Molecular genetics and metabolism最新文献

{"title":"Restoration of peripheral neuropathy in Fabry mice via intrathecal administration of an adeno-associated virus vector encoding mGLA cDNA","authors":"Takashi Higuchi ,&nbsp;Yohta Shimada ,&nbsp;Yukari Takahashi ,&nbsp;Fusao Kato ,&nbsp;Toya Ohashi ,&nbsp;Hiroshi Kobayashi","doi":"10.1016/j.ymgme.2024.108545","DOIUrl":"10.1016/j.ymgme.2024.108545","url":null,"abstract":"<div><p>Anderson-Fabry disease (FD) is an X-linked lysosomal storage disorder caused by a pathological variant of the α-galactosidase A (GLA) gene that results in deficient GLA activity. GLA deficiency leads to the accumulation of globotriaosylceramide (Gb3) and lyso-Gb3 in many tissues. A certain number of FD patients have burning pain or acroparesthesia in the feet and hands since childhood. Enzyme replacement therapy (ERT) is available for FD patients. However, ERT does not dramatically improve these FD-related peripheral neuropathic pain. We generated an adeno-associated virus serotype PHP.eB (AAV-PHP.eB) vector encoding mouse GLA cDNA, which was administered to FD mice intrathecally (it) or intravenously (iv). In the it-administered AAV (it-AAV) FD mice, the GLA enzyme activity in the lumbar dorsal root ganglion (DRG) was significantly greater than that in the untreated (NT) FD mice, and the level of activity was similar to that in wild-type (WT) B6 mice. However, in iv-administered AAV (iv-AAV) FD mice, GLA activity in the DRG did not increase compared to that in NT FD mice. Gb3 storage in the DRG of it-AAV FD mice was reduced compared to that in the DRG of NT FD mice. However, compared with NT FD mice, iv-AAV FD mice did not exhibit a significant reduction in the expression of the Gb3 substrate. Compared with WT mice, FD mice were thermally hyposensitive at 52 °C according to the hot plate test. The it-AAV FD mice showed significant recovery from thermal hyposensitivity. However, the iv-AAV FD mice did not exhibit significant improvement in thermal hyposensitivity. These results suggest that the intrathecal delivery of AAV-PHP.eB-mGLA may be a valuable tool for the treatment of FD-related peripheral neuropathic pain.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"143 1","pages":"Article 108545"},"PeriodicalIF":3.7,"publicationDate":"2024-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141788703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neurocognitive assessment platform for clinical trials in PKU: White paper developed by the NPKUA neurocognitive workgroup","authors":"Susan E. Waisbren ,&nbsp;Shawn E. Christ ,&nbsp;Deborah A. Bilder ,&nbsp;Kendra J. Bjoraker ,&nbsp;Scout Bolton ,&nbsp;Sarah Chamberlin ,&nbsp;Mitzie L. Grant ,&nbsp;Darren M. Janzen ,&nbsp;Rachel Katz ,&nbsp;Eugene Lubliner ,&nbsp;Arianna Martin ,&nbsp;Kelsey McQueen ,&nbsp;Olga Moshkovich ,&nbsp;Mina Nguyen-Driver ,&nbsp;Soo Shim ,&nbsp;Arianna K. Stefanatos ,&nbsp;Greta Wilkening ,&nbsp;Cary Harding","doi":"10.1016/j.ymgme.2024.108555","DOIUrl":"10.1016/j.ymgme.2024.108555","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"143 1","pages":"Article 108555"},"PeriodicalIF":3.7,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141846568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Natural history of deoxyguanosine kinase deficiency","authors":"Nandaki Keshavan ,&nbsp;Shamima Rahman","doi":"10.1016/j.ymgme.2024.108554","DOIUrl":"10.1016/j.ymgme.2024.108554","url":null,"abstract":"<div><h3>Background and objectives</h3><p>Deoxyguanosine kinase deficiency is one genetic cause of mtDNA depletion syndrome. Its major phenotypes include neonatal/infantile-onset hepatocerebral disease, isolated hepatic disease and myopathic disease. In this retrospective study, we seek to describe the natural history of deoxyguanosine kinase deficiency and identify any genotype-phenotype correlations.</p></div><div><h3>Methods</h3><p>Retrospective literature search and collation of data from genetically confirmed cases of deoxyguanosine kinase deficiency.</p></div><div><h3>Results</h3><p>173 cases of DGUOK deficiency were identified. Neonatal/infantile-onset hepatocerebral disease accounted for 128 (74%) of cases. Isolated liver disease was seen in 36 (21%) and myopathic disease in 9 (5%) of cases. The most frequently involved systems were liver (98%), brain (75%), growth (46%) and gastrointestinal tract (26%). Infantile-onset disease typically presented with cholestatic jaundice and lactic acidosis. Neurological involvement included hypotonia, nystagmus and developmental delay with MRI brain abnormalities in about half of cases. Missense variants accounted for 48% of all pathogenic variants while variants resulting in truncated transcripts accounted for 39%. Prognosis was poor, especially for neonatal/ infantile-onset hepatocerebral disease for which 1 year survival was 11%. Twenty-three patients received liver transplants, of whom 12 died within 2 years of transplant. Patients with two truncating variants had a higher risk of death and were more likely to have the neonatal/infantile-onset hepatocerebral disease phenotype. No blood biomarker predictive of neurological involvement was identified. Earlier onset correlated with increased mortality.</p></div><div><h3>Conclusions</h3><p>There is a narrow window for therapeutic intervention. For the hepatocerebral disease phenotype, median age of onset was 1 month while the median age of death was 6.5 months implying rapid disease progression.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"143 1","pages":"Article 108554"},"PeriodicalIF":3.7,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1096719224004384/pdfft?md5=f5b762db61c33b39991724895c9ec07b&pid=1-s2.0-S1096719224004384-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141775533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Initial results from the PHEFREE longitudinal natural history study: Cross-sectional observations in a cohort of individuals with phenylalanine hydroxylase (PAH) deficiency","authors":"Shawn E. Christ ,&nbsp;Georgianne Arnold ,&nbsp;Uta Lichter-Konecki ,&nbsp;Gerard T. Berry ,&nbsp;Dorothy K. Grange ,&nbsp;Cary O. Harding ,&nbsp;Elaina Jurecki ,&nbsp;Harvey Levy ,&nbsp;Nicola Longo ,&nbsp;Hadley Morotti ,&nbsp;Stephanie Sacharow ,&nbsp;Janet Thomas ,&nbsp;Desiree A. White","doi":"10.1016/j.ymgme.2024.108541","DOIUrl":"10.1016/j.ymgme.2024.108541","url":null,"abstract":"<div><p>Over fifty years have passed since the last large scale longitudinal study of individuals with PAH deficiency in the U.S. Since then, there have been significant changes in terms of treatment recommendations as well as treatment options. The Phenylalanine Families and Researchers Exploring Evidence (PHEFREE) Consortium was recently established to collect a more up-to-date and extensive longitudinal natural history in individuals with phenylketonuria across the lifespan. In the present paper, we describe the structure and methods of the PHEFREE longitudinal study protocol and report cross-sectional data from an initial sample of 73 individuals (5 months to 54 years of age) with PAH deficiency who have enrolled. Looking forward, the study holds the promise for advancing the field on several fronts including the validation of novel neurocognitive tools for assessment in individuals with PKU as well as evaluation of the long-term effects of changes in metabolic control (e.g., effects of Phe-lowering therapies) on outcome.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"143 1","pages":"Article 108541"},"PeriodicalIF":3.7,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141766744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Executive functions & metabolic control in phenylketonuria (PKU) and mild hyperphenylalaninemia (mHPA)","authors":"Anne Tomm ,&nbsp;Alena G. Thiele ,&nbsp;Carmen Rohde ,&nbsp;Stefanie Kirmse ,&nbsp;Wieland Kiess ,&nbsp;Skadi Beblo","doi":"10.1016/j.ymgme.2024.108544","DOIUrl":"10.1016/j.ymgme.2024.108544","url":null,"abstract":"<div><h3>Background</h3><p>Due to newborn screening and early treatment, patients with phenylketonuria (PKU) and mild hyperphenylalaninemia (mHPA) develop largely normal, in terms of IQ testing and academic attainment. However, the impact of metabolic control in various stages of development on more complex cognitive abilities, i.e. executive functions (EF), is still unclear.</p></div><div><h3>Methods</h3><p>EFs were tested in 28 patients with PKU/mHPA, aged 8–17 years, identified by newborn screening and continuously treated. The relation to current (testing day &amp; past 10 phenylalanine (Phe) values) and long-term metabolic control (age periods: childhood &lt;6, 6–10, adolescence &gt;10 years, lifetime Phe) was analyzed.</p></div><div><h3>Results</h3><p>EFs were in the lower normative range (IQR of T-values: 47.35–51.00). Patients reaction time was significantly slower than the population mean (divided attention/TAP: median 40, <em>p</em> &lt; 0.01). Both, long-term and current metabolic control correlated with performance in EF tests: Higher current Phe impaired reaction times (Go/No-Go, <em>r</em> = −0.387; working memory, <em>r</em> = −0.425; <em>p</em> &lt; 0.05) and performance in planning ability (ToL <em>r</em> = −0.465, p &lt; 0.01). Higher long-term Phe values both in childhood and adolescence mainly affected attention (omissions/TAP <em>r</em> = −0.357 and − 0.490, respectively, both p &lt; 0.05) as well as planning ability (ToL <em>r</em> = −0.422 and − 0.387, adolescence and lifetime, p &lt; 0.05).</p></div><div><h3>Conclusion</h3><p>Current and long-term metabolic control in PKU/mHPA, including the adolescent period, influence EFs, especially affecting reaction time and planning abilities. This should be taken into account in patient counselling.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"143 1","pages":"Article 108544"},"PeriodicalIF":3.7,"publicationDate":"2024-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1096719224004281/pdfft?md5=9541eec1bba19c4d2c831ebb9c6eeb83&pid=1-s2.0-S1096719224004281-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141766743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New findings about neuropathological outcomes in the PKU mouse throughout lifespan","authors":"Alessandro Bregalda ,&nbsp;Claudia Carducci ,&nbsp;Tiziana Pascucci ,&nbsp;Patrizia Ambrogini ,&nbsp;Stefano Sartini ,&nbsp;Francesca Pierigè ,&nbsp;Emanuele di Carlo ,&nbsp;Elena Fiori ,&nbsp;Donald Ielpo ,&nbsp;Marica Pagliarini ,&nbsp;Vincenzo Leuzzi ,&nbsp;Mauro Magnani ,&nbsp;Luigia Rossi","doi":"10.1016/j.ymgme.2024.108543","DOIUrl":"10.1016/j.ymgme.2024.108543","url":null,"abstract":"<div><p>Phenylketonuria (PKU, OMIM <span><span>261600</span><svg><path></path></svg></span>) is a genetic disorder caused by a deficiency of the hepatic enzyme phenylalanine hydroxylase (PAH). If left untreated, PKU leads to systemic phenylalanine (Phe) accumulation, which can result in irreversible brain damage and intellectual disabilities. In the last 60 years, early and strict dietary restriction of phenylalanine (Phe) intake proved to prevent the severe clinical phenotype of untreated PKU. While the specific mechanisms through which phenylalanine causes brain damage are still poorly understood, preclinical models have been deeply explored to characterize the neurotoxic effect of Phe on neurodevelopmental processes. At the same time, that on the aging brain still needs to be explored. In the brain of untreated PAH^{Enu2(−/−)} mouse, we previously reported a reduction of myelin basic protein (MBP) during postnatal development up to 60 PND. Later in the diseased mouse's life, a spontaneous and persistent restoration of MBP was detected. In this present longitudinal study, ranging from 14 to 540 post-natal days (PND) of untreated PAH^{Enu2(−/−)} mice, we further investigated: a) the long-life consistency of two Phe-related brain metabolic alterations, such as large neutral amino acids (LNAA) and biogenic amine neurotransmitters' depletion; b) the outcome of locomotor functions during the same life span; c) the integrity of myelin as assessed ex vivo by central (hippocampus) and peripheral (extensor digitorum longus-sciatic nerve) action potential conduction velocities. In contrast with the results of other studies, brain Leu, Ile, and Val concentrations were not significantly altered in the brain PAH^{Enu2(−/−)} mouse. On the other hand, 3-O-Methyldopa (3-OMD, a biomarker of L-DOPA), serotonin, and its associated metabolites were reduced throughout most of the considered time points, with consistent reductions observed prevalently from 14 to 60 PND. Normal saltatory conduction was restored after 60 PND and remained normal at the last examination at 360 PND, resulting nonetheless in a persistent locomotor impairment throughout a lifetime. These new findings contribute to laying the foundations for the preclinical characterization of aging in PKU, confirming neurotransmitter defects as consistent metabolic traits. LNAAs have a minor role, if any, in brain damage pathogenesis. Transient myelin synthesis failure may impact brain connectivity during postnatal development but not nervous signal conduction.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"143 1","pages":"Article 108543"},"PeriodicalIF":3.7,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141759852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extending diagnostic practices in gyrate atrophy: Enzymatic characterization and the development of an in vitro pyridoxine responsiveness assay","authors":"Berith M. Balfoort ,&nbsp;Gioena Pampalone ,&nbsp;Jos P.N. Ruiter ,&nbsp;Simone W. Denis ,&nbsp;Marion M. Brands ,&nbsp;GACR Bird's Eye View Consortium ,&nbsp;Corrie Timmer ,&nbsp;Margreet A.E.M. Wagenmakers ,&nbsp;Ronald J.A. Wanders ,&nbsp;Clara D. van Karnebeek ,&nbsp;Barbara Cellini ,&nbsp;Riekelt H. Houtkooper ,&nbsp;Sacha Ferdinandusse","doi":"10.1016/j.ymgme.2024.108542","DOIUrl":"10.1016/j.ymgme.2024.108542","url":null,"abstract":"<div><p>Gyrate atrophy of the choroid and retina (GACR) is caused by pathogenic biallelic variants in the gene encoding ornithine-δ-aminotransferase (OAT), and is characterized by progressive vision loss leading to blindness. OAT is a pyridoxal-5′-phosphate (PLP) dependent enzyme that is mainly involved in ornithine catabolism, and patients with a deficiency develop profound hyperornithinemia. Therapy is aimed at lowering ornithine levels through dietary arginine restriction and, in some cases, through enhancement of OAT activity <em>via</em> supraphysiological dosages of pyridoxine. In this study, we aimed to extend diagnostic practices in GACR by extensively characterizing the consequences of pathogenic variants on the enzymatic function of OAT, both at the level of the enzyme itself as well as the flux through the ornithine degradative pathway. In addition, we developed an <em>in vitro</em> pyridoxine responsiveness assay. We identified 14 different pathogenic variants, of which one variant was present in all patients of Dutch ancestry (p.(Gly353Asp)). In most patients the enzymatic activity of OAT as well as the rate of [¹⁴C]-ornithine flux was below the limit of quantification (LOQ). Apart from our positive control, only one patient cell line showed responsiveness to pyridoxine <em>in vitro</em>, which is in line with the reported <em>in vivo</em> pyridoxine responsiveness in this patient. None of the patients harboring the p.(Gly353Asp) substitution were responsive to pyridoxine <em>in vivo</em> or <em>in vitro</em>. <em>In silico</em> analysis and small-scale expression experiments showed that this variant causes a folding defect, leading to increased aggregation properties that could not be rescued by PLP. Using these results, we developed a diagnostic pipeline for new patients suspected of having GACR. Adding OAT enzymatic analyses and <em>in vitro</em> pyridoxine responsiveness to diagnostic practices will not only increase knowledge on the consequences of pathogenic variants in <em>OAT</em>, but will also enable expectation management for therapeutic modalities, thus eventually improving clinical care.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"143 1","pages":"Article 108542"},"PeriodicalIF":3.7,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1096719224004268/pdfft?md5=7e24bdb6141211ae4368d0892da3e27a&pid=1-s2.0-S1096719224004268-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141759851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HepG2 PMM2-CDG knockout model: A versatile platform for variant and therapeutic evaluation","authors":"Alicia Vilas ,&nbsp;Álvaro Briso-Montiano ,&nbsp;Cristina Segovia-Falquina ,&nbsp;Arturo Martín-Martínez ,&nbsp;Alejandro Soriano-Sexto ,&nbsp;Diana Gallego ,&nbsp;Vera Ruiz-Montés ,&nbsp;Alejandra Gámez ,&nbsp;Belén Pérez","doi":"10.1016/j.ymgme.2024.108538","DOIUrl":"10.1016/j.ymgme.2024.108538","url":null,"abstract":"<div><p>Phosphomannomutase 2 deficiency (PMM2-CDG), the most frequent congenital disorder of glycosylation, is an autosomal recessive disease caused by biallelic pathogenic variants in the <em>PMM2</em> gene. There is no cure for this multisystemic syndrome. Some of the therapeutic approaches that are currently in development include mannose-1-phosphate replacement therapy, drug repurposing, and the use of small chemical molecules to correct folding defects. Preclinical models are needed to evaluate the efficacy of treatments to overcome the high lethality of the available animal model. In addition, the number of variants with unknown significance is increasing in clinical settings. This study presents the generation of a cellular disease model by knocking out the <em>PMM2</em> gene in the hepatoma HepG2 cell line using CRISPR-Cas9 gene editing. The HepG2 knockout model accurately replicates the PMM2-CDG phenotype, exhibiting a complete absence of PMM2 protein and mRNA, a 90% decrease in PMM enzymatic activity, and altered ICAM-1, LAMP1 and A1AT glycoprotein patterns. The evaluation of <em>PMM2</em> disease-causing variants validates the model's utility for studying new <em>PMM2</em> clinical variants, providing insights for diagnosis and potentially for evaluating therapies. A CRISPR-Cas9-generated HepG2 knockout model accurately recapitulates the PMM2-CDG phenotype, providing a valuable tool for assessing disease-causing variants and advancing therapeutic strategies.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"143 1","pages":"Article 108538"},"PeriodicalIF":3.7,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1096719224004220/pdfft?md5=d8d6d170e864f8bf3eb685da8f456edd&pid=1-s2.0-S1096719224004220-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141845840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pro-cathepsin D prevents aberrant protein aggregation dependent on endoplasmic reticulum protein CLN6","authors":"Yuki Shiro,&nbsp;Syouichi Katayama,&nbsp;Haruka Tsukamoto,&nbsp;Tetsuo Yamazaki","doi":"10.1016/j.ymgme.2024.108539","DOIUrl":"10.1016/j.ymgme.2024.108539","url":null,"abstract":"<div><p>We previously expressed a chimeric protein in which the small heat-shock protein αB-crystallin (αBC) is fused at its N-terminus to the C-terminus of the first transmembrane segment of the endoplasmic reticulum (ER) protein mitsugumin 23 and confirmed its localization to the ER. Moreover, overexpression of this N-terminally modified αBC was shown to prevent the aggregation of the coexpressed R120G αBC variant, which is highly aggregation-prone and associated with the hereditary myopathy αB-crystallinopathy. To uncover a molecular mechanism by which the ER-anchored αBC negatively regulates the protein aggregation, we isolated proteins that bind to the ER-anchored αBC and identified the lysosomal protease cathepsin D (CTSD) as one such interacting protein. Proteolytically active CTSD is produced by multi-step processing of pro-cathepsin D (proCTSD), which is initially synthesized in the ER and delivered to lysosomes. When overexpressed, CTSD itself prevented the coexpressed R120G αBC variant from aggregating. This anti-aggregate activity was also elicited upon overexpression of the W383C CTSD variant, which is predominantly sequestered in the ER and consequently remains unprocessed, suggesting that proCTSD, rather than mature CTSD, serves to suppress the aggregation of the R120G αBC variant. Meanwhile, overexpression of the A58V CTSD variant, which is identical to wild-type CTSD except for the Ala58Val substitution within the pro-peptide, did not suppress the protein aggregation, indicating that the integrity of the pro-peptide is required for proCTSD to exert its anti-aggregate activity. Based on our previous finding that overexpression of the ER transmembrane protein CLN6 (ceroid-lipofuscinosis, neuronal 6), identified as an interacting protein of the ER-anchored αBC, prevents the R120G αBC variant from aggregating, the CLN6-proCTSD coupling was hypothesized to underpin the functionality of proCTSD within the ER. Indeed, CTSD, when overexpressed in CLN6-depleted cells, was unable to exert its anti-aggregate activity, supporting our view. Collectively, we show here that proCTSD prevents the protein aggregation through the functional association with CLN6 in the microenvironment surrounding the ER membrane, shedding light on a novel aspect of proCTSD and its potential involvement in CTSD-related disorders characterized by the accumulation of aberrant protein aggregates.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"143 1","pages":"Article 108539"},"PeriodicalIF":3.7,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141729476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The pyruvate dehydrogenase complex at the epigenetic crossroads of acetylation and lactylation","authors":"Peter W. Stacpoole ,&nbsp;Carolyn O. Dirain","doi":"10.1016/j.ymgme.2024.108540","DOIUrl":"10.1016/j.ymgme.2024.108540","url":null,"abstract":"<div><p>The pyruvate dehydrogenase complex (PDC) is remarkable for its size and structure as well as for its physiological and pathological importance. Its canonical location is in the mitochondrial matrix, where it primes the tricarboxylic acid (TCA) cycle by decarboxylating glycolytically-derived pyruvate to acetyl-CoA. Less well appreciated is its role in helping to shape the epigenetic landscape, from early development throughout mammalian life by its ability to “moonlight” in the nucleus, with major repercussions for human healthspan and lifespan. The PDC's influence on two crucial modifiers of the epigenome, acetylation and lactylation, is the focus of this brief review.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"143 1","pages":"Article 108540"},"PeriodicalIF":3.7,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141788704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}