Nuclear and degradative functions of the ESCRT-III pathway: implications for neurodegenerative disease

Nucleus, Journal Year: 2024, Volume and Issue: 15(1)

Published: May 3, 2024

The ESCRT machinery plays a pivotal role in membrane-remodeling events across multiple cellular processes including nuclear envelope repair and reformation, pore complex surveillance, endolysosomal trafficking, neuronal pruning. Alterations ESCRT-III functionality have been associated with neurodegenerative diseases Frontotemporal Dementia (FTD), Amyotrophic Lateral Sclerosis (ALS), Alzheimer's Disease (AD). In addition, mutations specific proteins identified FTD/ALS. Thus, understanding how disruptions the fundamental functions of this pathway its individual protein components human central nervous system (CNS) may offer valuable insights into mechanisms underlying disease pathogenesis identification potential therapeutic targets. review, we discuss components, dynamics, functions, focus on pathway. explore implications altered function for neurodegeneration primary emphasis surveillance trafficking within CNS.

Language: Английский

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Alterations in Lysosomal, Glial and Neurodegenerative Biomarkers in Patients with Sporadic and Genetic Forms of Frontotemporal Dementia

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

Published: Feb. 12, 2024

Abstract Background Frontotemporal dementia (FTD) is the most common cause of early-onset with 10-20% cases caused by mutations in one three genes: GRN , C9orf72 or MAPT . To effectively develop therapeutics for FTD, identification and characterization biomarkers to understand disease pathogenesis evaluate impact specific therapeutic strategies on target biology as well underlying pathology are essential. Moreover, tracking longitudinal changes these throughout progression crucial discern their correlation clinical manifestations potential prognostic usage. Methods We conducted a comprehensive investigation indicative lysosomal biology, glial cell activation, synaptic neuronal health cerebrospinal fluid (CSF) plasma from non-carrier controls, sporadic FTD (symptomatic non-carriers) symptomatic carriers GRN, C9orf72, asymptomatic mutation carriers. also assessed Furthermore, we examined biomarker levels impacted brain regions including middle temporal gyrus (MTG) superior frontal (SFG) disease-unaffected inferior occipital (IOG) Results confirmed glucosylsphingosine (GlcSph), regulated progranulin, was elevated carriers, both asymptomatic. GlcSph other such ganglioside GM2 globoside GB3 were increased affected SFG MTG but not IOG, compared same controls. The GFAP YKL40 CSF all groups, except group. Neuronal injury degeneration NfL plasma, UCHL1 patients forms FTD. Synaptic NPTXR, NPTX1/2, VGF reduced pronounced reductions observed demonstrated significantly positively correlated severity measured CDR+NACC FTLD□SB genetic NPTXR negatively Conclusions In conclusion, our replicated alterations biofluid function, across unveiled novel insights into dysregulation within tissues mutations. correlations between open promising avenues applications indicators drug efficacy trials. Our data implicated complicated relationship tissue future investigations should delve mechanistic underpinnings biomarkers, which will serve foundation development targeted

Language: Английский

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Peripheral expression of brain-penetrant progranulin rescues pathologies in mouse models of frontotemporal lobar degeneration

Science Translational Medicine, Journal Year: 2024, Volume and Issue: 16(750)

Published: June 5, 2024

Progranulin (PGRN) haploinsufficiency is a major risk factor for frontotemporal lobar degeneration with TAR DNA-binding protein 43 (TDP-43) pathology (FTLD- GRN ). Multiple therapeutic strategies are in clinical development to restore PGRN the CNS, including gene therapy. However, limitation of current therapy approaches aimed alleviate FTLD-associated pathologies may be their inefficient brain exposure and biodistribution. We therefore developed an adeno-associated virus (AAV) targeting liver (L) achieve sustained peripheral expression transferrin receptor (TfR) binding, brain-penetrant (b) variant [AAV(L):bPGRN] two mouse models FTLD- , namely, Grn knockout GrnxTmem106b double mice. This strategy avoids potential safety biodistribution issues CNS-administered AAVs maintains concentrations after single dose. AAV(L):bPGRN treatment reduced several –associated severe motor function deficits, aberrant TDP-43 phosphorylation, dysfunctional degradation, lipid metabolism, gliosis, neurodegeneration brain. The translatability our findings was tested vitro model using cocultured human induced pluripotent stem cell (hiPSC)–derived microglia lacking TMEM106B wild-type hiPSC-derived neurons. As mice, TDP-43, lysosomal dysfunction, neuronal loss were ameliorated exogenous TfR-binding transport vehicle fused (PTV:PGRN). Together, studies suggest that peripherally administered replacement ameliorate relevant phenotypes pathology, neurodegeneration, behavioral deficits. Our data provide preclinical proof concept use this AAV platform potentially other CNS disorders.

Language: Английский

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Title: Cell-autonomous and non-cell-autonomous effects of TRIM72 on ALS disease progression

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

Published: Jan. 13, 2025

Abstract Dysfunction of RNA-binding proteins, including TDP-43 and FUS, has been associated with amyotrophic lateral sclerosis (ALS); however, the underlying mechanisms are largely unknown. Here, we reported that a neuronal upregulation TRIM72 (Tripartite Motif Containing 72) in FUS mutation knockin ALS models slows disease progression. interacts Commander, protein complex for recycling membrane facilitating repair antioxidation. Exosomal is detected patient cerebrospinal fluid (CSF) extracellular application exosomal protects cell from damage. In sporadic cohort, CSF level associates AAV-mediated expression down progressions an without adverse effects over year treatment course. Taken together, our results suggest universal protection TRIM family cell-autonomous non-cell-autonomous manners ALS.

Language: Английский

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Upregulation of Autophagy During the Differentiation of Primary Human Term Cytotrophoblast Cells into Syncytial Cells: Ultrastructural Analysis

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(3), P. 1321 - 1321

Published: Feb. 4, 2025

The villous trophoblast cells are of fundamental importance because they fulfill a variety functions that vital for the growth fetus and maintenance pregnancy. A simple in vitro cell model grows on standard tissue culture plates has been utilized various functional studies cells. Despite potential value incorporating electron microscopy analysis reports primary human cells, is exclusively ancillary to previous publications. In context autophagy research using detailed ultrastructural flux imperative; however, it not conducted date. this study, we isolated term (i.e., cytotrophoblast CTB cells) most up-to-date isolation method isolating pure from placenta investigated dynamic process cultured by means transmission microscopy. initial 6 h resulted aggregation; majority did differentiate into syncytial contrast, after 72 h, exhibited promotion differentiation revealed upregulation visualized unique autophagic profiles during which perinuclear accumulation extremely large autophagosomes/autolysosomes. This study provides novel insights reproductive biology thereby demonstrating substantial as resources.

Language: Английский

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The role of autophagy in the pathogenesis and treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)

Autophagy Reports, Journal Year: 2025, Volume and Issue: 4(1)

Published: March 20, 2025

Language: Английский

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SLC38A9 is directly involved in Tat-induced endolysosome dysfunction and senescence in astrocytes

Life Science Alliance, Journal Year: 2025, Volume and Issue: 8(7), P. e202503231 - e202503231

Published: May 5, 2025

Cellular senescence contributes to accelerated aging and the development of various neurodegeneration disorders including HIV-associated neurocognitive disorders. The is attributed, at least in part, CNS persistence HIV-1 transactivator transcription (Tat), an essential protein for viral that actively secreted from HIV-1–infected cells. Secreted Tat enters cells via receptor-mediated endocytosis induces endolysosome dysfunction cellular Given represents early step exogenous Tat-induced senescence, we tested hypothesis endolysosome-dependent mechanism human astrocytes. We demonstrated internalized interacts with endolysosome-resident arginine sensor SLC38A9 arginine-rich basic domain. Such interaction between leads dysfunction, enhanced LTR transactivation, senescence. These findings suggest drives highlight novel role astrocyte

Language: Английский

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PI3P: Rising to the (DPR) challenge in C9-ALS/FTD

Neuron, Journal Year: 2025, Volume and Issue: 113(9), P. 1301 - 1303

Published: May 1, 2025

Language: Английский

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Cryo-EM structures of pathogenic fibrils and their impact on neurodegenerative disease research

Neuron, Journal Year: 2024, Volume and Issue: 112(14), P. 2269 - 2288

Published: June 3, 2024

Language: Английский

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Smell loss is associated with cognitive impairment in amyotrophic lateral sclerosis patients

CNS Neuroscience & Therapeutics, Journal Year: 2024, Volume and Issue: 30(7)

Published: July 1, 2024

Abstract Background Smell loss significantly impacts the quality of life in patients. However, there is limited research on smell individuals with amyotrophic lateral sclerosis (ALS), and correlation between cognitive impairment unclear. This study aimed to investigate cognition ALS Methods The included 216 Edinburgh Cognitive Behavioural Screen (ECAS) identification test specifically for Chinese population (CSIT) were administered evaluate participants' olfactory function, respectively. Results After covarying age, sex, BMI, education level, degree hunger, dietary bias, eagerness food, stress, smoking status, alcohol consumption, upper respiratory tract infection (URTI) or rhinitis, CSIT scores correlated ECAS ( r = 0.162, p 0.028), especially ALS‐specific 0.158, 0.031). Even after excluding patients URTI results similar. 0.224, 0.011), 0.205, 0.019). Conclusion In ALS, impairment, particularly frontotemporal dysfunction. dysfunction may lead worse performance

Language: Английский

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