Alpha-Synuclein and Its Role in Melanocytes.
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ABSTRACT:
SUBMITTER: Rachinger N
PROVIDER: S-EPMC9265281 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Parkinson's disease (PD) is a pathological condition characterized by the aggregation and the resultant presence of intraneuronal inclusions termed Lewy bodies (LBs) and Lewy neurites which are mainly composed of fibrillar α-synuclein (α-syn) protein. Pathogenic aggregation of α-syn is identified as the major cause of LBs deposition. Several mutations in α-syn showing varied aggregation kinetics in comparison to the wild type (WT) α-syn are reported in PD (A30P, E46K, H 50Q, G51D, A53E, and A53T). Also, the cell-to-cell spread of pathological α-syn plays a significant role in PD development. Interestingly, it has also been suggested that the pathology of PD may begin in the gastrointestinal tract and spread via the vagus nerve (VN) to brain proposing the gut-brain axis of α-syn pathology in PD. Despite multiple efforts, the behavior and functions of this protein in normal and pathological states (specifically in PD) is far from understood. Furthermore, the etiological factors responsible for triggering aggregation of this protein remain elusive. This review is an attempt to collate and present latest information on α-syn in relation to its structure, biochemistry and biophysics of aggregation in PD. Current advances in therapeutic efforts toward clearing the pathogenic α-syn via autophagy/lysosomal flux are also reviewed and reported.
| S-EPMC8194081 | biostudies-literature
Project description:alpha-Synuclein has been linked to the pathogenesis of Parkinson's disease and other synucleinopathies through its propensity to form toxic oligomers. The exact mechanism for oligomeric synuclein-directed cell vulnerability has not been fully elucidated, but one hypothesis portends the formation of synuclein-containing pores within cell membranes leading to leak channel-mediated calcium influx and subsequent cell death. Here we demonstrate synuclein-induced formation of sodium dodecyl sulfate-stable oligomers, intracellular synuclein-positive aggregates, alterations in membrane conductance reminiscent of leak channels and subsequent cytotoxicity in a dopaminergic-like cell line. Furthermore we demonstrate that the synuclein-induced membrane conductance changes are blocked by direct extracellular application of an anti-synuclein antibody. The work presented here confirms that synuclein overexpression leads to membrane conductance changes and demonstrates for the first time through antibody-blocking studies that synuclein plays a direct role in the formation of leak channels.
| S-EPMC2900531 | biostudies-literature
Project description:The abnormal accumulation of alpha-synuclein (α-syn) aggregates in neurons and glial cells is widely known to be associated with many neurodegenerative diseases, including Parkinson's disease (PD), Dementia with Lewy bodies (DLB), and Multiple system atrophy (MSA). Mitochondrial dysfunction in neurons and glia is known as a key feature of α-syn toxicity. Studies aimed at understanding α-syn-induced toxicity and its role in neurodegenerative diseases have primarily focused on neurons. However, a growing body of evidence demonstrates that glial cells such as microglia and astrocytes have been implicated in the initial pathogenesis and the progression of α-Synucleinopathy. Glial cells are important for supporting neuronal survival, synaptic functions, and local immunity. Furthermore, recent studies highlight the role of mitochondrial metabolism in the normal function of glial cells. In this work, we review the complex relationship between glial mitochondria and α-syn-mediated neurodegeneration, which may provide novel insights into the roles of glial cells in α-syn-associated neurodegenerative diseases.
| S-EPMC7686475 | biostudies-literature
Project description:BackgroundAlpha-synuclein (αS) is a nerve cell protein associated with Parkinson disease (PD). Accumulation of αS within the enteric nervous system (ENS) and its traffic from the gut to the brain are implicated in the pathogenesis and progression of PD. αS has no known function in humans and the reason for its accumulation within the ENS is unknown. Several recent studies conducted in rodents have linked αS to immune cell activation in the central nervous system. We hypothesized that αS in the ENS might play a role in the innate immune defenses of the human gastrointestinal (GI) tract.MethodsWe immunostained endoscopic biopsies for αS from children with documented gastric and duodenal inflammation and intestinal allograft recipients who contracted norovirus. To determine whether αS exhibited immune-modulatory activity, we examined whether human αS induced leukocyte migration and dendritic cell maturation.FindingsWe showed that the expression of αS in the enteric neurites of the upper GI tract of pediatric patients positively correlated with the degree of acute and chronic inflammation in the intestinal wall. In intestinal allograft subjects who were closely monitored for infection, expression of αS was induced during norovirus infection. We also demonstrated that both monomeric and oligomeric αS have potent chemoattractant activity, causing the migration of neutrophils and monocytes dependent on the presence of the integrin subunit, CD11b, and that both forms of αS stimulate dendritic cell maturation.InterpretationThese findings strongly suggest that αS is expressed within the human ENS to direct intestinal inflammation and implicates common GI infections in the pathogenesis of PD.
| S-EPMC5865636 | biostudies-literature
Project description:Amyloid fibrils of ?-synuclein are the main constituent of Lewy bodies deposited in substantial nigra of Parkinson's disease brains. ?-Synuclein is an intrinsically disordered protein lacking compact secondary and tertiary structures. To enhance the understanding of its structure and function relationship, we utilized temperature treatment to study ?-synuclein conformational changes and the subsequent effects. We found that after 1 hr of high temperature pretreatment, >80°C, ?-synuclein fibrillization was significantly inhibited. However, the temperature melting coupled with circular dichroism spectra showed that ?-synuclein was fully reversible and the NMR studies showed no observable structural changes of ?-synuclein after 95°C treatment. By using cross-linking and analytical ultracentrifugation, rare amount of pre-existing ?-synuclein oligomers were found to decrease after the high temperature treatment. In addition, a small portion of C-terminal truncation of ?-synuclein also occurred. The reduction of pre-existing oligomers of ?-synuclein may contribute to less seeding effect that retards the kinetics of amyloid fibrillization. Overall, our results showed that the pre-existing oligomeric species is a key factor contributing to ?-synuclein fibrillization. Our results facilitate the understanding of ?-synuclein fibrillization.
| S-EPMC3551866 | biostudies-literature
Project description:The α-synuclein is a major component of amyloid fibrils found in Lewy bodies, the characteristic intracellular proteinaceous deposits which are pathological hallmarks of neurodegenerative diseases such as Parkinson's disease (PD) and dementia. It is an intrinsically disordered protein that may undergo dramatic structural changes to form amyloid fibrils. Aggregation process from α-synuclein monomers to amyloid fibrils through oligomeric intermediates is considered as the disease-causative toxic mechanism. However, mechanism underlying aggregation is not well-known despite several attempts. To characterize the mechanism, we have explored the effects of pH and temperature on the structural properties of wild-type and mutant α-synuclein using molecular dynamics (MD) simulation technique. MD studies suggested that amyloid fibrils can grow by monomer. Conformational transformation of the natively unfolded protein into partially folded intermediate could be accountable for aggregation and fibrillation. An intermediate α-strand was observed in the hydrophobic non-amyloid-β component (NAC) region of α-synuclein that could proceed to α-sheet and initiate early assembly events. Water network around the intermediate was analyzed to determine its influence on the α-strand structure. Findings of this study provide novel insights into possible mechanism of α-synuclein aggregation and promising neuroprotective strategy that could aid alleviate PD and its symptoms.
| S-EPMC6329781 | biostudies-literature
Project description:Misfolded ?-synuclein is a key factor in the pathogenesis of Parkinson's disease (PD). However, knowledge about a physiological role for the native, unfolded ?-synuclein is limited. Using brains of mice lacking ?-, ?-, and ?-synuclein, we report that extracellular monomeric ?-synuclein enters neurons and localizes to mitochondria, interacts with ATP synthase subunit ?, and modulates ATP synthase function. Using a combination of biochemical, live-cell imaging and mitochondrial respiration analysis, we found that brain mitochondria of ?-, ?-, and ?-synuclein knock-out mice are uncoupled, as characterized by increased mitochondrial respiration and reduced mitochondrial membrane potential. Furthermore, synuclein deficiency results in reduced ATP synthase efficiency and lower ATP levels. Exogenous application of low unfolded ?-synuclein concentrations is able to increase the ATP synthase activity that rescues the mitochondrial phenotypes observed in synuclein deficiency. Overall, the data suggest that ?-synuclein is a previously unrecognized physiological regulator of mitochondrial bioenergetics through its ability to interact with ATP synthase and increase its efficiency. This may be of particular importance in times of stress or PD mutations leading to energy depletion and neuronal cell toxicity. SIGNIFICANCE STATEMENT:Misfolded ?-synuclein aggregations in the form of Lewy bodies have been shown to be a pathological hallmark in histological staining of Parkinson's disease (PD) patient brains. It is known that misfolded ?-synuclein is a key driver in PD pathogenesis, but the physiological role of unfolded monomeric ?-synuclein remains unclear. Using neuronal cocultures and isolated brain mitochondria of ?-, ?-, and ?-synuclein knock-out mice and monomeric ?-synuclein, this current study shows that ?-synuclein in its unfolded monomeric form improves ATP synthase efficiency and mitochondrial function. The ability of monomeric ?-synuclein to enhance ATP synthase efficiency under physiological conditions may be of importance when ?-synuclein undergoes the misfolding and aggregation reported in PD.
| S-EPMC5059426 | biostudies-literature
Project description:Parkinson's disease (PD) is a progressive brain disorder that interferes with activities of normal life. The main pathological feature of this disease is the loss of more than 80% of dopamine-producing neurons in the substantia nigra (SN). Dopaminergic neuronal cell death occurs when intraneuronal, insoluble, aggregated proteins start to form Lewy bodies (LBs), the most important component of which is a protein called α-synuclein (α-syn). α-Syn structurally contains hexameric repeats of 11 amino acids, which are characteristic of apolipoproteins and thus α-syn can also be considered an apolipoprotein. Moreover, apolipoproteins seem to be involved in the incidence and development of PD. Some apolipoproteins such as ApoD have a neuroprotective role in the brain. In PD, apoD levels increase in glial cells surrounding dopaminergic cells. However, elevated levels of some other apolipoproteins such as ApaA1 and ApoE are reported as a vulnerability factor of PD. At present, when a clinical diagnosis of PD is made, based on symptoms such as shaking, stiff muscles and slow movement, serious damage has already been done to nerve cells of the SN. The diagnosis of PD in its earlier stages, before this irreversible damage, would be of enormous benefit for future treatment strategies designed to slow or halt the progression of PD. This review presents the roles of apolipoproteins and α-syn in PD and how some of them could potentially be used as biomarkers for PD.
| S-EPMC5541107 | biostudies-other
Project description:Parkinson´s disease (PD) pathology progresses throughout the nervous system. Whereas motor symptoms are always present, there is a high variability in the prevalence of non-motor symptoms. It has been postulated that the progression of the pathology is based on a prion-like disease mechanism partly due to the seeding effect of endocytosed-alpha-synuclein (ASYN) on the endogenous ASYN. Here, we analyzed the role of endogenous ASYN in the progression of PD-like pathology in vivo and in vitro and compared the effect of endocytosed-ASYN as well as paraquat and rotenone on primary enteric, dopaminergic and cortical neurons from wild-type and ASYN-KO mice. Our results show that, in vivo, pathology progression did not occur in the absence of endogenous ASYN. Remarkably, the damage caused by endocytosed-ASYN, rotenone or paraquat was independent from endogenous ASYN and related to the alteration of the host´s mitochondrial membrane potential. Dopaminergic neurons were very sensitive to these noxae compared to other neuronal subtypes. These results suggest that ASYN-mitochondrial interactions play a major role in initiating the pathological process in the host neuron and endogenous ASYN is essential for the transsynaptical transmission of the pathology. Our results also suggest that protecting mitochondrial function is a valid primary therapeutic target.
| S-EPMC9763379 | biostudies-literature
Project description:Emerging evidence supports that altered α-tubulin acetylation occurs in Parkinson's disease (PD), a neurodegenerative disorder characterized by the deposition of α-synuclein fibrillary aggregates within Lewy bodies and nigrostriatal neuron degeneration. Nevertheless, studies addressing the interplay between α-tubulin acetylation and α-synuclein are lacking. Here, we investigated the relationship between α-synuclein and microtubules in primary midbrain murine neurons and the substantia nigra of post-mortem human brains. Taking advantage of immunofluorescence and Proximity Ligation Assay (PLA), a method allowing us to visualize protein-protein interactions in situ, combined with confocal and super-resolution microscopy, we found that α-synuclein and acetylated α-tubulin colocalized and were in close proximity. Next, we employed an α-synuclein overexpressing cellular model and tested the role of α-tubulin acetylation in α-synuclein oligomer formation. We used the α-tubulin deacetylase HDAC6 inhibitor Tubacin to modulate α-tubulin acetylation, and we evaluated the presence of α-synuclein oligomers by PLA. We found that the increase in acetylated α-tubulin significantly induced α-synuclein oligomerization. In conclusion, we unraveled the link between acetylated α-tubulin and α-synuclein and demonstrated that α-tubulin acetylation could trigger the early step of α-synuclein aggregation. These data suggest that the proper regulation of α-tubulin acetylation might be considered a therapeutic strategy to take on PD.
| S-EPMC10418364 | biostudies-literature