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Biomolecules ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 142
Author(s):  
Junna Hayashi ◽  
John A. Carver

α-Synuclein (αS) is a small, unstructured, presynaptic protein expressed in the brain. Its aggregated form is a major component of Lewy bodies, the large proteinaceous deposits in Parkinson’s disease. The closely related protein, β-Synuclein (βS), is co-expressed with αS. In vitro, βS acts as a molecular chaperone to inhibit αS aggregation. As a result of this assignation, βS has been largely understudied in comparison to αS. However, recent reports suggest that βS promotes neurotoxicity, implying that βS is involved in other cellular pathways with functions independent of αS. Here, we review the current literature pertaining to human βS in order to understand better the role of βS in homeostasis and pathology. Firstly, the structure of βS is discussed. Secondly, the ability of βS to (i) act as a molecular chaperone; (ii) regulate synaptic function, lipid binding, and the nigrostriatal dopaminergic system; (iii) mediate apoptosis; (iv) participate in protein degradation pathways; (v) modulate intracellular metal levels; and (vi) promote cellular toxicity and protein aggregation is explored. Thirdly, the P123H and V70M mutations of βS, which are associated with dementia with Lewy bodies, are discussed. Finally, the importance of post-translational modifications on the structure and function of βS is reviewed. Overall, it is concluded that βS has both synergistic and antagonistic interactions with αS, but it may also possess important cellular functions independent of αS.


Author(s):  
Berkiye Sonustun ◽  
Firat M Altay ◽  
Catherine Strand ◽  
Geshanthi Hondhamuni ◽  
Thomas T Warner ◽  
...  

Aggregated alpha-synuclein (-synuclein) is the main component of Lewy bodies (LBs), Lewy neurites (LNs), and glial cytoplasmic inclusions (GCIs), which are pathological hallmarks of idiopathic Parkinson’s disease (IPD) and multiple system atrophy (MSA), respectively. Initiating factors that culminate in forming LBs/LNs/GCIs remain elusive. Several species of -synuclein exist, including phosphorylated and nitrated forms. It is unclear which -synuclein post-translational modifications (PTMs) appear within aggregates throughout disease pathology. Herein we aimed to establish the predominant synuclein PTMs in post-mortem IPD and MSA pathology using immunohistochemistry. We examined the patterns of three -synuclein PTMs (pS87, pS129, nY39) simultaneously in pathology-affected regions of 15 PD, 5 MSA, 6 neurologically normal controls. All antibodies recognized LBs, LNs, and GCIs, albeit to a variable extent. pS129 -synuclein antibody was particularly immunopositive for LNs and synaptic dot-like structures followed by nY39 -synuclein antibody. GCIs, neuronal inclusions, and small threads were positive for nY39 -synuclein in MSA. Quantification of the LB scores revealed that pS129 -synuclein was the dominant and earliest -synuclein PTM followed by nY39 -synuclein, while lower amounts of pSer87 -synuclein appeared later in disease progression in PD. These results may have implications for novel biomarker and therapeutic developments.


2022 ◽  
Author(s):  
Berkiye Sonustun ◽  
Firat M Altay ◽  
Catherine Strand ◽  
Geshanthi Hondhamuni ◽  
Thomas T Warner ◽  
...  

Aggregated alpha-synuclein (α-synuclein) is the main component of Lewy bodies (LBs), Lewy neurites (LNs), and glial cytoplasmic inclusions (GCIs), which are pathological hallmarks of idiopathic Parkinson′s disease (IPD) and multiple system atrophy (MSA), respectively. Initiating factors that culminate in forming LBs/LNs/GCIs remain elusive. Several species of α-synuclein exist, including phosphorylated and nitrated forms. It is unclear which α-synuclein post-translational modifications (PTMs) appear within aggregates throughout disease pathology. Herein we aimed to establish the predominant α-synuclein PTMs in post-mortem IPD and MSA pathology using immunohistochemistry. We examined the patterns of three α-synuclein PTMs (pS87, pS129, nY39) simultaneously in pathology-affected regions of 15 PD, 5 MSA, 6 neurologically normal controls. All antibodies recognized LBs, LNs, and GCIs, albeit to a variable extent. pS129 α-synuclein antibody was particularly immunopositive for LNs and synaptic dot-like structures followed by nY39 -synuclein antibody. GCIs, neuronal inclusions, and small threads were positive for nY39 α-synuclein in MSA. Quantification of the LB scores revealed that pS129 α-synuclein was the dominant and earliest α-synuclein PTM followed by nY39 α-synuclein, while lower amounts of pSer87 α-synuclein appeared later in disease progression in PD. These results may have implications for novel biomarker and therapeutic developments.


Author(s):  
Saima Owais ◽  
Yasir Hasan Siddique

Abstract: Parkinson’s disease (PD) is the second most debilitating neurodegenerative movement disorder. It is characterized by the presence of fibrillar alpha-synuclein amassed in the neurons, known as Lewy bodies. Certain cellular and molecular events are involved leading to the degeneration of dopaminergic neurons. However, the origin and implication of such events are still uncertain. Nevertheless, the role of microRNAs (miRNAs) as important biomarkers and therapeutic molecules is unquestionable. The most challenging task by far in PD treatment has been its late diagnosis followed by therapeutics. miRNAs are an emerging hope to meet the need of early diagnosis, thereby promising an improved movement symptom and prolonged life of the patients. The continuous efforts in discovering the role of miRNAs could be made possible by the utilisation of various animal models of PD. These models help us to understand insights into the mechanism of the disease. Moreover, miRNAs have been surfaced as therapeutically important molecules with distinct delivery systems enhancing their success rate. This review aims at providing an outline of different miRNAs implicated in either PD-associated gene regulation or involved in therapeutics.


2022 ◽  
Vol 12 ◽  
Author(s):  
Han Zhu ◽  
Hao Lu ◽  
Fei Wang ◽  
Shuai Liu ◽  
Zhihong Shi ◽  
...  

Introduction: Currently, there is still clinical overlap between dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) patients, which may affect the accuracy of the early diagnosis of DLB. For better diagnosis and prognosis, further exploration of local cortical atrophy patterns and white matter lesions is needed.Methods: We reviewed the outpatient medical records of 97 DLB patients and 173 AD patients from January 2018 to September 2020 along with 30 matched outpatient clinic normal elderly people. MRI visual rating scales, including medial temporal lobe atrophy (MTA), global cortical atrophy-frontal subscale (GCA-F), posterior atrophy (PA), Fazekas scale, Evans Index and cerebral microbleeds were evaluated and analyzed in DLB and AD patients with different severities and normal controls.Results: Overall, patients with DLB had higher scores on all visual rating scales than the normal controls. Meanwhile, compared with AD, DLB had lower MTA scores in the mild to moderate groups (both p ≤ 0.001), but the GCA-F and PA scores were similar (all p > 0.05). The Fazekas scores in the moderate to severe DLB group were lower than those in the AD group (p = 0.024 and p = 0.027, respectively). In addition, the diagnostic performance and sensitivity of multiple imaging indicators for DLB were better than that of MTA alone (the combination of MTA, GCA-F, PA, Fazekas visual rating scales, AUC = 0.756, 95%CI: 0.700–0.813, sensitivity = 0.647, specificity = 0.804 and MTA visual rating scale, AUC = 0.726, 95%CI: 0.667–0.785, sensitivity = 0.497, specificity = 0.876, respectively).Conclusion: The medial temporal lobe of DLB patients was relatively preserved, the frontal and parietal lobes were similarly atrophied to AD patients, and the white matter hyperintensity was lighter than that in AD patients. Combined multiple visual rating scales may provide a novel idea for the diagnosis of early DLB.


PLoS ONE ◽  
2022 ◽  
Vol 17 (1) ◽  
pp. e0262464
Author(s):  
Roger Pamphlett ◽  
David P. Bishop

Objective Environmental toxicants are suspected to play a part in the pathogenesis of idiopathic Parkinson’s disease (PD) and may underlie its increasing incidence. Mercury exposure in humans is common and is increasing due to accelerating levels of atmospheric mercury, and mercury damages cells via oxidative stress, cell membrane damage, and autoimmunity, mechanisms suspected in the pathogenesis of PD. We therefore compared the cellular distribution of mercury in the tissues of people with and without PD who had evidence of previous mercury exposure by mercury being present in their locus ceruleus neurons. Materials and methods Paraffin sections from the brain and general organs of two people with PD, two people without PD with a history of mercury exposure, and ten people without PD or known mercury exposure, were stained for inorganic mercury using autometallography, combined with immunostaining for a-synuclein and glial cells. All had mercury-containing neurons in locus ceruleus neurons. Laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) was used to confirm the presence of mercury and to look for other potentially toxic elements. Autometallography-stained locus ceruleus paraffin sections were examined to compare the frequency of previous mercury exposure between 20 PD and 40 non-PD individuals. Results In PD brains, autometallography-detected mercury was seen in neurons affected by the disease, such as those in the substantia nigra, motor cortex, striatum, thalamus, and cerebellum. Mercury was seen in oligodendrocytes in white and grey matter. Mercury often co-localised with Lewy bodies and neurites. A more restricted distribution of brain mercury was seen in people without PD (both with or without known mercury exposure), with no mercury present in the substantia nigra, striatum, or thalamus. The presence of autometallography-detected mercury in PD was confirmed with LA-ICP-MS, which demonstrated other potentially toxic metals in the locus ceruleus and high iron levels in white matter. Autometallography-detected mercury was found in locus ceruleus neurons in a similar proportion of PD (65%) and non-PD (63%) individuals. Conclusions In people with PD, mercury was found in neurons and oligodendrocytes in regions of the brain that are affected by the disease, and often co-localised with aggregated a-synuclein. Mercury in the motor cortex, thalamus and striatum could result in bradykinesia and rigidity, and mercury in the cerebellum could cause tremor. People without PD had a restricted uptake of mercury into the brain. The similar frequency of mercury in the locus ceruleus of people with and without PD suggests these two groups have had comparable previous mercury exposures but that PD brains have a greater predisposition to take up circulating mercury. While this post mortem study does not provide a direct link between mercury and idiopathic PD, it adds to the body of evidence that metal toxicants such as mercury play a role in the disease. A precautionary approach would be to reduce rising mercury levels in the atmosphere by limiting the burning of fossil fuels, which may be contributing to the increasing incidence of PD.


npj Vaccines ◽  
2022 ◽  
Vol 7 (1) ◽  
Author(s):  
Changyoun Kim ◽  
Armine Hovakimyan ◽  
Karen Zagorski ◽  
Tatevik Antonyan ◽  
Irina Petrushina ◽  
...  

AbstractAccumulation of misfolded proteins such as amyloid-β (Aβ), tau, and α-synuclein (α-Syn) in the brain leads to synaptic dysfunction, neuronal damage, and the onset of relevant neurodegenerative disorder/s. Dementia with Lewy bodies (DLB) and Parkinson’s disease (PD) are characterized by the aberrant accumulation of α-Syn intracytoplasmic Lewy body inclusions and dystrophic Lewy neurites resulting in neurodegeneration associated with inflammation. Cell to cell propagation of α-Syn aggregates is implicated in the progression of PD/DLB, and high concentrations of anti-α-Syn antibodies could inhibit/reduce the spreading of this pathological molecule in the brain. To ensure sufficient therapeutic concentrations of anti-α-Syn antibodies in the periphery and CNS, we developed four α-Syn DNA vaccines based on the universal MultiTEP platform technology designed especially for the elderly with immunosenescence. Here, we are reporting on the efficacy and immunogenicity of these vaccines targeting three B-cell epitopes of hα-Syn aa85–99 (PV-1947D), aa109–126 (PV-1948D), aa126–140 (PV-1949D) separately or simultaneously (PV-1950D) in a mouse model of synucleinopathies mimicking PD/DLB. All vaccines induced high titers of antibodies specific to hα-Syn that significantly reduced PD/DLB-like pathology in hα-Syn D line mice. The most significant reduction of the total and protein kinase resistant hα-Syn, as well as neurodegeneration, were observed in various brain regions of mice vaccinated with PV-1949D and PV-1950D in a sex-dependent manner. Based on these preclinical data, we selected the PV-1950D vaccine for future IND enabling preclinical studies and clinical development.


Author(s):  
Renu Minda

I wish to suggest a physiological function for alpha-synuclein (a-syn) that has the potential to explain its role in pathology. Intraneuronal proteinaceous Lewy Bodies (LBs), the pathological hallmark of Parkinson’s disease and other synucleinopathies, consist majorly of a-syn. Ample evidence suggests that LBs are not the result of simple amyloidosis of cytosolic a-syn. Benign soluble unstructured a-syn gets converted into toxic species which preferentially accumulates in LBs. But how these aberrant a-syn molecules are produced in the cytosol, is still not clear. The present hypothesis is an effort to relate a metabolic reaction specific to neuronal function, that is, phase transition, with the pathobiology of a-syn. During high frequency stimulation, which entails rapid phase transition reactions at the presynaptic compartment, aberrant interaction of a-syn with the membrane occasionally generates toxic a-syn molecules. My conjecture is that the physiological function of a-syn is to modulate membrane fluidity by a process wherein it goes through a conformation cycle driven by a flux of energy from mitochondria. It is the range of toxic a-syn produced during aberrant phase transition reaction that is responsible for pathology, not the normal a-syn that reenters the conformation cycle, thereby, resolving the paradox of the Janus-face of a-syn.


2022 ◽  
Vol 8 (1) ◽  
Author(s):  
Mingmin Yan ◽  
Min Xiong ◽  
Lijun Dai ◽  
Xingyu Zhang ◽  
Yunhong Zha ◽  
...  

AbstractThe pathological hallmark of Parkinson’s disease (PD) is the presence of Lewy bodies (LBs) with aggregated α-synuclein being the major component. The abnormal α-synuclein aggregates transfer between cells, recruit endogenous α-synuclein into toxic LBs, and finally trigger neuronal injury. However, the molecular mechanisms mediating the aggregation and transmission of pathological α-synuclein remain unknown. Previously we found that cofilin 1, a member of the actin-binding protein, promotes the aggregation and pathogenicity of α-synuclein in vitro. Here we further investigated the effect of cofilin 1 in mouse models of PD. We found that the mixed fibrils composed of cofilin 1 and α-synuclein are more pathogenic to mice and more prone to propagation than pure α-synuclein fibrils. Overexpression of cofilin 1 enhances the seeding and spreading of α-synuclein aggregates, and induces PD-like behavioral impairments in mice. Together, these results illustrate the important role of cofilin 1 in the pathogenicity and transmission of α-synuclein during the onset and progression of PD.


2022 ◽  
Vol 8 (1) ◽  
Author(s):  
Kateřina Menšíková ◽  
Radoslav Matěj ◽  
Carlo Colosimo ◽  
Raymond Rosales ◽  
Lucie Tučková ◽  
...  

AbstractThe current nosological concept of α-synucleinopathies characterized by the presence of Lewy bodies (LBs) includes Parkinson’s disease (PD), Parkinson’s disease dementia (PDD), and dementia with Lewy bodies (DLB), for which the term “Lewy body disease” (LBD) has recently been proposed due to their considerable clinical and pathological overlap. However, even this term does not seem to describe the true nature of this group of diseases. The subsequent discoveries of α-synuclein (αSyn), SNCA gene, and the introduction of new immunohistochemical methods have started intensive research into the molecular-biological aspects of these diseases. In light of today’s knowledge, the role of LBs in the pathogenesis and classification of these nosological entities remains somewhat uncertain. An increasingly more important role is attributed to other factors as the presence of various LBs precursors, post-translational αSyn modifications, various αSyn strains, the deposition of other pathological proteins (particularly β-amyloid), and the discovery of selective vulnerability of specific cells due to anatomical configuration or synaptic dysfunction. Resulting genetic inputs can undoubtedly be considered as the main essence of these factors. Molecular–genetic data indicate that not only in PD but also in DLB, a unique genetic architecture can be ascertained, predisposing to the development of specific disease phenotypes. The presence of LBs thus remains only a kind of link between these disorders, and the term “diseases with Lewy bodies” therefore results somewhat more accurate.


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