Protective Effects of Ambroxol on Aβ and α-Synuclein-Induced Neurotoxicity Through Glucocerebrosidase Activation in HT-22 Hippocampal Neuronal Cells DOI Open Access
Sheng‐Chieh Lin, Ching‐Chi Chang, Sing‐Hua Tsou

и другие.

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(22), С. 12114 - 12114

Опубликована: Ноя. 12, 2024

Dementia with Lewy bodies (DLB) is a progressive neurodegenerative disorder marked by the accumulation of α-synuclein (αSyn), often co-existing amyloid β (Aβ) pathology. Current treatments are largely symptomatic, highlighting critical need for disease-modifying therapies. Evidence suggests that αSyn aggregates contribute to neuronal death in DLB, particularly when exacerbated Aβ. Given role autophagy clearing misfolded proteins, exploring agents promote this pathway essential developing effective treatments. Ambroxol (AMBX), mucolytic drug, has demonstrated potential activating glucocerebrosidase (GCase), an enzyme enhances lysosomal function and facilitates autophagic clearance toxic protein aggregates, including αSyn. This study aims evaluate AMBX’s neuroprotective effects cellular model goal identifying new therapeutic target underlying pathology DLB. In study, HT-22 hippocampal cells were exposed Aβ, followed AMBX treatment. Our results showed significantly improved cell viability reduced apoptosis co-treated Additionally, restored GCase activity, promoted autophagy, oxidative stress, which turn mitigated aggregation phosphorylation. These findings suggest enhancing may help alleviate DLB-associated neurodegeneration. underscores as agent DLB supports further investigation animal models clinical trials validate its efficacy disease contexts.

Язык: Английский

Lysosomal storage, impaired autophagy and innate immunity in Gaucher and Parkinson's diseases: insights for drug discovery DOI Creative Commons
Alexander Hull, Magda L. Atilano,

Laith Gergi

и другие.

Philosophical Transactions of the Royal Society B Biological Sciences, Год журнала: 2024, Номер 379(1899)

Опубликована: Фев. 19, 2024

Impairment of autophagic–lysosomal pathways is increasingly being implicated in Parkinson's disease (PD). GBA1 mutations cause the lysosomal storage disorder Gaucher (GD) and are commonest known genetic risk factor for PD. have been shown to impairment. Defective autophagic degradation unwanted cellular constituents associated with several pathologies, including loss normal protein homeostasis, particularly α-synuclein, innate immune dysfunction. The latter observed both peripherally centrally PD GD. Here, we will discuss mechanistic links between autophagy dysregulation, possible role these pathologies communication gut brain disorders. Recent work a fly model neuronopathic GD (nGD) revealed intestinal defects leading gastrointestinal dysfunction activation. Rapamycin treatment partially reversed block reduced activity, association increased survival improved locomotor performance. Alterations microbiome critical driver neuroinflammation, studies that eradication nGD mouse models ameliorate inflammation. Following observations, lysosomal–autophagic pathways, signalling dysbiosis discussed as potential therapeutic targets This article part discussion meeting issue ‘Understanding endo-lysosomal network neurodegeneration’.

Язык: Английский

Процитировано

12
Gaucher disease provides a unique window into Parkinson disease pathogenesis DOI
Ellen Hertz, Yu Chen, Ellen Sidransky

и другие.

Nature Reviews Neurology, Год журнала: 2024, Номер 20(9), С. 526 - 540

Опубликована: Авг. 6, 2024

Язык: Английский

Процитировано

11
Clinical, mechanistic, biomarker, and therapeutic advances in GBA1-associated Parkinson’s disease DOI Creative Commons
Xuxiang Zhang,

Heng Wu,

Beisha Tang

и другие.

Translational Neurodegeneration, Год журнала: 2024, Номер 13(1)

Опубликована: Сен. 12, 2024

Язык: Английский

Процитировано

9
A protective role of ABCA5 in response to elevated sphingomyelin levels in Parkinson’s disease DOI Creative Commons
Yuhong Fu, Russell Pickford, Jasmin Galper

и другие.

npj Parkinson s Disease, Год журнала: 2024, Номер 10(1)

Опубликована: Янв. 11, 2024

Abstract Parkinson’s disease (PD) is a chronic neurodegenerative disorder that affects the motor system. Increasing evidence indicates lysosomal dysfunction pivotal in pathogenesis of PD, typically characterized by dysregulation sphingolipids lysosomes. ATP-binding cassette subfamily A member 5 (ABCA5) transporter mediates removal excess sphingomyelin from We therefore investigated whether expression levels ABCA5 are associated with and α-synuclein pathology PD. Firstly, we undertook comprehensive assessment six sphingolipid classes part salvage pathway disease-affected amygdala disease-unaffected visual cortex using liquid chromatography-mass spectrometry. found were significantly increased PD compared to controls correlated duration only amygdala, whereas, five other slightly altered or unaltered. Concomitantly, was upregulated strongly levels. Using neuronal cells, further verified dependent on cellular sphingomyelin. Interestingly, related expression. Finally, revealed also plasma controls, identical species both brain plasma. When put together, these results suggest regions accumulating reduce potentially as protective measure. This process may provide new targets for therapeutic intervention biomarker development

Язык: Английский

Процитировано

6
GBA1 inactivation in oligodendrocytes affects myelination and induces neurodegenerative hallmarks and lipid dyshomeostasis in mice DOI Creative Commons
Di Gregorio, Loris Russo, Enrica Torretta

и другие.

Molecular Neurodegeneration, Год журнала: 2024, Номер 19(1)

Опубликована: Март 7, 2024

Abstract Background Mutations in the β-glucocerebrosidase ( GBA1 ) gene do cause lysosomal storage Gaucher disease (GD) and are among most frequent genetic risk factors for Parkinson’s (PD). So far, studies on both neuronopathic GD PD primarily focused neuronal manifestations, besides evaluation of microglial astrocyte implication. White matter alterations were described central nervous system paediatric type 1 patients suggested to sustain or even play a role process, although contribution oligodendrocytes has been so far scarcely investigated. Methods We exploited study induction myelination vitro, consisting Oli-neu cells treated with dibutyryl-cAMP, order evaluate expression levels function during oligodendrocyte differentiation. Conduritol-B-epoxide, irreversible inhibitor was used dissect impact inactivation process myelination, degradation α-synuclein accumulation vitro. Moreover, white vivo, we developed novel mouse transgenic line which is abolished myelinating glia, by crossing Cnp1-cre bearing loxP sequences flanking Gba1 exons 9–11, encoding catalytic domain. Immunofluorescence, western blot lipidomic analyses performed brain samples from wild-type knockout animals assess onset early neurodegenerative hallmarks, together differentiation analysis primary cultures. Results Here show that induces dysfunction inhibits oligodendrocyte-specific loss-of-function sufficient induce vivo demyelination including axonal degeneration, astrogliosis, lipid dyshomeostasis functional impairment. Conclusions Our sheds light GBA1-related diseases supports need better characterizing as actors playing diseases, also pointing at them potential targets set brake progression.

Язык: Английский

Процитировано

6
Exosomes in the Diagnosis of Neuropsychiatric Diseases: A Review DOI Creative Commons
Song Wu,

Xin-miao Shang,

Meng Guo

и другие.

Biology, Год журнала: 2024, Номер 13(6), С. 387 - 387

Опубликована: Май 28, 2024

Exosomes are 30–150 nm small extracellular vesicles (sEVs) which highly stable and encapsulated by a phospholipid bilayer. contain proteins, lipids, RNAs (mRNAs, microRNAs/miRNAs, long non-coding RNAs/lncRNAs), DNA of their parent cell. In pathological conditions, the composition exosomes is altered, making potential source biomarkers for disease diagnosis. can cross blood–brain barrier (BBB), an advantage using in diagnosis central nervous system (CNS) diseases. Neuropsychiatric diseases belong to CNS diseases, many diagnostic markers have been identified neuropsychiatric Here, we review discuss application exosomal early accurate these Additionally, outline limitations future directions

Язык: Английский

Процитировано

4
Increased glucosylsphingosine levels and Gaucher Disease in GBA1-associated Parkinson’s Disease. DOI
Massimo Marano, Carmela Zizzo, Maria Chiara Malaguti

и другие.

Parkinsonism & Related Disorders, Год журнала: 2024, Номер 124, С. 107023 - 107023

Опубликована: Июнь 1, 2024

Язык: Английский

Процитировано

4
Application of a near-infrared viscosity-responsive fluorescent probe for lysosomal targeting in fatty liver mice DOI

Junlei Hao,

Xiaoying Li,

Suntao Shi

и другие.

Bioorganic Chemistry, Год журнала: 2025, Номер 155, С. 108162 - 108162

Опубликована: Янв. 13, 2025

Язык: Английский

Процитировано

0
Strategies targeting endoplasmic reticulum stress to improve Parkinson’s disease DOI Creative Commons
Danni Wang,

Shuhui Qu,

Zaijun Zhang

и другие.

Frontiers in Pharmacology, Год журнала: 2023, Номер 14

Опубликована: Ноя. 10, 2023

Parkinson’s disease (PD) is a common neurodegenerative disorder with motor symptoms, which caused by the progressive death of dopaminergic (DA) neurons in substantia nigra pars compacta (SNpc). Accumulating evidence shows that endoplasmic reticulum (ER) stress occurring SNpc DA an early event development PD. ER triggers activation unfolded protein response (UPR) to reduce and restore function. However, excessive continuous UPR exacerbate risk neuron through crosstalk other PD events. Thus, considered promising therapeutic target for treatment Various strategies targeting modulation signaling, increase ER’s folding ability, enhancement degradation are developed alleviate neuronal models. In this review, we summarize pathological role update improve homeostasis PD-related

Язык: Английский

Процитировано

9
An AAV capsid reprogrammed to bind human Transferrin Receptor mediates brain-wide gene delivery DOI Creative Commons
Qin Huang, Ken Y. Chan, Shan Lou

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Дек. 22, 2023

Developing vehicles that efficiently deliver genes throughout the human central nervous system (CNS) will broaden range of treatable genetic diseases. We engineered an AAV capsid, BI-hTFR1, binds Transferrin Receptor (TfR1), a protein expressed on blood-brain barrier (BBB). BI-hTFR1 was actively transported across brain endothelial cell layer and, relative to AAV9, provided 40-50 times greater reporter expression in CNS

Язык: Английский

Процитировано

4