Developmental and physiological impacts of pathogenic human huntingtin protein in the nervous system DOI Creative Commons

Tadros A. Hana,

Veronika G. Mousa,

Alice Lin

et al.

Neurobiology of Disease, Journal Year: 2024, Volume and Issue: 203, P. 106732 - 106732

Published: Nov. 12, 2024

Huntington's Disease (HD) is a neurodegenerative disorder, part of the nine identified inherited polyglutamine (polyQ) diseases. Most commonly, HD pathophysiology manifests in middle-aged adults with symptoms including progressive loss motor control, cognitive decline, and psychiatric disturbances. Associated formation insoluble fragments huntingtin protein (htt) that tend to aggregate nucleus cytoplasm neurons. To track both intracellular progression aggregation phenotype as well physiological deficits associated mutant htt, two constructs human HTT were expressed Drosophila melanogaster nervous system varying polyQ lengths, non-pathogenic-htt (NP-htt) pathogenic-htt (P-htt), an N-terminal RFP tag for vivo visualization. P-htt aggregates accumulate ventral nerve cord cell bodies early 24 h post hatching significant form segmental branches at 48 hatching. Organelle trafficking up- downstream formed neurons showed severe dynamics. explore putative htt aggregation, ultrastructural changes presynaptic muscles assessed, but no effects observed. However, force kinetics muscle contractions severely affected animals, reminiscent chorea. Reduced production translated altered locomotory behavior. A novel model was established throughout adulthood wing, showing similar patterns larvae. Expressing adult resulted significantly reduced lifespan, which could be partially rescued by feeding flies mTOR inhibitor rapamycin. These findings advance our understanding impacts on peripheral tissues.

Language: Английский

Huntington’s Disease: Complex Pathogenesis and Therapeutic Strategies DOI Open Access
Huichun Tong, Tianqi Yang, Shuying Xu

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(7), P. 3845 - 3845

Published: March 29, 2024

Huntington’s disease (HD) arises from the abnormal expansion of CAG repeats in huntingtin gene (HTT), resulting production mutant protein (mHTT) with a polyglutamine stretch its N-terminus. The pathogenic mechanisms underlying HD are complex and not yet fully elucidated. However, mHTT forms aggregates accumulates abnormally neuronal nuclei processes, leading to disruptions multiple cellular functions. Although there is currently no effective curative treatment for HD, significant progress has been made developing various therapeutic strategies treat HD. In addition drugs targeting toxicity mHTT, therapy approaches that aim reduce expression HTT hold great promise therapy. This review provides an overview current treatments, discusses different strategies, aims facilitate future advancements field.

Language: Английский

Citations

21
Therapeutic approaches targeting aging and cellular senescence in Huntington's disease DOI Creative Commons
Asif Ahmad Bhat, Ehssan Moglad, Muhammad Afzal

et al.

CNS Neuroscience & Therapeutics, Journal Year: 2024, Volume and Issue: 30(10)

Published: Oct. 1, 2024

Huntington's disease (HD) is a devastating neurodegenerative that manifested by gradual loss of physical, cognitive, and mental abilities. As the advances, age has major impact on pathogenic signature mutant huntingtin (mHTT) protein aggregation. This review aims to explore intricate relationship between aging, mHTT toxicity, cellular senescence in HD. Scientific data interplay mHTT, HD were collected from several academic databases, including PubMed, Google Scholar, Google, ScienceDirect. The search terms employed "AGING," "HUNTINGTON'S DISEASE," "MUTANT HUNTINGTIN," "CELLULAR SENESCENCE." Additionally, gather information molecular mechanisms potential therapeutic targets, was extended include relevant such as "DNA DAMAGE," "OXIDATIVE STRESS," "AUTOPHAGY." According research, aging leads worsening pathophysiology through some processes. result accumulation, promoted, which causes DNA damage, oxidative stress, decreased autophagy, increased inflammatory responses. Pro-inflammatory cytokines other substances are released senescent cells, may worsen neuronal damage course disease. It been shown treatments directed at these pathways reduce symptoms enhance longevity experimental animals, pointing new possibility treating condition. Through their amplification harmful effects play crucial roles development Comprehending interplays creates novel opportunities for measures targeted alleviating enhancing patients' quality life.

Language: Английский

Citations

6
Regulation of lipid dysmetabolism and neuroinflammation linked with Alzheimer's disease through modulation of Dgat2 DOI Creative Commons
Archana Yadav,

Xiaosen Ouyang,

Morgan Barkley

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 19, 2025

Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) plaque accumulation, cognitive decline, lipid dysregulation, and neuroinflammation. Mutations in the Amyloid Precursor Protein (APP), accumulation of A β42 contribute to AD, however, underlying mechanisms linking beta amyloid metabolism neuroinflammation remain unclear. Using Drosophila models, we demonstrate that App NLG Aβ42 lead locomotor impairments, disrupted sleep activity, memory deficits, loss synaptic integrity, Lipid have also been observed NLG-F knockin mouse model, supporting their involvement AD pathogenesis. Furthermore, role Diacylglycerol O-acyltransferase 2 (Dgat2), key enzyme regulation, modulating phenotypes, as Dgat2 levels its potential transcription factors were altered models. In knockdown reduced restored improved function, attenuated Additionally, modulation quality circadian rhythms, further implicating progression. mice, inhibition mitigated dysmetabolism decreased neuroinflammatory responses, expression risk genes. These findings underscore intricate interplay between pathology, neuroinflammation, suggest targeting may provide novel therapeutic strategy for mitigating AD-associated dysfunction. Understanding conserved impact homeostasis across species offers valuable insights into translational interventions AD.

Language: Английский

Citations

0
Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances DOI Creative Commons
Qiu Jiang, Jie Liu, Shan Huang

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: March 10, 2025

Abstract In the context of global ageing, prevalence neurodegenerative diseases and dementia, such as Alzheimer’s disease (AD), is increasing. However, current symptomatic disease-modifying therapies have achieved limited benefits for in clinical settings. Halting progress neurodegeneration cognitive decline or even improving impaired cognition function are clinically meaningful goals treatments diseases. Ageing primary risk factor their associated comorbidities, vascular pathologies, elderly individuals. Thus, we aim to elucidate role ageing from perspective a complex system, which brain core peripheral organs tissues form holistic network support functions. During progressive deterioration structure entire body hampers its active adaptive responses various stimuli, thereby rendering individuals more vulnerable Consequently, propose that prevention treatment should be grounded antiageing rejuvenation means complemented by interventions targeting disease-specific pathogenic events. This integrated approach promising strategy effectively prevent, pause slow down progression

Language: Английский

Citations

0
Brain–Periphery Interactions in Huntington’s Disease: Mediators and Lifestyle Interventions DOI Open Access
Johannes Burtscher, Barbara Strasser, Giuseppe Pepe

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(9), P. 4696 - 4696

Published: April 25, 2024

Prominent pathological features of Huntington’s disease (HD) are aggregations mutated Huntingtin protein (mHtt) in the brain and neurodegeneration, which causes characteristic motor (such as chorea dystonia) non-motor symptoms. However, numerous systemic peripheral deficits HD have gained increasing attention recently, since those factors likely modulate progression, including pathology. While whole-body metabolic abnormalities organ-specific pathologies been relatively well described, potential mediators compromised inter-organ communication insufficiently characterized. Therefore, we applied an exploratory literature search to identify such mediators. Unsurprisingly, dysregulation inflammatory factors, circulating mHtt, many other messenger molecules (hormones, lipids, RNAs) were found that suggest impaired communication, gut–brain muscle–brain axis. Based on these findings, aimed assess risks potentials lifestyle interventions thought improve across axes: dietary strategies exercise. We conclude appropriate great reduce symptoms potentially modify progression (possibly via improving signaling) HD. metabolism warrant particular care design exercise programs for people with

Language: Английский

Citations

2
Metformin Lysosomal Targeting: A Novel Aspect to Be Investigated for Metformin Repurposing in Neurodegenerative Diseases? DOI Open Access
Nadia Papini, Paola Giussani, Cristina Tringali

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(16), P. 8884 - 8884

Published: Aug. 15, 2024

Metformin is a widely employed drug in type 2 diabetes. In addition to warranting good short- and long-term glycemic control, metformin displays many intriguing properties as protection against cardiovascular neurodegenerative diseases, anti-tumorigenic longevity promotion. being low-cost drug, generally well tolerated. However, despite the enthusiastic drive aliment these novel studies, contradictory results suggest importance of better elucidating complexity action different tissues/cells establish its possible employment diseases. This review summarises recent data identifying lysosomal-dependent processes lysosomal targets, such endosomal Na+/H+ exchangers, presenilin enhancer (PEN2), pathway leading AMP-activated protein kinase (AMPK) activation, transcription factor EB (TFEB), modulated by metformin. Lysosomal dysfunctions resulting autophagic acidification biogenesis impairment appear be hallmarks inherited acquired Lysosomes are not yet seen sort cellular dump but crucial determining key signalling paths involved clearance aggregated proteins. Thus, possibility pharmacologically modulating them deserves great interest. Despite potentiality this context, additional important issues, dosing, should addressed future.

Language: Английский

Citations

2
Mitochondrial homeostasis regulation: A promising therapeutic target for Parkinson's disease DOI Creative Commons

Meng‐Fan Yao,

Tao Dang,

Huajun Wang

et al.

Behavioural Brain Research, Journal Year: 2023, Volume and Issue: 459, P. 114811 - 114811

Published: Dec. 14, 2023

Parkinson's disease (PD) is a neurodegenerative characterized by progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) and presence Lewy bodies (LBs) or neurites (LNs) which consist α-synuclein (α-syn) complex mix other biomolecules. Mitochondrial dysfunction widely believed to play an essential role pathogenesis PD related diseases. But mitochondrial subject genetic regulation. There increasing evidence that PD-related genes directly indirectly affect integrity. Therefore, targeted regulation function has great clinical application prospects treatment PD. However, lots drugs targeting mitochondria have been developed but their therapeutic effects are not ideal. This review aims reveal diseases based on structure function, may highlight potential interventions targets for development recover

Language: Английский

Citations

5
Developmental and physiological impacts of pathogenic human huntingtin protein in the nervous system DOI Open Access

Tadros A. Hana,

Veronika G. Mousa,

Alice Lin

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 2, 2024

Huntington's Disease (HD) is a neurodegenerative disorder, part of the nine identified inherited polyglutamine (polyQ) diseases. Most commonly, HD pathophysiology manifests in middle-aged adults with symptoms including progressive loss motor control, cognitive decline, and psychiatric disturbances. Associated formation insoluble fragments huntingtin protein (htt) that tend to aggregate nucleus cytoplasm neurons. To track both intracellular progression aggregation phenotype as well physiological deficits associated mutant htt, two constructs human HTT were expressed varying polyQ lengths, non-pathogenic-htt (Q15, NP-htt) pathogenic-htt (Q138, P-htt), an N-terminal RFP tag for

Language: Английский

Citations

0
Developmental and physiological impacts of pathogenic human huntingtin protein in the nervous system DOI Creative Commons

Tadros A. Hana,

Veronika G. Mousa,

Alice Lin

et al.

Neurobiology of Disease, Journal Year: 2024, Volume and Issue: 203, P. 106732 - 106732

Published: Nov. 12, 2024

Huntington's Disease (HD) is a neurodegenerative disorder, part of the nine identified inherited polyglutamine (polyQ) diseases. Most commonly, HD pathophysiology manifests in middle-aged adults with symptoms including progressive loss motor control, cognitive decline, and psychiatric disturbances. Associated formation insoluble fragments huntingtin protein (htt) that tend to aggregate nucleus cytoplasm neurons. To track both intracellular progression aggregation phenotype as well physiological deficits associated mutant htt, two constructs human HTT were expressed Drosophila melanogaster nervous system varying polyQ lengths, non-pathogenic-htt (NP-htt) pathogenic-htt (P-htt), an N-terminal RFP tag for vivo visualization. P-htt aggregates accumulate ventral nerve cord cell bodies early 24 h post hatching significant form segmental branches at 48 hatching. Organelle trafficking up- downstream formed neurons showed severe dynamics. explore putative htt aggregation, ultrastructural changes presynaptic muscles assessed, but no effects observed. However, force kinetics muscle contractions severely affected animals, reminiscent chorea. Reduced production translated altered locomotory behavior. A novel model was established throughout adulthood wing, showing similar patterns larvae. Expressing adult resulted significantly reduced lifespan, which could be partially rescued by feeding flies mTOR inhibitor rapamycin. These findings advance our understanding impacts on peripheral tissues.

Language: Английский

Citations

0