Huntingtin HTT1a is generated in a CAG repeat-length-dependent manner in human tissues DOI Creative Commons

Franziska Hoschek,

Julia Natan,

Maximilian Wagner

et al.

Molecular Medicine, Journal Year: 2024, Volume and Issue: 30(1)

Published: March 8, 2024

Abstract Background The disease-causing mutation in Huntington disease (HD) is a CAG trinucleotide expansion the huntingtin ( HTT ) gene. mutated tract results production of small RNA, HTT1a , coding for only exon 1 HTT. generated by block splicing reaction to 2 followed cleavage intron and polyadenylation. Translation leads expression highly toxic protein fragment. We have previously shown that levels mouse models HD dependent on repeat length. However, these data are lacking human tissues. Methods To answer this question, we developed sensitive digital PCR assays determine samples. These allow absolute quantification transcript numbers thus also facilitate comparison between tissues, cell types across different studies. Furthermore, measured sizes every sample used study. Finally, analysed our with ANOVA linear modelling correlation sizes. Results In summary, show indeed expressed repeat-length-dependent manner post mortem brain tissues as well several peripheral types. particular, PBMCs statistically significant positive length, elevated even adult-onset range. Conclusions Our occurs throughout wide range likely all lengths. from sources demonstrate body manner. Therefore, might be marker state and/or progression should monitored over time, especially clinical trials targeting expression.

Language: Английский

Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases DOI Creative Commons
Jian Sheng Loh, Wen Qi Mak, Li Tan

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Feb. 16, 2024

Abstract The human gastrointestinal tract is populated with a diverse microbial community. vast genetic and metabolic potential of the gut microbiome underpins its ubiquity in nearly every aspect biology, including health maintenance, development, aging, disease. advent new sequencing technologies culture-independent methods has allowed researchers to move beyond correlative studies toward mechanistic explorations shed light on microbiome–host interactions. Evidence unveiled bidirectional communication between central nervous system, referred as “microbiota–gut–brain axis”. microbiota–gut–brain axis represents an important regulator glial functions, making it actionable target ameliorate development progression neurodegenerative diseases. In this review, we discuss mechanisms As provides essential cues microglia, astrocytes, oligodendrocytes, examine communications microbiota these cells during healthy states Subsequently, diseases using metabolite-centric approach, while also examining role microbiota-related neurotransmitters hormones. Next, targeting intestinal barrier, blood–brain meninges, peripheral immune system counteract dysfunction neurodegeneration. Finally, conclude by assessing pre-clinical clinical evidence probiotics, prebiotics, fecal transplantation A thorough comprehension will foster effective therapeutic interventions for management

Language: Английский

Citations

219
Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer’s disease: a phase 1b, randomized, placebo-controlled trial DOI Creative Commons
Catherine J. Mummery,

Anne Börjesson‐Hanson,

D. Blackburn

et al.

Nature Medicine, Journal Year: 2023, Volume and Issue: 29(6), P. 1437 - 1447

Published: April 24, 2023

Tau plays a key role in Alzheimer's disease (AD) pathophysiology, and accumulating evidence suggests that lowering tau may reduce this pathology. We sought to inhibit MAPT expression with tau-targeting antisense oligonucleotide (MAPT

Language: Английский

Citations

149
Amyotrophic lateral sclerosis: translating genetic discoveries into therapies DOI
Fulya Akçimen, Elia R. Lopez, John E. Landers

et al.

Nature Reviews Genetics, Journal Year: 2023, Volume and Issue: 24(9), P. 642 - 658

Published: April 6, 2023

Language: Английский

Citations

108
Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family in physiological and pathophysiological process and diseases DOI Creative Commons
Qian Lu, Yanli Zhu, Chao Deng

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: March 1, 2024

Abstract Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family (PGC-1s), consisting of three members encompassing PGC-1α, PGC-1β, and PGC-1-related coactivator (PRC), was discovered more than a quarter-century ago. PGC-1s are essential coordinators many vital cellular events, including mitochondrial functions, oxidative stress, endoplasmic reticulum homeostasis, inflammation. Accumulating evidence has shown that implicated in diseases, such as cancers, cardiac diseases cardiovascular neurological disorders, kidney motor system metabolic disorders. Examining the upstream modulators co-activated partners identifying critical biological events modulated by downstream effectors contribute to presentation elaborate network PGC-1s. Furthermore, discussing correlation between well summarizing therapy targeting helps make individualized precise intervention methods. In this review, we summarize basic knowledge regarding molecular regulatory network, discuss physio-pathological roles human review application PGC-1s, diagnostic prognostic value several therapies pre-clinical studies, suggest directions for future investigations. This presents immense potential treatment hopefully facilitates promotion new therapeutic targets.

Language: Английский

Citations

73
Alternative splicing and related RNA binding proteins in human health and disease DOI Creative Commons

Yining Tao,

Qi Zhang, Haoyu Wang

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Feb. 2, 2024

Abstract Alternative splicing (AS) serves as a pivotal mechanism in transcriptional regulation, engendering transcript diversity, and modifications protein structure functionality. Across varying tissues, developmental stages, or under specific conditions, AS gives rise to distinct splice isoforms. This implies that these isoforms possess unique temporal spatial roles, thereby associating with standard biological activities diseases. Among these, AS-related RNA-binding proteins (RBPs) play an instrumental role regulating alternative events. Under physiological the diversity of mediated by influences structure, function, interaction, localization proteins, participating differentiation development array tissues organs. pathological alterations are linked various diseases, particularly cancer. These changes can lead gene patterns, culminating loss For instance, cancer, abnormalities RBPs may result aberrant expression cancer-associated genes, promoting onset progression tumors. also associated numerous neurodegenerative diseases autoimmune Consequently, study across different holds significant value. review provides detailed account recent advancements tissue which aids deepening understanding complexity offers new insights methodologies for precision medicine.

Language: Английский

Citations

71
Curcumin-Based Nanomedicines in the Treatment of Inflammatory and Immunomodulated Diseases: An Evidence-Based Comprehensive Review DOI Creative Commons
Lucas Fornari Laurindo,

Gabriel Magno de Carvalho,

Bárbara de Oliveira Zanuso

et al.

Pharmaceutics, Journal Year: 2023, Volume and Issue: 15(1), P. 229 - 229

Published: Jan. 10, 2023

Curcumin (CUR) is a polyphenol extracted from the rhizome of Curcuma longa that possesses potent anti-inflammatory and antioxidant potential. Despite CUR’s numerous beneficial effects on human health, it has limitations, such as poor absorption. Nano-based drug delivery systems have recently been applied to improve solubility bioavailability potentialize its health effects. This review investigated different CUR-based nanomedicines inflammatory immunomodulated diseases. PUBMED, EMBASE, COCHRANE, GOOGLE SCHOLAR databases were searched, Scale for Assessment Narrative Review Articles (SANRA) was used quality assessment PRISMA guidelines. Overall, 66 studies included comprising atherosclerosis, rheumatoid arthritis (RA), Alzheimer’s disease (AD), Parkinson’s (PD), multiple sclerosis (MS), Huntington’s (HD), bowel diseases (IBD), psoriasis, liver fibrosis, epilepsy, COVID-19. The available scientific show there are many known nanoformulations with curcumin. They can be found in nanosuspensions, nanoparticles, nanoemulsions, solid lipid particles, nanocapsules, nanospheres, liposomes. These formulations CUR effectively adjuvants several immune-mediated atheroma plaque formation, RA, dementia, AD, PD, MS, IBD, COVID-19, anti-fibrotic fibrotic disease.

Language: Английский

Citations

50
Autosomal dominant cerebellar ataxias: new genes and progress towards treatments DOI Creative Commons
Giulia Coarelli, Marie Coutelier, Alexandra Dürr

et al.

The Lancet Neurology, Journal Year: 2023, Volume and Issue: 22(8), P. 735 - 749

Published: July 19, 2023

Language: Английский

Citations

44
Iron homeostasis and ferroptosis in human diseases: mechanisms and therapeutic prospects DOI Creative Commons

Qin Ru,

Yusheng Li,

Lin Chen

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Oct. 14, 2024

Iron, an essential mineral in the body, is involved numerous physiological processes, making maintenance of iron homeostasis crucial for overall health. Both overload and deficiency can cause various disorders human diseases. Ferroptosis, a form cell death dependent on iron, characterized by extensive peroxidation lipids. Unlike other kinds classical unprogrammed death, ferroptosis primarily linked to disruptions metabolism, lipid peroxidation, antioxidant system imbalance. Ferroptosis regulated through transcription, translation, post-translational modifications, which affect cellular sensitivity ferroptosis. Over past decade or so, diseases have been as part their etiology, including cancers, metabolic disorders, autoimmune diseases, central nervous cardiovascular musculoskeletal Ferroptosis-related proteins become attractive targets many major that are currently incurable, some regulators shown therapeutic effects clinical trials although further validation potential needed. Therefore, in-depth analysis its molecular mechanisms may offer additional strategies prevention treatment. In this review, we discuss significance contribution etiology development along with evidence supporting targeting approach. Importantly, evaluate recent promising interventions, providing guidance future targeted treatment therapies against

Language: Английский

Citations

42
Nucleic Acid Therapeutics: Successes, Milestones, and Upcoming Innovation DOI
Jillian Belgrad, Hassan H. Fakih,

Anastasia Khvorova

et al.

Nucleic Acid Therapeutics, Journal Year: 2024, Volume and Issue: 34(2), P. 52 - 72

Published: March 20, 2024

Nucleic acid-based therapies have become the third major drug class after small molecules and antibodies. The role of nucleic has been strengthened by recent regulatory approvals tremendous clinical success. In this review, we look at obstacles that hindered field, historical milestones achieved, what is yet to be resolved anticipated soon. This review provides a view key innovations are expanding acid capabilities, setting stage for future therapeutics.

Language: Английский

Citations

32
Protein translation: biological processes and therapeutic strategies for human diseases DOI Creative Commons

Xuechao Jia,

Xinyu He,

Chuntian Huang

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Feb. 23, 2024

Abstract Protein translation is a tightly regulated cellular process that essential for gene expression and protein synthesis. The deregulation of this increasingly recognized as critical factor in the pathogenesis various human diseases. In review, we discuss how deregulated can lead to aberrant synthesis, altered functions, disease progression. We explore key mechanisms contributing translation, including functional alterations factors, tRNA, mRNA, ribosome function. Deregulated leads abnormal expression, disrupted signaling, perturbed functions- all which contribute pathogenesis. development profiling techniques along with mass spectrometry-based proteomics, mRNA sequencing single-cell approaches have opened new avenues detecting diseases related errors. Importantly, highlight recent advances therapies targeting translation-related disorders their potential applications neurodegenerative diseases, cancer, infectious cardiovascular Moreover, growing interest lies targeted aimed at restoring precise control over diseased cells discussed. conclusion, comprehensive review underscores role its therapeutic target. Advancements understanding molecular deregulation, coupled therapies, offer promising improving outcomes Additionally, it will unlock doors possibility precision medicine by offering personalized deeper underpinnings future.

Language: Английский

Citations

25