Autophagy, aging, and age-related neurodegeneration

Neuron, Год журнала: 2024, Номер unknown

Опубликована: Окт. 1, 2024

Autophagy is a conserved mechanism that degrades damaged or superfluous cellular contents and enables nutrient recycling under starvation conditions. Many neurodegeneration-associated proteins are autophagy substrates, upregulation ameliorates disease in many animal models of neurodegeneration by enhancing the clearance toxic proteins, proinflammatory molecules, dysfunctional organelles. inhibition also induces neuronal glial senescence, phenomenon occurs with increasing age non-diseased brains as well response to stresses. However, aging mutations impair autophagy. This creates potentially detrimental feedback loop whereby accumulation these disease-associated impairs their autophagic clearance, facilitating further aggregation. Thus, understanding how interacts aging, neurodegenerative diseases temporal, cellular, genetic context important for future clinical application autophagy-modulating therapies neurodegeneration.

Язык: Английский

---

Interplay of Proteostasis Capacity and Protein Aggregation: Implications for Cellular Function and Disease

Journal of Molecular Biology, Год журнала: 2024, Номер 436(14), С. 168615 - 168615

Опубликована: Май 16, 2024

Eukaryotic cells are equipped with an intricate proteostasis network (PN), comprising nearly 3,000 components dedicated to preserving proteome integrity and sustaining protein homeostasis. This protective system is particularly important under conditions of external intrinsic cell stress, where inherently dynamic proteins may unfold lose functionality. A decline in capacity associated the aging process, resulting a reduced folding efficiency newly synthesized deficit cellular degrade misfolded proteins. critical consequence PN insufficiency accumulation cytotoxic aggregates that underlie various age-related neurodegenerative other pathologies. By interfering specific components, toxic place excessive burden on PN's ability maintain integrity. initiates feed-forward loop, wherein generation aggregated ultimately leads collapse demise.

Язык: Английский

---

Tau fibrils evade autophagy by excessive p62 coating and TAX1BP1 exclusion

Science Advances, Год журнала: 2024, Номер 10(24)

Опубликована: Июнь 12, 2024

The accumulation of protein aggregates is a hallmark many diseases, including Alzheimer’s disease. As major pillar the proteostasis network, autophagy mediates degradation aggregates. cargo receptor p62 recognizes ubiquitin on proteins and cooperates with TAX1BP1 to recruit machinery. Paradoxically, are not degraded in various diseases despite association. Here, we reconstituted recognition by receptors physiological pathological Tau forms. Monomeric recruits via sequential actions chaperone ubiquitylation machineries. In contrast, fibrils from disease brains recognized but fail TAX1BP1. This failure due masking moieties p62. resistant deubiquitylation, and, thus, this nonproductive interaction irreversible. Our results shed light mechanism underlying evasion their consequent

Язык: Английский

---

Molecular Insights into Aggrephagy: Their Cellular Functions in the Context of Neurodegenerative Diseases

Journal of Molecular Biology, Год журнала: 2024, Номер 436(15), С. 168493 - 168493

Опубликована: Фев. 14, 2024

Protein homeostasis or proteostasis is an equilibrium of biosynthetic production, folding and transport proteins, their timely efficient degradation. Proteostasis guaranteed by a network protein quality control systems aimed at maintaining the proteome functional avoiding accumulation potentially cytotoxic proteins. Terminal unfolded dysfunctional proteins can be directly turned over ubiquitin-proteasome system (UPS) first amassed into aggregates prior to Aggregates also disposed lysosomes selective type autophagy known as aggrephagy, which relies on set so-called receptors (SARs) adaptor Failure in eliminating aggregates, due defects have devastating effects underscored several neurodegenerative diseases proteinopathies, are characterized mostly formed specific disease-associated, aggregate-prone depending clinical pathology. Despite its medical relevance, however, process aggrephagy far from being understood. Here we review findings that helped assigning possible function SARs context highlight interplay between pathogenesis proteinopathies.

Язык: Английский

---

Disruption of the mitochondrial network in a mouse model of Huntington's disease visualized by in-tissue multiscale 3D electron microscopy

Acta Neuropathologica Communications, Год журнала: 2024, Номер 12(1)

Опубликована: Июнь 5, 2024

Abstract Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by expanded CAG repeat in the coding sequence of huntingtin protein. Initially, it predominantly affects medium-sized spiny neurons (MSSNs) corpus striatum. No effective treatment still available, thus urging identification potential therapeutic targets. While evidence mitochondrial structural alterations HD exists, previous studies mainly employed 2D approaches and were performed outside strictly native brain context. In this study, we adopted a novel multiscale approach to conduct comprehensive 3D situ analysis disturbances mouse model HD. We investigated MSSNs within tissue under optimal conditions utilizing state-of-the-art imaging technologies, specifically FIB/SEM for complete neuronal somas Electron Tomography detailed morphological examination, image processing-based quantitative analysis. Our findings suggest disruption network towards fragmentation The interlaced, slim long mitochondria observed healthy transforms into isolated, swollen short entities, with internal cristae disorganization, cavities abnormally large matrix granules.

Язык: Английский

---

Heat-shock chaperone HSPB1 mitigates poly-glycine-induced neurodegeneration via restoration of autophagic flux

Autophagy, Год журнала: 2025, Номер unknown

Опубликована: Фев. 12, 2025

The CGG repeat expansions in the 5"-UTR regions of certain genes have been implicated various neurodegenerative and muscular disorders. However, underlying pathogenic mechanisms are not well understood. In this study, we explore role small molecular chaperone HSPB1 counteracting neurodegeneration induced by poly-glycine (poly-G) aggregates. Employing a reporter system, demonstrate that within GIPC1 gene produce poly-G proteins, repeat-associated non-AUG (RAN) translation. Through proximity labeling subsequent mass spectrometry analysis, characterize composition insoluble aggregates reveal these sequester key macroautophagy/autophagy receptors, SQSTM1/p62 TOLLIP. This sequestration disrupts MAP1LC3/LC3 recruitment impairs autophagosome formation, thereby compromising autophagic pathway. Importantly, show facilitates dissociation receptors from consequently restores function. Overexpressing alleviates poly-G-induced mouse models. Taken together, findings highlight mechanistic basis for neuroprotective effects suggest its potential as therapeutic target treating poly-G-associated diseases.

Язык: Английский

---

How does autophagy impact neurological function?

The Neuroscientist, Год журнала: 2025, Номер unknown

Опубликована: Март 13, 2025

Autophagies describe a set of processes in which cells degrade their cytoplasmic contents via various routes that terminate with the lysosome. In macroautophagy (the focus this review, henceforth autophagy), contents, including misfolded proteins, protein complexes, dysfunctional organelles, and pathogens, are captured within double membranes called autophagosomes, ultimately fuse lysosomes, after degraded. Autophagy is important maintaining neuronal glial function; consequently, disrupted autophagy associated neurologic diseases. This review provides broad perspective on roles CNS, highlighting recent literature furthers our understanding multifaceted role healthy nervous system.

Язык: Английский

---

Temporal control of acute protein aggregate turnover by UBE3C and NRF1-dependent proteasomal pathways

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Сен. 1, 2024

A hallmark of neurodegenerative diseases is the progressive loss proteostasis, leading to accumulation misfolded proteins or protein aggregates, with subsequent cytotoxicity. To combat this toxicity, cells have evolved degradation pathways (ubiquitin-proteasome system and autophagy) that detect degrade proteins. However, studying underlying cellular mechanisms has remained a challenge, as formation many types aggregates asynchronous, individual displaying distinct kinetics, thereby hindering rigorous time-course studies. Here, we merge kinetically tractable synchronous agDD-GFP for aggregate targeted gene knockdowns, uncover used in response acute formation. We find forms amorphous by cryo-electron tomography at both early late stages Aggregate turnover occurs proteasome-dependent mechanism manner dictated burden, no evidence involvement autophagy. Lower levels agDD-GFP, enriched oligomers, utilizes UBE3C-dependent proteasomal pathway independent RPN13 ubiquitylation UBE3C. Higher burden activates NRF1 transcription factor increase proteasome subunit transcription, capacity cells. Loss gain function alters under conditions high burden. Together, these results define role UBE3C class aggregation-prone reveals proteostasis control widespread aggregation.

Язык: Английский

---

Modulation of autophagy by melatonin and its receptors: implications in brain disorders

Acta Pharmacologica Sinica, Год журнала: 2024, Номер unknown

Опубликована: Окт. 24, 2024

Язык: Английский

---

Native ultrastructure of fresh human brain vitrified directly from autopsy revealed by cryo-electron tomography with cryo-plasma focused ion beam milling

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

Опубликована: Сен. 17, 2023

Ultrastructure of human brain tissue has traditionally been examined using electron microscopy (EM) following chemical fixation, staining, and mechanical sectioning, which limit attainable resolution introduce artifacts. Alternatively, cryo-electron tomography (cryo-ET) offers the potential to image unfixed cellular samples at higher while preserving their native structures, but it requires be frozen free from crystalline ice thin enough via transmission EM. Due these requirements, cryo-ET yet employed investigate ultrastructure unfixed, never previously tissue. Here we present a method for generating lamellae in obtained time autopsy that can imaged cryo-ET. We vitrify directly on cryo-EM grids plunge-freezing, as opposed high pressure freezing is generally used thick samples. Following vitrification, use xenon plasma focused ion beam (FIB) milling generate on-grid. In comparison gallium FIB, commonly biological samples, FIB powerful efficiently mill large volume such Additionally, our approach allows generated variable depth inside being limited starting surface Lamellae Alzheimer's disease by reveal intact subcellular structures including components autophagy tau fibrils. Furthermore, visualize myelin revealing compact functional cytoplasmic expansions channels inner tongue. From images also measure dimensions membranes, providing insight into how basic protein forces out oligodendrocyte cytoplasm form tightly links intracellular polar head groups membrane. This provides first view prepared cryo-plasma

Язык: Английский

---