Role of ESCRT pathway and autophagy in neurodegenerative diseases.

Roles of autophagy in brain homeostasis and disease.

Mitophagy in neuronal health and disease: from mechanisms to neurodegeneration

Regulation of mitochondrial health is critical for maintaining cellular homeostasis in the nervous system. Damaged mitochondria can have detrimental effects on neuronal health and are thought to be key contributors to the progression of neurodegenerative disorders including Parkinson’s disease and amyotrophic lateral sclerosis. To mitigate this damage, multiple quality control mechanisms have evolved to eliminate aged or damaged mitochondria. One such quality control process is autophagy, a process that involves turnover of mitochondria at presynaptic sites and the axon terminal under basal conditions. This highly conserved mechanism sequesters mitochondria from the cytosol within autophagosomes followed by degradation upon fusion with a lysosome. Acute mitochondrial damage activates a selective form of autophagy called mitophagy that involves receptor-mediated engulfment and degradation of the damaged organelle. Multiple mechanisms have been shown to drive efficient mitophagy in neurons and glia, including PTEN induced kinase 1 (PINK1)/Parkin–dependent mitophagy and receptor-mediated mitophagy. Genetic, pathological, and experimental evidence all implicate defects in the removal of damaged mitochondria in the onset or progression of neurodegenerative disease. Both the initiation of PINK1/Parkin–dependent mitophagy and deficits in the removal of damaged mitochondria are linked to activation of neuroinflammatory pathways, including NF-κB and cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING) signaling. In this Review, we discuss the molecular pathways governing mitophagy in neurons and glial cells and how deficits in these pathways may lead to neurodegeneration. We also highlight emerging therapeutic strategies aimed at restoring mitophagy to preserve neuronal homeostasis and function.

Mechanisms of autophagy–lysosome pathway impairment in Alzheimer's disease

The autophagy–lysosomal pathway is key for the removal of harmful substances in cells. This article integrates evidence that highlights the role of lysosomal function and the autophagy–lysosomal pathway in maintaining intracellular homeostasis and the effects of their dysfunction on protein secretion and metabolic disorders, leading to the pathogenesis of Alzheimer's disease (AD) and other tau diseases. Dysfunction of the autophagy-lysosomal pathway is believed to be the main factor leading to the accumulation of amyloid-β and tau proteins, which are also pathological features of AD. This article also discusses why autophagy is indispensable in the early to mature stages of neuronal development and how damage to the function of autophagy can cause neurodevelopmental abnormalities and neurodegenerative diseases. We also summarized the potential role of oligodendrocytes. We believe that its relationship with lysosomes can provide a new perspective and research direction for future research on neurodegenerative diseases. Autophagy-lysosomal pathway damage is considered to be a key factor in the pathology and diagnosis of multiple sclerosis, but we believe that the challenge associated with its transformation into clinical treatment is enormous. These findings suggest that enhancing or improving autophagy function may be an effective treatment method to alleviate the condition of AD patients, which can provide new strategies for clinical treatment and intervention of AD in the future.

The Autophagy-Senescence-Inflammasome Axis: A Novel Triad in Neurodegenerative Diseases?

Chronic neuroinflammation is a defining feature of brain ageing and neurodegenerative disorders, yet the molecular mechanisms responsible for its persistence remain incompletely understood. Although autophagy dysfunction, glial senescence, and inflammasome activation are well-established contributors to progressive neurodegeneration, these processes are often analysed independently or through pairwise interactions, leaving their collective contribution to persistent neuroinflammation and disease progression insufficiently defined. Here, we synthesise emerging evidence supporting an integrated 'Autophagy-Senescence-Inflammasome (ASI) axis', in which reciprocal interactions among impaired autophagy, senescent glia, and inflammasome signalling establish a self-sustaining cycle of neuroinflammation. We discuss how defective autophagy promotes mitochondrial dysfunction, oxidative stress, and danger signalling, while senescent astrocytes and microglia amplify inflammatory responses through the senescence-associated secretory phenotype (SASP). These intertwined processes converge on chronic inflammasome activation, with mitochondrial dysfunction emerging as a central mechanistic hub. Evidence across Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, stroke, and chronic neuropathic pain highlight the broad relevance of this pathological network. We further analyse current therapeutic strategies targeting autophagy, senescence, and inflammasome pathways, emphasising the limitations of single-target approaches and the potential of multi-target interventions. By integrating these processes into a unified framework, this review provides new insights into the possible molecular mechanisms underlying neuroinflammaging and identifies the 'ASI axis' as a promising target for neurodegenerative disease-modifying therapies.

Implication of Proteostasis Impairment and Endoplasmic Reticulum Stress in Age-Related Neurodegeneration

In insights on the research regarding therapeutic approaches of NDs which intend to target molecular components, a general understanding of proteostasis, ER stress, UPR signalling and how these cellular processes are related to neurodegeneration is provided.

G3BP1 depletion, observed in Parkinson's Disease, drives Golgi-lysosome-autophagy defects.

The RNA binding G3BP1 is depleted in several neurodegenerative diseases, yet its functional consequences at the cellular level remain poorly understood. While best known for its critical role in stress granule formation, we demonstrate that G3BP1 also stabilises the COPI vesicle protein beta-COP by promoting its interaction with the deubiquitinase USP10. G3BP1 depletion disrupts this interaction leading to increased ubiquitination of beta-COP, which accelerates its proteasomal degradation. This leads to compromised Golgi structure and function, and impaired lysosomal homeostasis, which causes defective autophagic flux. Consequently, the autophagic clearance of α-synuclein, a protein that can drive Parkinson's disease (PD), is significantly slowed. Importantly, we observe a concurrent reduction of both G3BP1 and beta-COP protein levels in brain sections from PD and dementia with Lewy Body (DLB) patients and from a PD mouse model. These findings reveal a novel mechanistic link between G3BP1, vesicular trafficking, and proteostasis in neurodegeneration.