Molecular Mechanisms of Cellular Senescence in Neurodegenerative Diseases.

Neurodegenerative diseases, such as Alzheimer's and Parkinson's, are characterized by several pathological features, including selective neuronal loss, aggregation of specific proteins, and chronic inflammation. Aging is the most critical risk factor of these disorders. However, the mechanism by which aging contributes to the pathogenesis of neurodegenerative diseases is not clearly understood.

Inflammation promotes synucleinopathy propagation.

The clinical progression of neurodegenerative diseases correlates with the spread of proteinopathy in the brain. The current understanding of the mechanism of proteinopathy spread is far from complete. Here, we propose that inflammation is fundamental to proteinopathy spread.

Senescence and impaired DNA damage responses in alpha-synucleinopathy models.

α-Synuclein is a crucial element in the pathogenesis of Parkinson's disease (PD) and related neurological diseases. Although numerous studies have presented potential mechanisms underlying its pathogenesis, the understanding of α-synuclein-mediated neurodegeneration remains far from complete. Here, we show that overexpression of α-synuclein leads to impaired DNA repair and cellular senescence.

Alpha-Synuclein Inclusion Formation in Human Oligodendrocytes.

Multiple system atrophy (MSA) is a neurodegenerative disease characterized by presence of α-synuclein-positive inclusions in the cytoplasm of oligodendrocytes. These glial cytoplasmic inclusions (GCIs) are considered an integral part of the pathogenesis of MSA, leading to demyelination and neuronal demise. What is most puzzling in the research fields of GCIs is the origin of α-synuclein aggregates in GCIs, since adult oligodendrocytes do not express high levels of α-synuclein.

Models of multiple system atrophy.

Multiple system atrophy (MSA) is a neurodegenerative disease with diverse clinical manifestations, including parkinsonism, cerebellar syndrome, and autonomic failure. Pathologically, MSA is characterized by glial cytoplasmic inclusions in oligodendrocytes, which contain fibrillary forms of α-synuclein. MSA is categorized as one of the α-synucleinopathy, and α-synuclein aggregation is thought to be the culprit of the disease pathogenesis.

Arylsulfatase A, a genetic modifier of Parkinson's disease, is an α-synuclein chaperone.

Mutations in lysosomal genes increase the risk of neurodegenerative diseases, as is the case for Parkinson's disease. Here, we found that pathogenic and protective mutations in arylsulfatase A (ARSA), a gene responsible for metachromatic leukodystrophy, a lysosomal storage disorder, are linked to Parkinson's disease. Plasma ARSA protein levels were changed in Parkinson's disease patients.

LRRK2 kinase regulates α-synuclein propagation via RAB35 phosphorylation.

Propagation of α-synuclein aggregates has been suggested as a contributing factor in Parkinson's disease (PD) progression. However, the molecular mechanisms underlying α-synuclein aggregation are not fully understood. Here, we demonstrate in cell culture, nematode, and rodent models of PD that leucine-rich repeat kinase 2 (LRRK2), a PD-linked kinase, modulates α-synuclein propagation in a kinase activity-dependent manner.

Immunotherapy targeting toll-like receptor 2 alleviates neurodegeneration in models of synucleinopathy by modulating α-synuclein transmission and neuroinflammation.

Background: Synucleinopathies of the aging population are an heterogeneous group of neurological disorders that includes Parkinson's disease (PD) and dementia with Lewy bodies (DLB) and are characterized by the progressive accumulation of α-synuclein in neuronal and glial cells. Toll-like receptor 2 (TLR2), a pattern recognition immune receptor, has been implicated in the pathogenesis of synucleinopathies because TLR2 is elevated in the brains of patients with PD and TLR2 is a mediator of the neurotoxic and pro-inflammatory effects of extracellular α-synuclein aggregates. Therefore, blocking TLR2 might alleviate α-synuclein pathological and functional effects.

Mechanism of neuroprotection by trehalose: controversy surrounding autophagy induction.

Trehalose is a non-reducing disaccharide with two glucose molecules linked through an α, α-1,1-glucosidic bond. Trehalose has received attention for the past few decades for its role in neuroprotection especially in animal models of various neurodegenerative diseases, such as Parkinson and Huntington diseases. The mechanism underlying the neuroprotective effects of trehalose remains elusive.

Amplification of distinct α-synuclein fibril conformers through protein misfolding cyclic amplification.

Amyloid fibril formation has been implicated in the pathogenesis of neurodegenerative diseases. Fibrillation generates numerous conformers. Presumably, the conformers may possess specific biological properties, thus providing a biochemical framework for strains of prions.

Exposure to bacterial endotoxin generates a distinct strain of α-synuclein fibril.

A single amyloidogenic protein is implicated in multiple neurological diseases and capable of generating a number of aggregate "strains" with distinct structures. Among the amyloidogenic proteins, α-synuclein generates multiple patterns of proteinopathies in a group of diseases, such as Parkinson disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). However, the link between specific conformations and distinct pathologies, the key concept of the strain hypothesis, remains elusive.

Non-cell-autonomous Neurotoxicity of α-synuclein Through Microglial Toll-like Receptor 2.

Synucleinopathies are a collection of neurological diseases that are characterized by deposition of α-synuclein aggregates in neurons and glia. These diseases include Parkinson's disease (PD), dementia with Lewy bodies, and multiple system atrophy. Although it has been increasingly clear that α-synuclein is implicated in the pathogenesis of PD and other synucleinopathies, the precise mechanism underlying the disease process remains to be unraveled.

Antagonizing Neuronal Toll-like Receptor 2 Prevents Synucleinopathy by Activating Autophagy.

Impaired autophagy has been implicated in many neurodegenerative diseases, such as Parkinson's disease (PD), and might be responsible for deposition of aggregated proteins in neurons. However, little is known about how neuronal autophagy and clearance of aggregated proteins are regulated. Here, we show a role for Toll-like receptor 2 (TLR2), a pathogen-recognizing receptor in innate immunity, in regulation of neuronal autophagy and clearance of α-synuclein, a protein aggregated in synucleinopathies, including in PD.

Cell Models to Study Cell-to-Cell Transmission of α-Synuclein.

The cell-to-cell transmission of protein aggregates has been implicated in the progression of pathological phenotypes in neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. In recent years, several experimental model systems have been developed to study the mechanisms of cell-to-cell transmission. Herein, we describe cell culture models with which cell-to-cell transmission of α-synuclein can be quantitatively analyzed.

Loss of glucocerebrosidase 1 activity causes lysosomal dysfunction and α-synuclein aggregation.

Lysosomal dysfunction is a common pathological feature of neurodegenerative diseases. GTP-binding protein type A1 (GBA1) encodes β-glucocerebrosidase 1 (GCase 1), a lysosomal hydrolase. Homozygous mutations in GBA1 cause Gaucher disease, the most common lysosomal storage disease, while heterozygous mutations are strong risk factors for Parkinson's disease.

ATP13A2/PARK9 Deficiency Neither Cause Lysosomal Impairment Nor Alter α-Synuclein Metabolism in SH-SY5Y Cells.

Parkinson's disease is a multifactorial disorder with several genes linked to the familial types of the disease. ATP13A2 is one of those genes and encode for a transmembrane protein localized in lysosomes and late endosomes. Previous studies suggested the roles of this protein in lysosomal functions and cellular ion homeostasis.

Effects of plant-based Korean food extracts on lipopolysaccharide-stimulated production of inflammatory mediators in vitro.

Background/objectives: The traditional Korean diet is plant-based and rich in antioxidants. Previous studies have investigated the potential health benefits of individual nutrients of Korean foods. However, the cumulative effects of a Korean diet on inflammation remain poorly understood.