biophys Acta. 2016 Jul;1857(7):980-90. doi: 10.1016/j.bbabio.2016.03.031. Epub 2016 Apr 1.

 


 

Sengers syndrome: six novel AGK mutations in seven new families and review of the phenotypic and mutational spectrum of 29 patients.

 

Authors

Haghighi A, Haack TB, Atiq M, Mottaghi H, Haghighi-Kakhki H, Bashir RA, Ahting U, Feichtinger RG, Mayr JA, Rötig A, Lebre AS, Klopstock T, Dworschak A, Pulido N, Saeed MA, Saleh-Gohari N, Holzerova E, Chinnery PF, Taylor RW, Prokisch H.

 

Journal

Orphanet J Rare Dis. 2014 Aug 20;9:119. doi: 10.1186/s13023-014-0119-3.

 


 

Human thioredoxin 2 deficiency impairs mitochondrial redox homeostasis and causes early-onset neurodegeneration.

 

Authors

Holzerova E, Danhauser K, Haack TB, Kremer LS, Melcher M, Ingold I, Kobayashi S, Terrile C, Wolf P, Schaper J, Mayatepek E, Baertling F, Friedmann Angeli JP, Conrad M, Strom TM, Meitinger T, Prokisch H, Distelmaier F.

 

Journal

Brain. 2016 Feb;139(Pt 2):346-54. doi: 10.1093/brain/awv350. Epub 2015 Dec 1.

 


 

Riboflavin-Responsive and -Non-responsive Mutations in FAD Synthase Cause Multiple Acyl-CoA Dehydrogenase and Combined Respiratory-Chain Deficiency 

 

Authors

Olsen RK, Koňaříková E, Giancaspero TA, Mosegaard S, Boczonadi V, Mataković L, Veauville-Merllié A, Terrile C, Schwarzmayr T, Haack TB, Auranen M, Leone P, Galluccio M, Imbard A, Gutierrez-Rios P, Palmfeldt J, Graf E, Vianey-Saban C, Oppenheim M, Schiff M, Pichard S, Rigal O, Pyle A, Chinnery PF, Konstantopoulou V, Möslinger D, Feichtinger RG, Talim B, Topaloglu H, Coskun T, Gucer S, Botta A, Pegoraro E, Malena A, Vergani L, Mazzà D, Zollino M, Ghezzi D, Acquaviva C, Tyni T, Boneh A, Meitinger T, Strom TM, Gregersen N, Mayr JA, Horvath R, Barile M, Prokisch H

 

Journal

Am J Hum Genet. 2016 Jun 2;98(6):1130-45. doi: 10.1016/j.ajhg.2016.04.006.

 


 

Defective lipid metabolism in neurodegeneration with brain iron accumulation (NBIA) syndromes: not only a matter of iron.

 

Authors

Colombelli C, Aoun M, Tiranti V.

 

Journal

J Inherit Metab Dis. 2015 Jan;38(1):123-36. doi: 10.1007/s10545-014-9770-z. Epub 2014 Oct 10.

 


 

Altered RNA metabolism due to a homozygous RBM7 mutation in a patient with spinal motor neuropathy

 

Authors

Giunta M, Edvardson S, Xu Y, Schuelke M, Gomez-Duran A, Boczonadi V, Elpeleg O, Müller JS and Horvath R.

 

Journal

Hum Mol Genet. 2016 Jul 15;25(14):2985-2996. Epub 2016 May 18. DOI:10.1093/hmg/ddw149

 


 

A unique combination of rare mitochondrial ribosomal RNA variants affects the kinetics of complex I assembly

 

Authors

Porcelli AM, Calvaruso MA, Iommarini L, Kurelac I, Zuntini R, Ferrari S and Gasparre G.

 

Journal

Int J Biochem Cell Biol. 2016 Jun;75:117-22. doi: 10.1016/j.biocel.2016.04.007.

 


 

A multi-parametric workflow for the prioritization of mitochondrial DNA variants of clinical interest

 

Authors

Santorsola M, Calabrese C, Girolimetti G, Diroma MA, Gasparre G and Attimonelli M.

 

Journal

Human Genetics. 2015 Nov 30. doi: 10.​1007/​s00439-015-1615-9

 


 

Exosomal Protein Deficiencies: How Abnormal RNA Metabolism Results in Childhood-Onset Neurological Diseases

 

Authors

Muller JS, Giunta M and Horvath R.

 

Journal

Journal of Neuromuscular Diseases. 2 (2015) S31–S37 DOI 10.3233/JND-150086

 

Comment by MEETer Giunta M.

Neurodegenerative disorders are a group of heterogenic diseases characterized by progressive degeneration and death of neuronal cells. Although many advances have been done in the recent years in the discovery of new pathogenic mechanisms of some neurodegenerative diseases, some questions remain unresolved.
Correct RNA processing (maturation and degradation) is being recognized as a major factor in the development of neurological disorders.
The exosome complex is the main RNA processing machinery within the cell, and its defective functions have been linked to the development of severe childhood onset neurological disorders such as pontocerebellar hypoplasia type 1 (PCH1), spinal muscular atrophy (SMA) and central nervous system hypomyelination.
The exosome complex is formed by 9 subunits. 6 of them forming the central structure of the complex with a central pore where the RNA passes through in order to be degraded, and 3 sub-units forming the “cap” of the complex (Fig.1), with RNA binding properties. The exosome is responsible for the degradation and maturation of many different types of RNAs: long non coding RNAs, mRNAs, tRNAs, defective or not functional RNAs (quality control functions) and degradation of RNAs for which only a transient expression is required (such as AU-rich element genes). RNA metabolism  is a step which needs to be finely tuned: each of these RNAs must be processed at the right time and in the right way. Accumulation of these molecules within the cell due to exosome complex defective functions or wrong processing can lead to cell dysfunction.
Such a high specificity of the exosome complex in metabolizing so many different types of RNA is guaranteed by the interaction with different co-factors which bind and carry toward the exosome, only specific subtypes of RNAs. These co-factors are the NEXT complex, the SKI complex and the TRAMP complex (Fig. 1). Why and how mutation on different exosome components affect specifically the neural system is still a matter of investigation. It is known that other types of mutations in RNA processing molecules cause neurological disorders such (e.g. tRNA splicing endonuclease subunit genes (PCH2, PCH4, PCH5) or mitochondrial tRNA synthetases (PCH6). Splicing of the pre-mRNAs by the spliceosome depends on small nuclear ribonucleoproteins (snRNPs), which require Spinal Motor Neuron 1 (SMN1) protein for their assembly and defect of SMN1 results in spinal muscular atrophy (SMA). The fact that defects in RNA processing and degradation can cause severe neurological disorders emphasises the role of the RNA metabolism for the development and maintenance of cells in the nervous system. It remains to be determined why neuronal cells are more vulnerable to changes in RNA levels than other cell types.
Giunta Michele, MEET Fellow, University of Newcastle Upon Tyne
 

 

Zebrafish as a model system in RNA metabolism deficiencies

 

Authors

Giunta M, Müller JS, Boczonadi V, Elpeleg O, Edvardson S, Chinnery PF, Horvath R.

 

Poster presentation at: 8th UK Neuromuscular Translational Research Conference19-20 March 2015, Newcastle upon Tyne

 

Comment by MEETer Giunta M. 

The exosome is a multi sub-unit complex involved in gene expression regulation through RNA degradation. It is considered the main RNA degradation machinery within the cell and it is known to play a key role in the correct development of the neural system.
The exosome complex degradation system works via a highly specific mechanism, in order to metabolise only those types of RNA which need to be degraded (e.g. defective or non-functional RNAs, RNAs for which only a transient expression is required).
Other that being involved in the degradation process of many different types of RNAs through different pathways, the exosome complex is also involved in maturation and processing  of pre-mRNA.
Such a high specificity of the exosome complex in performing so many different tasks, is guaranteed by the interaction with different co-factors, which bind and carry toward the exosome complex only specific subtypes of RNA. We recently identified a single patient with SMA-like symptoms, with a mutation on a gene (RBM7) which belongs to a co-factor of the exosome complex (NEXT complex).
In order to understand the roles of different sub-units/co-factors of the exosome complex in the development of the neural system, we decided to perform functional studies using a tropical freshwater fish known as “zebrafish” (Danio rerio) as a model system. Zebrafish is a very useful tool to study neurodevelopmental and neurodegenerative disorders, used by many research groups all over the world. Furthermore, functions of the exosome complex are known to be very highly conserved through all forms of life - from bacteria to humans - including zebrafish. Mimicking the mutations using a special chemical compound (morpholino) we impaired the functionality of specific sub-units and co-factors of the exosome complex, resembling what observed in human. We show that the three target genes (exosc3, exosc8 and rbm7) are essential for correct development of cerebellum and the growth of motor-neuron axons confirming their role in the pathogenicity of some severe neurological disorders.
Giunta Michele, MEET Fellow, University of Newcastle Upon Tyne

 


 

Mitochondrial diseases: Drosophilia melanogaster as a model to evaluate potential therapeutics.

 

Authors

Foriel S, Willems P, Smeitink J, Schenck A, Beyrath J.

 

Journal

Int J Biochem Cell Biol. 2015 Feb 7. doi: 10.1016/j.biocel.2015.01.024

 

Comment by MEETer Foriel S.

Mitochondrial diseases are very variable in their causes, symptoms and severity. This complicates highly the understanding of the overall family of mitochondrial diseases. In order to better understand a particular disease but also to try to find new potential treatments, the use of models that resemble what different patients are suffering from (genetic mutations, symptoms) is crucial. In this review, we made a list of the fruit fly (Drosophila melanogaster) models that have already been developed and could be used to elucidate how each particular mitochondrial disease develops and could be treated.

Foriel Sarah, MEET Fellow, Khondrion, Nijmegen, Netherlands

 


 

The complex crosstalk between mitochondria and the nucleus: What goes in between?

 

Authors

Cagin U, Enriquez JA.

 

Journal

Int J Biochem Cell Biol. 2015 Feb 7. doi: 10.1016/j.biocel.2015.01.026.


 

Mitochondria: Much ado about nothing? How dangerous is reactive oxygen species production?

 

Authors

Holzerová E, Prokisch H.

 

Journal

Int J Biochem Cell Biol. 2015 Feb 7. doi: 10.1016/j.biocel.2015.01.021.

 


 

Mitochondria: A crossroads for lipid metabolism defect in neurodegeneration with brain iron accumulation diseases.

 

Authors

Aoun M, Tiranti V.

 

Journal

Int J Biochem Cell Biol. 2015 Feb 7. doi: 10.1016/j.biocel.2015.01.018.

 

Comment by MEETer Aoun M.

Pantothenate Kinase-Associated Neurodegeneration (PKAN) is an autosomal recessive disorder of coenzyme A homeostasis caused by defects in the mitochondrial pantothenate kinase 2 (pank2). Patients with PKAN present progressive neurological decline, brain iron accumulation and movement disorder. Brain iron accumulation and mitochondrial disorders could, directly or indirectly, cause brain injury, neuroinflammation, oxidative stress, thus increasing neuronal cell death and leading to a rapid progression of the pathology. To date, many questions of pathogenesis remain unanswered. But now, investigators have available animal and cellular models of disease to enable many of these to be answered and to search for new therapies.

Aoun Manar, MEET Fellow, FINCB

 


 

A comprehensive characterization of mitochondrial DNA mutations in glioblastoma multiforme.

 

Authors

Vidone M, Clima R, Santorsola M, Calabrese C, Girolimetti G, Kurelac I, Amato LB, Iommarini L, Trevisan E, Leone M, Soffietti R, Morra I, Faccani G, Attimonelli M, Porcelli AM, Gasparre G.

 

Journal

Int J Biochem Cell Biol. 2015 Feb 7. doi: 10.1016/j.biocel.2015.01.027

 


 

Toward high-content screening of mitochondrial morphology and membrane potential in living cells.

 

Authors

Iannetti EF, Willems PH, Pellegrini M, Beyrath J, Smeitink JA, Blanchet L, Koopman WJ.

 

Journal

Int J Biochem Cell Biol. 2015 Feb 8. doi: 10.1016/j.biocel.2015.01.020.

 

Comment by MEETer Iannetti EF.

Mitochondria are substructure of the cells involved in various key physiological processes.
The structure and the function of mitochondria continuously variate according to energetic demand and stress conditions. In this review article, we report the latest advances in fluorescence microscopy technology to study the relationship between function and structure of mitochondria. These novel strategies seem to be ideally suited to study new drugs to be used in therapeutics development for mitochondrial disease.

Iannetti Eligio, MEET Fellow, Khondrion, Nijmegen, Netherlands

 


 

Investigating the role of the physiological isoform switch of cytochrome c oxidase subunits in reversible mitochondrial disease.

 

Authors

Boczonadi V, Giunta M, Lane M, Tulinius M, Schara U, Horvath R.

 

Journal

Int J Biochem Cell Biol. 2015 Feb 7. doi: 10.1016/j.biocel.2015.01.025.

 

Comment by MEETer Giunta M.

Reversible Infantile Respiratory Chain Deficiency (RIRCD) is a mitochondrial myopathy with a peculiar disease course. Patients are born with severe muscle weakness, respiratory and feeding difficulties requiring vigorous life supporting measures, but if they survive the first weeks or months of life they spontaneously recover by 1 year of age. Our group identified a mutation on the mitochondrial tRNAGlu which is present in all affected and non-affected family members. It is thought to be responsible for the degradation of the mt-tRNAGlu itself and consequent impairment of mitochondrial translation during the symptomatic phase of the disease. Although the finding of this mutation can be considered as a reliable diagnostic tool to discriminate the reversible form of this disease from the lethal one, many questions such as why only about 30% of the carriers of the mutation are symptomatic, the reason(s) of the tissue specificity and of the spontaneous recovery remain unanswered.
In order to investigate if a switch of different mitochondrial proteins isoforms might be the trigger of the clinical manifestation, we analysed the expression of COX6A and COX7A subunits of cytochrome c oxidase during the development in human and mice.
We demonstrate a developmental isoform switch of COX6A and COX7A subunits in human and mouse skeletal muscle. Our data in follow-up biopsies of patients with RIRCD indicate that the physiological isoform switch does not contribute to the clinical manifestation and to the spontaneous recovery of this disease. However, understanding developmental changes of the different cytochrome c oxidase isoforms may have implications for other mitochondrial diseases.
Giunta Michele, MEET Fellow, University of Newcastle Upon Tyne

 


 

MITOCHONDRIA: Biogenesis and mitophagy balance in segregation and clonal expansion of mitochondrial DNA mutations

 

Authors

Carelli V, Maresca A, Caporali L, Trifunov S, Zanna C, Rugolo M.

 

Journal

Int J Biochem Cell Biol. 2015 Feb 6. doi: 10.1016/j.biocel.2015.01.023

 


 

Targeting respiratory complex I to prevent the Warburg effect

 

Authors

Vatrinet R, Iommarini L, Kurelac I, De Luise M, Gasparre G, Porcelli AM.

 

Journal

Int J Biochem Cell Biol. 2015 Feb 7 doi: 10.1016/j.biocel.2015.01.017

 

Comment by MEETer Vatrinet R.

Cancer metabolism is a new and always expanding field of cancer research. Malignant cells, unlike healthy cells, display increased glucose consumption in order to highly proliferate. This prominent feature is called the Warburg effect. Previous studies in our laboratories have highlighted the involvement of a particular enzyme, the mitochondrial respiratory complex I within the mitochondria, in sustaining this behavior. The complex I can therefore be considered a target for potential anticancer strategy, as discussed in detail in this review.

Vatrinet Renaud, MEET Fellow, University of Bologna

 


 

MITOCHONDRIA: The ketogenic diet-a metabolism-based therapy

 

Authors

Vidali SAminzadeh S, Lambert B, Rutherford T, Sperl W, Kofler B, Feichtinger RG.

 

Journal

Int J Biochem Cell Biol. 2015 Feb 6 doi: 10.1016/j.biocel.2015.01.022.

 

Comment by MEETer Vidali S.

Cells produce energy mostly through organelles called mitochondria. They transform either carbohydrate, fat or protein into ATP, the primary cellular energy fuel.
The ketogenic diet is a high fat and low carbohydrate diet that allows cells to utilize fat as primary energy source. This diet is already used for the treatment of diseases with defective glucose metabolism.
Cancer cells mainly relay on glucose consumption. Thus, ketogenic diet, reducing glucose levels, has been proven beneficial in cancer therapy.

Vidali Silvia, MEET Fellow, SALK

 


 

Energy metabolism in neuroblastoma and Wilms tumor

 

Authors

Aminzadeh S, Vidali S, Sperl W, Kofler B, Feichtinger RG.

 

Journal

Translational Pediatrics 2015 Jan 27. doi: 10.3978/j.issn.2224-4336.2015.01.04.

 

Comment by MEETer Vidali S.

Normal cells produce their energy mainly via the respiration of little organelles called mitochondria. Many cancer cells reduce their mitochondrial respiration and increase glucose uptake, receiving their energy mainly by the process of glucose degradation (glycolysis).
Neuroblastoma (NB) and Wilms tumor (WT) are the two most frequent solid tumors in children. Both types of tumors seem to decrease their respiration, albeit the mechanisms how to achieve this differ.
This review provides an overview on the current knowledge on these metabolic alterations.

Vidali Silvia, MEET Fellow, SALK

 


 

Mitochondrial changes in endometrial carcinoma: Possible role in tumor diagnosis and prognosis (Review)

 

Authors

Cormio A, Cormio G, Musicco C, Sardanelli AM, Gasparre G, Gadaleta MN

 

Journal

Oncol Rep. 2014 Dec 22. doi: 10.3892/or.2014.3690.

 


 

Expanding the clinical and molecular spectrum of thiamine pyrophosphokinase deficiency: A treatable neurological disorder caused by TPK1 mutations.

 

Authors

Banka S, de Goede C, Yue WW, Morris A.A.M, von Bremen B, Chandler K.E, Feichtinger RG, Hart C, Khan N, Lunzer V, Mataković L, Marquardt T, Makowski C, Prokisch H, Debus O, Nosaka K, Sonwalkar H, Zimmermann FA, Sperl W, Mayr JA.

 

Journal

Mol. Genet. Metab. 2014 Oct 5. doi:10.1016/j.ymgme.2014.09.010

 

Comment by MEETer Mataković L.

Here we report on a human enzyme called thiamine pyrophosphokinase, or TPK. The enzyme, which converts the vitamin B1 or thiamine into thiamine pyrophosphate, a cofactor or helper molecule which is needed by several important mitochondrial enzymes to function properly. Our studies have shown that there are genetic mutations that make people's enzymes less efficient than normal, and that simple supplementation with vitamin B1 can restore these defective enzymes to normal activity.

Mataković Lavinija, MEET Fellow, SALK

 


 

Sengers syndrome: six novel AGK mutations in seven new families and review of the phenotypic and mutational spectrum of 29 patients.

 

Authors

Haghighi A, Haack TB, Atiq M, Mottaghi H, Haghighi-Kakhki H, Bashir RA, AhtingU, Feichtinger RG, Mayr JA, Rötig A, Lebre AS, Klopstock T, Dworschak A, Pulido N, Saeed MA, Saleh-Gohari N, Holzerova E, Chinnery PF, Taylor RW, Prokisch H.

 

Journal

Orphanet J Rare Dis. 2014 Aug 20. doi: 10.1186/s13023-014-0119-3.

 


 

EXOSC8 mutations alter mRNA metabolism and cause hypomyelination with spinal muscular atrophy and cerebellar hypoplasia.

 

Authors

Boczonadi V, Müller JS, Pyle A, Munkley J, Dor T, Quartararo J, Ferrero I, Karcagi V, Giunta M, Polvikoski T, Birchall D, Princzinger A, Cinnamon Y, Lützkendorf S, Piko H, Reza M, Florez L, Santibanez-Koref M, Griffin H, Schuelke M, Elpeleg O, Kalaydjieva L, Lochmüller H, Elliott DJ, Chinnery PF, Edvardson S, Horvath R.

 

Journal

Nat Commun. 2014 Jul 3. doi: 10.1038/ncomms5287.

 

Comment by MEETer Giunta M.

RNA metabolism is an essential step in order to regulate gene expression during development. The exosome is a multi-protein complex which is the main RNA degradation machinery within the cell and its defective functionality is known to be causative of severe childhood-onset neurological disorder such as pontocerebellar hypoplasia type 1 (PCH1). We identified 22 patients from 3 different families with overlapping symptoms of  PCH, spinal muscular atrophy (SMA) and central nervous system hypomyelination. Through genome sequencing we identified a new candidate mutation which is responsible for the disease, situated in EXOSC8 gene, a sub-unit of the exosome complex. Using different functional approaches we demonstrate that EXOSC8 gene is involved in correct myelination (myelin is the substance that allows neurons to be isolated and transmit the neuronal stimuli through the whole length of the neurons).
Myelin Basic Protein (MBP) is a fundamental protein in myelination process (Fig. 1) which expression is tightly regulated (also) by the exosome complex. We observed an overexpression of MBP in patients’ cells as well as in biological model systems together with hypomyelination features. As it often happens, too much of a protein is not good for the cell. Therefore, overexpression of MBP, caused by impaired functionality of the exosome complex, due to the mutation on EXOSC8, is thought to be responsible for the hypomyelination observed in patients. These findings provide new knowledge on mechanisms of neurodegeneration and a new target gene for potential future therapies.
Giunta Michele, MEET Fellow, University of Newcastle Upon Tyne
 

MEET Project - Grant Agreement no. 317433 - Start date 14th Jan 2013 - Final date 13th Jan 2017 - Privacy and Cookies policy