Intraparenchymal delivery of adeno-associated virus vectors for the gene therapy of neurological diseases

Expert Opinion on Biological Therapy, Journal Year: 2024, Volume and Issue: 24(8), P. 773 - 785

Published: July 27, 2024

In gene therapy with adeno-associated virus (AAV) vectors for diseases of the central nervous system, can be administered into blood vessels, cerebrospinal fluid space, or brain parenchyma. When transfer to a large area is required, first two methods are used, but in which local expected effective, directly

Language: Английский

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Neuroprotective Effects of Myrtle Berry By-Product Extracts on 6-OHDA-Induced Cytotoxicity in PC12 Cells

Antioxidants, Journal Year: 2025, Volume and Issue: 14(1), P. 88 - 88

Published: Jan. 13, 2025

The rising global focus on healthy lifestyles and environmental sustainability has prompted interest in repurposing plant-based by-products for health benefits. With increasing life expectancy, the incidence of neurodegenerative diseases—characterized by complex, multifactorial mechanisms such as abnormal protein aggregation, mitochondrial dysfunction, oxidative stress, inflammation—continues to grow. Medicinal plants, with their diverse bioactive compounds, offer promising therapeutic avenues conditions. Myrtus communis L., a Mediterranean plant primarily used liquor production, generates significant waste rich antioxidant anti-inflammatory properties. This study explores neuroprotective potential berry cellular model neurodegeneration. Using PC12 cells exposed 6-hydroxydopamine (6-OHDA), we assessed cell viability via MTT assay measured reactive oxygen species (ROS) production using DCFDA fluorescence. Additionally, analyzed expression genes linked stress neuronal function, including AChE, PON2, Grin1, Gabrd, c-fos, RT-PCR. Our findings reveal that extract significantly protects against 6-OHDA-induced cytotoxicity, reduces ROS levels, modulates key stress-related genes, underscoring its agent. These results highlight promise extracts mitigating processes, paving way future interventions.

Language: Английский

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Peripheral proteinopathy in neurodegenerative diseases

Translational Neurodegeneration, Journal Year: 2025, Volume and Issue: 14(1)

Published: Jan. 16, 2025

Proteinopathies in neurology typically refer to pathological changes proteins associated with neurological diseases, such as the aggregation of amyloid β and Tau Alzheimer's disease, α-synuclein Parkinson's disease multiple system atrophy, TAR DNA-binding protein 43 amyotrophic lateral sclerosis frontotemporal dementia. Interestingly, these are also commonly found peripheral tissues, raising important questions about their roles disorders. Multiple studies have shown that peripherally derived not only travel brain through various routes, aggravating pathology, but contribute significantly dysfunction, highlighting crucial impact on diseases. Investigating how influence progression disorders could open new horizons for achieving early diagnosis treatment. This review summarizes distribution, transportation pathways, pathogenic mechanisms several neurodegenerative disease-related periphery, proposing targeting be a promising strategy preventing managing

Language: Английский

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Bridging the gap: investigating the role of phosphorylation at the serine 129 site of α-synuclein in VAPB-PTPIP51 interactions

Acta Neuropathologica Communications, Journal Year: 2025, Volume and Issue: 13(1)

Published: Feb. 24, 2025

Parkinson's Disease (PD) is characterized by the aggregation and accumulation of α-synuclein (α-syn), along with abnormally high levels α-syn phosphorylation at serine 129 site (pSer α-syn, p-α-syn). However, mechanisms underlying extensive in pathogenesis PD, as well role p-α-syn process, remain unclear. Furthermore, though could bind to VAPB loosen Endoplasmic Reticulum (ER)-mitochondria associations disrupting VAPB-PTPIP51 tethers, whether how regulates interactions, remains Herein, Co-Immunoprecipitation Mass Spectrometry (CO-IP/MS) studies were preformed identify compare Protein-Protein Interactions (PPIs) phosphorylated total midbrains Thy1-SNCA transgenic mice. We further performed CO-IP Molecular Dynamics (MD) simulation assays confirm influence on aforementioned interactions. Additionally, we Gene Ontology (GO) Kyoto Encyclopedia Genes Genomes (KEGG) analyses annotate functional features common interacting proteins VAPB. The potential downstream verified via CO-IP. According MD results, increased interacted directly PTPIP51. pathway enrichment revealed that significantly involved protein binding, metal ion structural constituent cytoskeleton, intermediate filament microtubule organization processes. Moreover, our findings confirmed interactions target (CLTC, CAMK2A, ATP1A3, TUBB4B) These collectively elucidate underpinnings interaction between both hope these will provide valuable insights into regulatory pertinent diseases.

Language: Английский

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Massage‐Mimicking Nanosheets Mechanically Reorganize Inter‐organelle Contacts to Restore Mitochondrial Functions in Parkinson's Disease

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: April 13, 2025

Abstract Parkinson's disease (PD) is exacerbated by dysfunction of inter‐organelle contact, which depends on cellular responses to the mechanical microenvironment and can be regulated external forces. Delivering dynamic forces neural cells proves challenging due skull. Inspired effects massage; here PEGylated black phosphorus nanosheets (PEG‐BPNS), known for their excellent biocompatibility, biodegradability, specific surface area, strength, flexibility, are introduced, capable adhering cell membrane generating stimulation with lateral size 200 nm, exhibiting therapeutic potential in a 1‐methyl‐4‐phenyl‐1,2,3,6‐te‐trahydropyridine‐induced PD mouse model regulating contacts. Specifically, it found that nm PEG‐BPNS, acting as “NanoMassage,” significantly increase plasma tension, evidenced fluorescent lipid tension reporter fluorescence lifetime analysis. This force modulates actin reorganization, subsequently contacts between actin, mitochondria, endoplasmic reticulum, further controlling mitochondrial fission mitigating PD, efficacy via intranasal administration. These findings provide noninvasive strategy applying deep brain areas elucidate mechanism NanoMassage mediating contacts, suggesting rational design “NanoMassage” remodel communications neurodegenerative treatment.

Language: Английский

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Deep brain stimulation halts Parkinson’s disease-related immune dysregulation in the brain and peripheral blood

Brain Behavior and Immunity, Journal Year: 2024, Volume and Issue: 123, P. 851 - 862

Published: Oct. 30, 2024

Language: Английский

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The AAV-α-Synuclein Model of Parkinson’s Disease: An Update

Journal of Parkinson s Disease, Journal Year: 2024, Volume and Issue: 14(6), P. 1077 - 1094

Published: July 19, 2024

Targeted delivery of α-synuclein using AAV vectors has over the two decades since its introduction developed into a versatile tool for modeling different aspects synucleinopathy, mimicking those seen in Parkinson's disease and related Lewy body disorders. The viral vector approach to is attractive that expression α-synuclein, wild-type or mutated, can be confined defined anatomical structures targeted selected cell populations either cell-type specific promoter constructs natural engineered serotypes. AAV-α-synuclein was initially used model progressive pathology nigral dopamine neurons, and, like standard 6-OHDA model, it most commonly been applied unilaterally, non-injected side as reference control. In recent years, however, become more widely induce Parkinson-like synuclein other relevant neuronal systems, such brainstem noradrenergic serotonergic vagal motor well oligodendrocytes, prime target multiple system atrophy. purpose this review give an overview progress made use last summarize state-of-the art rats mice.

Language: Английский

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Haploinsufficiency ofITSN1is associated with Parkinson’s disease

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

Published: July 27, 2024

Abstract Background Despite its significant heritability, the genetic underpinnings of Parkinson disease (PD) remain incompletely understood, particularly role rare variants. Advances in population-scale sequencing now provide an unprecedented opportunity to uncover additional large-effect risk factors and expand our understanding mechanisms. Methods We leveraged whole-genome sequence data with linked electronic health records from 490,560 UK Biobank participants, identifying 3,809 PD cases 247,101 controls without a neurological disorder. performed both variant-and gene-level association analyses identify novel associations PD. analyzed two independent case-control cohorts for replication (totaling 3,739 58,156 controls). Additionally, we functional validation human synuclein-expressing Drosophila model. Findings In Biobank, replicated well-established loci including GBA1 LRRK2. also identified between protein-truncating variants (PTVs) ITSN1 increased PD, effect size exceeding those established (Fisher’s Exact Test: p=6.1x10 -7 ; Odds ratio [95% confidence interval] = 10.53 [5.20, 21.34]). signal meta-analysis across all (Cochran-Mantel-Haenszel test p=5.7x10 -9 9.20 [4.66, 16.70]). , haploinsufficiency ortholog ( Dap160 ) exacerbated α-synuclein-induced compound eye degeneration motor deficits. Interpretation establish as gene PTVs substantially increasing risk. encodes scaffold protein involved synaptic vesicle endocytosis, critical pathway increasingly recognized pathogenesis. Our findings highlight power large-scale coupled preclinical modeling variant elucidate

Language: Английский

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The Role and Mechanism of Metformin in the Treatment of Nervous System Diseases

Biomolecules, Journal Year: 2024, Volume and Issue: 14(12), P. 1579 - 1579

Published: Dec. 10, 2024

Nervous system diseases represent a significant global burden, affecting approximately 16% of the world’s population and leading to disability mortality. These conditions, encompassing both central nervous (CNS) peripheral (PNS) disorders, have substantial social economic impacts. Metformin, guanidine derivative derived from plant source, exhibits therapeutic properties in various health conditions such as cancer, aging, immune-related polycystic ovary syndrome, cardiovascular ailments, more. Recent studies highlight metformin’s ability cross blood–brain barrier, stimulate neurogenesis, provide beneficial effects specific neurological disorders through diverse mechanisms. This review discusses advancements research on role mechanisms treating within systems, aiming facilitate further investigation, utilization, clinical application metformin neurology.

Language: Английский

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The mechanistic view of non-coding RNAs as a regulator of inflammatory pathogenesis of Parkinson’s disease

Pathology - Research and Practice, Journal Year: 2024, Volume and Issue: 258, P. 155349 - 155349

Published: May 16, 2024

Language: Английский

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