Key genes and convergent pathogenic mechanisms in Parkinson disease

Nature reviews. Neuroscience, Journal Year: 2024, Volume and Issue: 25(6), P. 393 - 413

Published: April 10, 2024

Language: Английский

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Cell biology of Parkinson's disease: Mechanisms of synaptic, lysosomal, and mitochondrial dysfunction

Current Opinion in Neurobiology, Journal Year: 2024, Volume and Issue: 85, P. 102841 - 102841

Published: Feb. 1, 2024

Language: Английский

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Autophagy, aging, and age-related neurodegeneration

Neuron, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 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.

Language: Английский

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Neuronal Autophagy: Regulations and Implications in Health and Disease

Cells, Journal Year: 2024, Volume and Issue: 13(1), P. 103 - 103

Published: Jan. 4, 2024

Autophagy is a major degradative pathway that plays key role in sustaining cell homeostasis, integrity, and physiological functions. Macroautophagy, which ensures the clearance of cytoplasmic components engulfed double-membrane autophagosome fuses with lysosomes, orchestrated by complex cascade events. has particularly strong impact on nervous system, mutations core cause numerous neurological diseases. We first review regulation autophagy, from biogenesis to lysosomal degradation associated neurodevelopmental/neurodegenerative disorders. then describe how this process specifically regulated axon somatodendritic compartment it altered In particular, we present neuronal specificities spatial control biogenesis, close relationship maturation axonal transport, synaptic activity. Finally, discuss functions autophagy during development adulthood.

Language: Английский

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Identification of secretory autophagy as a mechanism modulating activity-induced synaptic remodeling

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(16)

Published: April 8, 2024

The ability of neurons to rapidly remodel their synaptic structure and strength in response neuronal activity is highly conserved across species crucial for complex brain functions. However, mechanisms required elicit coordinate the acute, activity-dependent structural changes synapses are not well understood, as neurodevelopment plasticity tightly linked. Here, using an RNAi screen Drosophila against genes affecting nervous system functions humans, we uncouple cellular processes important synapse development. We find mutations associated with neurodegenerative mental health disorders 2-times more likely affect activity-induced remodeling than report that while both development at fly NMJ require macroautophagy (hereafter referred autophagy), bifurcation autophagy pathway differentially impacts plasticity. demonstrate enhances activation but diminishes degradative autophagy, thereby driving towards autophagy-based secretion. Presynaptic knockdown Snap29, Sec22, or Rab8, proteins implicated secretory pathway, sufficient abolish remodeling. This study uncovers a transsynaptic signaling mechanism modulating

Language: Английский

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Epigenetic regulation of autophagy-related genes: Implications for neurodevelopmental disorders

Autophagy, Journal Year: 2023, Volume and Issue: 20(1), P. 15 - 28

Published: Sept. 6, 2023

Macroautophagy/autophagy is an evolutionarily highly conserved catabolic process that important for the clearance of cytosolic contents to maintain cellular homeostasis and survival. Recent findings point toward a critical role autophagy in brain function, not only by preserving neuronal health, but especially controlling different aspects development functioning. In line with this, mutations autophagy-related genes are linked various key characteristics symptoms neurodevelopmental disorders (NDDs), including autism, micro-/macrocephaly, epilepsy. However, group NDDs caused relatively small. A significant proportion associated encoding epigenetic regulatory proteins modulate gene expression, so-called chromatinopathies. Intriguingly, several NDD-linked chromatinopathy have been shown regulate genes, albeit non-neuronal contexts. From these studies it becomes evident tight transcriptional regulation crucial control autophagic activity. This opens exciting possibility aberrant might underly nervous system impairments disturbed regulation. We here summarize NDD-related known genes. Thereby, we want highlight as candidate hub mechanism

Language: Английский

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Endophilin-A/SH3GL2 calcium switch for synaptic autophagy induction is impaired by a Parkinson’s risk variant

Autophagy, Journal Year: 2023, Volume and Issue: 20(4), P. 925 - 927

Published: April 17, 2023

At the synapse, proteins are reused several times during neuronal activity, causing a decline in protein function over time. Although emerging evidence supports role of autophagy synaptic function, precise molecular mechanisms linking and dysfunction vastly unknown. We show how extracellular calcium influx pre-synaptic terminal constitutes initial stimulus for autophagosome formation response to activity. This mechanism likely acts rapidly support homeostasis quality control when intense activity challenges proteome. identified residue flexible region EndoA (Endophilin A) that dictates calcium-dependent mobility from plasma membrane cytosol, where this interacts with autophagic membranes promote formation. discovered novel Parkinson's disease-risk mutation SH3GL2 (SH3 domain containing GRB2 like 2, endophilin A1) disrupts sensing SH3GL2, leading an immobile cannot respond therefore disrupting induction at synapses. Our work shows is connected maintain survival.

Language: Английский

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Dysfunction of synaptic endocytic trafficking in Parkinson’s disease

Neural Regeneration Research, Journal Year: 2024, Volume and Issue: 19(12), P. 2649 - 2660

Published: March 1, 2024

Parkinson’s disease is characterized by the selective degeneration of dopamine neurons in nigrostriatal pathway and deficiency striatum. The precise reasons behind specific these remain largely elusive. Genetic investigations have identified over 20 causative PARK genes 90 genomic risk loci associated with both familial sporadic disease. Notably, several are linked to synaptic vesicle recycling process, particularly clathrin-mediated endocytosis pathway. This suggests that impaired might represent an early feature disease, followed axonal eventual loss cell bodies midbrain via a “dying back” mechanism. Recently, new animal cellular models disease-linked mutations affecting endocytic been created extensively characterized. These faithfully recapitulate certain disease-like features at animal, circuit, levels, exhibit defects membrane trafficking, further supporting findings from human genetics clinical studies. In this review, we will first summarize molecular two clathrin uncoating proteins: auxilin ( DNAJC6 / PARK19 ) synaptojanin 1 SYNJ1 PARK20 ). mouse carrying gene phenocopy each other terminal pathology display potent synergistic effect. Subsequently, delve into involvement endocytosis-related proteins (GAK, endophilin A1, SAC2/INPP5F, synaptotagmin-11), as factors through genome-wide association studies, pathogenesis. We also explore direct or indirect roles some common (alpha-synuclein (PARK1/4), Parkin (PARK2), LRRK2 (PARK8)) trafficking. Additionally, discuss emerging novel functions downstream traffic pathways, autophagy. Given dysfunction considered event deeper understanding mechanisms underlying trafficking may unveil targets for diagnosis development interventional therapies Future research should aim elucidate why generalized leads

Language: Английский

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Mechanisms of Copper-Induced Autophagy and Links with Human Diseases

Pharmaceuticals, Journal Year: 2025, Volume and Issue: 18(1), P. 99 - 99

Published: Jan. 15, 2025

As a structural and catalytic cofactor, copper is involved in many biological pathways required for the biochemistry of all living organisms. However, excess intracellular can induce cell death due to its potential catalyze generation reactive oxygen species, thus homeostasis strictly regulated. And deficiency or accumulation connected with various pathological conditions. Since success platinum-based compounds clinical treatment types neoplasias, metal-based drugs have shown encouraging perspectives drug development. Compared platinum, an essential trace element that may better prospects development than platinum. Recently, therapeutic role copper-induced autophagy chronic diseases such as Parkinson’s, Wilson’s, cardiovascular disease has already been demonstrated. In brief, ions, numerous complexes, copper-based nano-preparations could autophagy, lysosome-dependent process plays important human diseases. this review, we not only focus on current advances elucidating mechanisms compounds/preparations regulation but also outline association between

Language: Английский

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Neuronal autophagy in the control of synapse function

Neuron, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Neurons are long-lived postmitotic cells that capitalize on autophagy to remove toxic or defective proteins and organelles maintain neurotransmission the integrity of their functional proteome. Mutations in genes cause congenital diseases, sharing prominent brain dysfunctions including epilepsy, intellectual disability, neurodegeneration. Ablation core neurons glia disrupts normal behavior, leading motor deficits, memory impairment, altered sociability, which associated with defects synapse maturation, plasticity, neurotransmitter release. In spite importance for physiology, substrates neuronal mechanisms by affect synaptic function health disease remain controversial. Here, we summarize current state knowledge autophagy, address existing controversies inconsistencies field, provide a roadmap future research role control function.

Language: Английский

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