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Hematology (Amsterdam, Netherlands) Dec 2022α-synuclein (α-syn) is a highly conserved and thermostable protein that is widely distributed in human brain. An intracellular aggregation of α-syn in dopaminergic... (Review)
Review
α-synuclein (α-syn) is a highly conserved and thermostable protein that is widely distributed in human brain. An intracellular aggregation of α-syn in dopaminergic neurons is the hallmark of a group of neurodegenerative diseases including Parkinson's disease. Interestingly, α-syn is also highly expressed in red blood cells and is considered as one of the most abundant proteins in red blood cells. Moreover, α-syn is thought to play a regulatory role during normal erythropoiesis. However, whether α-syn participates in the pathogenesis of erythroid diseases has not been reported. In this review, we discuss the protein structure of α-syn and the importance of α-syn in erythropoiesis.
Topics: Brain; Erythropoiesis; Humans; Neurodegenerative Diseases; Parkinson Disease; alpha-Synuclein
PubMed: 35621991
DOI: 10.1080/16078454.2022.2078041 -
Experimental & Molecular Medicine Dec 2022The clinical progression of neurodegenerative diseases correlates with the spread of proteinopathy in the brain. The current understanding of the mechanism of...
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. A sequence variant of α-synuclein (V40G) was much less capable of fibril formation than wild-type α-synuclein (WT-syn) and, when mixed with WT-syn, interfered with its fibrillation. However, when V40G was injected intracerebrally into mice, it induced aggregate spreading even more effectively than WT-syn. Aggregate spreading was preceded by sustained microgliosis and inflammatory responses, which were more robust with V40G than with WT-syn. Oral administration of an anti-inflammatory agent suppressed aggregate spreading, inflammation, and behavioral deficits in mice. Furthermore, exposure of cells to inflammatory cytokines increased the cell-to-cell propagation of α-synuclein. These results suggest that the inflammatory microenvironment is the major driver of the spread of synucleinopathy in the brain.
Topics: Mice; Animals; alpha-Synuclein; Synucleinopathies; Brain; Neurodegenerative Diseases; Inflammation; Disease Models, Animal
PubMed: 36473937
DOI: 10.1038/s12276-022-00895-w -
Methods in Cell Biology 2022Alpha-synuclein (α-syn) is a natively unfolded protein that is abundantly expressed in the central nervous system. Although it has been shown to be involved in...
Alpha-synuclein (α-syn) is a natively unfolded protein that is abundantly expressed in the central nervous system. Although it has been shown to be involved in neurotransmission and cognition, its exact functions remain elusive. The misfolding of this protein into β-sheet-rich amyloid structures and subsequent aggregation has been associated with several neurodegenerative diseases, including Parkinson's disease. The interaction of α-syn with lipid membranes has been implicated in the formation of these pathological aggregates. At the same time, some physiological functions of α-syn also seem to require membrane interactions. A majority of the disease-associated mutations of α-syn occur in the lipid binding domain, further indicating the importance of membrane interactions in health and disease. A comprehensive understanding of the factors that modulate these interactions will help delineate the physiological and pathological states of this protein.
Topics: Lipids; Mutation; alpha-Synuclein
PubMed: 35623711
DOI: 10.1016/bs.mcb.2021.12.002 -
Science Advances Mar 2024Stressed cells secret misfolded proteins lacking signaling sequence via an unconventional protein secretion (UcPS) pathway, but how misfolded proteins are targeted...
Stressed cells secret misfolded proteins lacking signaling sequence via an unconventional protein secretion (UcPS) pathway, but how misfolded proteins are targeted selectively in UcPS is unclear. Here, we report that misfolded UcPS clients are subject to modification by a ubiquitin-like protein named ubiquitin-fold modifier 1 (UFM1). Using α-synuclein (α-Syn) as a UcPS model, we show that mutating the UFMylation sites in α-Syn or genetic inhibition of the UFMylation system mitigates α-Syn secretion, whereas overexpression of UFBP1, a component of the endoplasmic reticulum-associated UFMylation ligase complex, augments α-Syn secretion in mammalian cells and in model organisms. UFM1 itself is cosecreted with α-Syn, and the serum UFM1 level correlates with that of α-Syn. Because UFM1 can be directly recognized by ubiquitin specific peptidase 19 (USP19), a previously established UcPS stimulator known to associate with several chaperoning activities, UFMylation might facilitate substrate engagement by USP19, allowing stringent and regulated selection of misfolded proteins for secretion and proteotoxic stress alleviation.
Topics: Animals; Humans; alpha-Synuclein; Protein Transport; Endoplasmic Reticulum; Mammals; Endopeptidases
PubMed: 38489364
DOI: 10.1126/sciadv.adk2542 -
Aging Cell Mar 2023The aggregation of α-synuclein plays a pivotal role in the pathogenesis of Parkinson's disease (PD). Epidemiological evidence indicates that high level of homocysteine...
The aggregation of α-synuclein plays a pivotal role in the pathogenesis of Parkinson's disease (PD). Epidemiological evidence indicates that high level of homocysteine (Hcy) is associated with an increased risk of PD. However, the molecular mechanisms remain elusive. Here, we report that homocysteine thiolactone (HTL), a reactive thioester of Hcy, covalently modifies α-synuclein on the K80 residue. The levels of α-synuclein K80Hcy in the brain are increased in an age-dependent manner in the TgA53T mice, correlating with elevated levels of Hcy and HTL in the brain during aging. The N-homocysteinylation of α-synuclein stimulates its aggregation and forms fibrils with enhanced seeding activity and neurotoxicity. Intrastriatal injection of homocysteinylated α-synuclein fibrils induces more severe α-synuclein pathology and motor deficits when compared with unmodified α-synuclein fibrils. Increasing the levels of Hcy aggravates α-synuclein neuropathology in a mouse model of PD. In contrast, blocking the N-homocysteinylation of α-synuclein ameliorates α-synuclein pathology and degeneration of dopaminergic neurons. These findings suggest that the covalent modification of α-synuclein by HTL promotes its aggregation. Targeting the N-homocysteinylation of α-synuclein could be a novel therapeutic strategy against PD.
Topics: Animals; Mice; alpha-Synuclein; Parkinson Disease
PubMed: 36437524
DOI: 10.1111/acel.13745 -
Nature Reviews. Neuroscience Feb 2022For the last two decades, pathogenic concepts in Parkinson disease (PD) have revolved around the toxicity and spread of α-synuclein. Thus, α-synuclein would follow... (Review)
Review
For the last two decades, pathogenic concepts in Parkinson disease (PD) have revolved around the toxicity and spread of α-synuclein. Thus, α-synuclein would follow caudo-rostral propagation from the periphery to the central nervous system, first producing non-motor manifestations (such as constipation, sleep disorders and hyposmia), and subsequently impinging upon the mesencephalon to account for the cardinal motor features before reaching the neocortex as the disease evolves towards dementia. This model is the prevailing theory of the principal neurobiological mechanism of disease. Here, we scrutinize the temporal evolution of motor and non-motor manifestations in PD and suggest that, even though the postulated bottom-up mechanisms are likely to be involved, early involvement of the nigrostriatal system is a key and prominent pathophysiological mechanism. Upcoming studies of detailed clinical manifestations with newer neuroimaging techniques will allow us to more closely define, in vivo, the role of α-synuclein aggregates with respect to neuronal loss during the onset and progression of PD.
Topics: Animals; Efferent Pathways; Humans; Neural Pathways; Parkinson Disease; alpha-Synuclein
PubMed: 34907352
DOI: 10.1038/s41583-021-00542-9 -
Translational Neurodegeneration Apr 2022Alpha-synuclein (α-syn) exhibits pathological misfolding in many human neurodegenerative disorders. We previously showed that α-syn is arginylated in the mouse brain...
BACKGROUND
Alpha-synuclein (α-syn) exhibits pathological misfolding in many human neurodegenerative disorders. We previously showed that α-syn is arginylated in the mouse brain and that lack of arginylation leads to neurodegeneration in mice.
METHODS
Here, we tested α-syn arginylation in human brain pathology using newly derived antibodies in combination with Western blotting, biochemical assays, and experiments in live neurons.
RESULTS
We found that α-syn was arginylated in the human brain on E46 and E83, two sites previously implicated in α-syn pathology and familial cases of Parkinson's disease. The levels of arginylation in different brain samples ranged between ~ 3% and ~ 50% of the total α-syn pool, and this arginylation nearly exclusively concentrated in the subcellular α-syn fraction that sedimented at low centrifugation speeds and appeared to be simultaneously targeted by multiple posttranslational modifications. Arginylated α-syn was less susceptible to S129 phosphorylation and pathological aggregation in neurons. The arginylation level inversely correlated with the overall α-syn levels and with patient age, suggesting a possible causal relationship between arginylation decline and α-syn-dependent neuropathology.
CONCLUSION
We propose that α-syn arginylation constitutes a potential neuroprotective mechanism that prevents its abnormal accumulation during neurodegeneration and aging in the human brain.
Topics: Animals; Brain; Humans; Mice; Neurodegenerative Diseases; Parkinson Disease; Synucleinopathies; alpha-Synuclein
PubMed: 35395956
DOI: 10.1186/s40035-022-00295-0 -
International Journal of Molecular... Jun 2022α-Synuclein is a protein with a molecular weight of 14.5 kDa and consists of 140 amino acids encoded by the gene. Missense mutations and gene duplications in the gene... (Review)
Review
α-Synuclein is a protein with a molecular weight of 14.5 kDa and consists of 140 amino acids encoded by the gene. Missense mutations and gene duplications in the gene cause hereditary Parkinson's disease. Highly phosphorylated and abnormally aggregated α-synuclein is a major component of Lewy bodies found in neuronal cells of patients with sporadic Parkinson's disease, dementia with Lewy bodies, and glial cytoplasmic inclusion bodies in oligodendrocytes with multiple system atrophy. Aggregated α-synuclein is cytotoxic and plays a central role in the pathogenesis of the above-mentioned synucleinopathies. In a healthy brain, most α-synuclein is unphosphorylated; however, more than 90% of abnormally aggregated α-synuclein in Lewy bodies of patients with Parkinson's disease is phosphorylated at Ser129, which is presumed to be of pathological significance. Several kinases catalyze Ser129 phosphorylation, but the role of phosphorylation enzymes in disease pathogenesis and their relationship to cellular toxicity from phosphorylation are not fully understood in α-synucleinopathy. Consequently, this review focuses on the pathogenic impact of α-synuclein phosphorylation and its kinases during the neurodegeneration process in α-synucleinopathy.
Topics: Humans; Lewy Bodies; Parkinson Disease; Phosphorylation; Synucleinopathies; alpha-Synuclein
PubMed: 35682892
DOI: 10.3390/ijms23116216 -
International Journal of Molecular... Mar 2024Synucleins are a family of proteins consisting of α, β, and γ synuclein (syn) [...].
Synucleins are a family of proteins consisting of α, β, and γ synuclein (syn) [...].
Topics: alpha-Synuclein; beta-Synuclein; gamma-Synuclein
PubMed: 38542197
DOI: 10.3390/ijms25063223 -
Proceedings of the National Academy of... Jun 2023α-Synuclein accumulates in Lewy bodies, and this accumulation is a pathological hallmark of Parkinson's disease (PD). Previous studies have indicated a causal role of...
α-Synuclein accumulates in Lewy bodies, and this accumulation is a pathological hallmark of Parkinson's disease (PD). Previous studies have indicated a causal role of α-synuclein in the pathogenesis of PD. However, the molecular and cellular mechanisms of α-synuclein toxicity remain elusive. Here, we describe a novel phosphorylation site of α-synuclein at T64 and the detailed characteristics of this post-translational modification. T64 phosphorylation was enhanced in both PD models and human PD brains. T64D phosphomimetic mutation led to distinct oligomer formation, and the structure of the oligomer was similar to that of α-synuclein oligomer with A53T mutation. Such phosphomimetic mutation induced mitochondrial dysfunction, lysosomal disorder, and cell death in cells and neurodegeneration in vivo, indicating a pathogenic role of α-synuclein phosphorylation at T64 in PD.
Topics: Humans; Parkinson Disease; alpha-Synuclein; Phosphorylation; Lewy Bodies; Brain
PubMed: 37252975
DOI: 10.1073/pnas.2214652120