The Complex Interplay between Toxic Hallmark Proteins, Calmodulin-Binding Proteins, Ion Channels, and Receptors Involved in Calcium Dyshomeostasis in Neurodegeneration

Biomolecules, Journal Year: 2024, Volume and Issue: 14(2), P. 173 - 173

Published: Jan. 31, 2024

Calcium dyshomeostasis is an early critical event in neurodegeneration as exemplified by Alzheimer’s (AD), Huntington’s (HD) and Parkinson’s (PD) diseases. Neuronal calcium homeostasis maintained a diversity of ion channels, buffers, calcium-binding protein effectors, intracellular storage the endoplasmic reticulum, mitochondria, lysosomes. The function these components compartments impacted toxic hallmark proteins AD (amyloid beta Tau), HD (huntingtin) PD (alpha-synuclein) well interactions with downstream proteins, especially calmodulin. Each beta, Tau, huntingtin, alpha-synuclein) binds to Multiple channels receptors involved dysregulation also bind are regulated primary goal this review show complexity how they can impact research search for therapies. A secondary suggest that therapeutic targets from may offer greater opportunities success.

Language: Английский

---

Longitudinal autophagy profiling of the mammalian brain reveals sustained mitophagy throughout healthy aging

The EMBO Journal, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 4, 2024

Abstract Mitophagy neutralizes mitochondrial damage, thereby preventing cellular dysfunction and apoptosis. Defects in mitophagy have been strongly implicated age-related neurodegenerative disorders such as Parkinson’s Alzheimer’s disease. While decreases throughout the lifespan of short-lived model organisms, it remains unknown whether a decline occurs aging mammalian brain—a question fundamental importance for understanding cell type- region-specific susceptibility to neurodegeneration. Here, we define longitudinal dynamics basal macroautophagy across neuronal non-neuronal types within intact mouse brain vivo. Quantitative profiling reporter cohorts from young geriatric ages reveals cell- tissue-specific alterations between distinct subregions populations, including dopaminergic neurons, cerebellar Purkinje cells, astrocytes, microglia interneurons. We also find that healthy is hallmarked by dynamic accumulation differentially acidified lysosomes several neural subsets. Our findings argue against any widespread mitophagic activity, instead demonstrating fluctuations trajectory, with strong implications ongoing theragnostic development.

Language: Английский

---

Inter-organellar Communication in Parkinson's and Alzheimer's Disease: Looking Beyond Endoplasmic Reticulum-Mitochondria Contact Sites

Frontiers in Neuroscience, Journal Year: 2022, Volume and Issue: 16

Published: June 21, 2022

Neurodegenerative diseases (NDs) are generally considered proteinopathies but whereas this may initiate disease in familial cases, onset sporadic originate from a gradually disrupted organellar homeostasis. Herein, endolysosomal abnormalities, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and altered lipid metabolism commonly observed early preclinical stages of major NDs, including Parkinson's (PD) Alzheimer's (AD). Among the multitude underlying defective molecular mechanisms that have been suggested past decades, dysregulation inter-organellar communication through so-called membrane contact sites (MCSs) is becoming increasingly apparent. Although MCSs exist between almost every other type subcellular organelle, to date, most focus has put on ER mitochondria given these compartments critical neuronal survival. Contributions MCSs, notably those with endolysosomes droplets emerging, supported as well by genetic studies, identifying genes functionally involved lysosomal In review, we summarize identity organelle interactome yeast mammalian cells, critically evaluate evidence supporting contribution disturbed general homeostasis taking PD AD examples.

Language: Английский

---

Transmembrane Protein 175, a Lysosomal Ion Channel Related to Parkinson’s Disease

Biomolecules, Journal Year: 2023, Volume and Issue: 13(5), P. 802 - 802

Published: May 9, 2023

Lysosomes are membrane-bound organelles with an acidic lumen and traditionally characterized as a recycling center in cells. Lysosomal ion channels integral membrane proteins that form pores lysosomal membranes allow the influx efflux of essential ions. Transmembrane protein 175 (TMEM175) is unique potassium channel shares little sequence similarity other channels. It found bacteria, archaea, animals. The prokaryotic TMEM175 consists one six-transmembrane domain adopts tetrameric architecture, while mammalian comprised two domains function dimer membranes. Previous studies have demonstrated K+ conductance mediated by critical for setting potential, maintaining pH stability, regulating lysosome–autophagosome fusion. AKT B-cell lymphoma 2 regulate TMEM175’s activity through direct binding. Two recent reported human also proton-selective under normal (4.5–5.5) permeation dramatically decreased at low H+ current greatly increased. Genome-wide association functional mouse models established implicated pathogenesis Parkinson’s disease, which sparks more research interests this channel.

Language: Английский

---

Valosin containing protein (VCP): initiator, modifier, and potential drug target for neurodegenerative diseases

Molecular Neurodegeneration, Journal Year: 2023, Volume and Issue: 18(1)

Published: Aug. 7, 2023

Abstract The AAA + ATPase valosin containing protein (VCP) is essential for cell and organ homeostasis, especially in cells of the nervous system. As part a large network, VCP collaborates with many cofactors to ensure proteostasis under normal, stress, disease conditions. A number mutations have revealed importance human health. In particular, facilitates dismantling aggregates removal dysfunctional organelles. These are critical events prevent malfunction brain other parts line this idea, mutants linked onset progression neurodegeneration diseases. intricate molecular mechanisms that connect distinct pathologies continue be uncovered. Emerging evidence supports model controls cellular functions on multiple levels type specific fashion. Accordingly, derail homeostasis through several can instigate disease. Our review focuses association between neurodegeneration. We discuss latest insights field, emphasize open questions, speculate potential as drug target some most devastating forms

Language: Английский

---