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Vitamin C in Neurological Function and Neurodegenerative Disease
Published in Qi Chen, Margreet C.M. Vissers, Vitamin C, 2020
Shilpy Dixit, David C. Consoli, Krista C. Paffenroth, Jordyn M. Wilcox, Fiona E. Harrison
Lewy bodies are primarily composed of α-synuclein protein aggregates and, although no consensus has been reached as to the function of this protein, they are believed to play a critical role in the pathology of the disease because they appear long before the emergence of clinical symptoms [204,205]. The toxicity exerted by oligomerized α-synuclein is similar to that of β-amyloid, though the direct mechanism by which α-synuclein causes dopaminergic cell loss is still unknown. α-Synuclein oligomers can permeabilize lipid membranes, activate endoplasmic reticulum stress response, disrupt protein degradation mechanisms, and disrupt energy production by interacting with mitochondria [204]. Oxidative stress can increase phosphorylation of α-synuclein in in vitro models, increasing the formation of protein inclusions and perpetuating a detrimental cycle [206,207]. In a meta-analysis of 80 studies designed to quantify systemic oxidative stress markers, Wei et al. showed elevated blood levels in 4 (8-OhdG, MDA, nitrite, and ferritin) of the 22 markers of oxidative damage tested, as well as a marked decrease in the antioxidants glutathione, catalase, and uric acid in PD (7212) and healthy control (6037) subjects [18].
Micronutrients for the Prevention and Improvement of the Standard Therapy for Parkinson’s Disease
Published in Kedar N. Prasad, Micronutrients in Health and Disease, 2019
The degeneration of DA neurons of the substantia nigra is a characteristic feature of PD. Surviving neurons contains Lewy bodies, a pathological hallmark of PD. The Lewy bodies are present in other area of the brain, particularly brain stems area like the locus coeruleus that sends out processes throughout the brain. Thus, PD is not just a disease of substantia nigra DA neurons alone. The incidence of Lewy bodies in 139 autopsied brain samples of elderly individuals with normal cognitive function and without any type of movement disorders was evaluated. The results showed that about 23% of the samples contained Lewy bodies in various regions of the brains. The most common regions involved were medulla (26%), amygdale (24%), pons (20%), and midbrain (20%).25 Lewy bodies contain predominantly neurofilaments that are important components of the neuronal cytoskeleton and ubiquitin that degrades abnormal proteins. Lewy bodies also contain high levels of alpha-synuclein. The presence of another protein FOXO3 (a transcriptional activator that can trigger neuronal death upon oxidative stress) was demonstrated in Lewy bodies in the autopsied brain samples of PD as well as in the Lewy body dementia.26 Lewy bodies are considered consequences of neuronal damage. They can be transferred from one neuron to another by endocytosis. This was demonstrated by the fact that Lewy bodies were present in the neurons grafted in patients with PD and in a transgenic animal model of PD.27
Pathology, aetiology and pathogenesis
Published in Jeremy Playfer, John Hindle, Andrew Lees, Parkinson's Disease in the Older Patient, 2018
In 1990, the pedigree of an Italian American family was described in which parkinsonism was inherited as an autosomal-dominant condition.49 Clinically, the disease was consistent with idiopathic PD, but there was a tendency for an earlier age of onset and a rather more aggressive course than usual. Post-mortem studies have confirmed the presence of typical pathology with Lewy bodies. Subsequent investigations showed that the problem lay in a mutation of the α-synuclein gene on chromosome 4 [PARK 1].50 The same mutation has subsequently been identified in three Greek families, and a second mutation in a German family.51 The biological role of α-synuclein is unknown but it is involved in the regulation of dopamine metabolism.52 It has been postulated that the mutation results in an abnormality in folding of the protein, causing it to accumulate.53
Chlorogenic acid delays the progression of Parkinson's disease via autophagy induction in Caenorhabditis elegans
Published in Nutritional Neuroscience, 2023
Chang-Long He, Yong Tang, Jian-Ming Wu, Tao Long, Lu Yu, Jin-Feng Teng, Wen-Qiao Qiu, Rong Pan, Chong-Lin Yu, Da-Lian Qin, An-Guo Wu, Xiao-Gang Zhou
PD is the second common age-related neurodegenerative disease and predominantly affects people aged over 60 years of age. The main pathological hallmark of PD includes the accumulation of α-synuclein in neurons and the degeneration of DA neurons. PD is a progressive neurodegenerative disorder that exhibits motor impairment, and there is still no cure for this disease [1]. Numerous studies show that the development of PD is closely associated with oxidative stress, mitochondrial dysfunction, cell apoptosis, and neuroinflammation. Human α-synuclein is encoded by the SNCA gene (PARK1). The excessive accumulation of α-synuclein the brain of PD patient forms inclusions and aggregates to induce neurotoxicity and neuroinflammation [26]. Therefore, the inhibition or clearance of aggregated α-synuclein has become a promising strategy for the treatment of PD.
CIITA expression is regulated by histone deacetylase enzymes and has a role in α-synuclein pre-formed fibril-induced antigen presentation in murine microglial cell line
Published in Immunopharmacology and Immunotoxicology, 2022
Caner Günaydın, Z. Betül Çelik, S. Sırrı Bilge
Cell viability was assessed after single and combination treatments with pFF α-synuclein. CUDC-907 significantly decreased cell viability at the 30, 100, 300, and 1000 nM, concentrations (p < .001, Supp Fig1A). TMP-195 significantly decreased cell viability at the 300 and 1000 nM concentrations (p < .001, Supp Fig1B). However, pFF α-synuclein did not affect cellular viability at the 3.9, 7.8, 15.6, 31.2, 62.5, 125, 250, 500 nM concentrations, and it significantly decreased cellular viability at the 1000 nM concentration (Supp Fig1C). Therefore, 10 nM for CUDC-907 and 100 nM for TMP-195 concentrations were selected for combination treatment with 125, 250 and 500 nM2 concentrations of pFF α-synuclein. Our results demonstrated that either CUDC-907 or TMP-195 did not significantly affect cellular viability after combination with pFF α-synuclein (p > .05, Figure 1).
Neuroprotective effects of mitoquinone and oleandrin on Parkinson’s disease model in zebrafish
Published in International Journal of Neuroscience, 2020
İsmail Ünal, Esin Çalışkan-Ak, Ünsal V. Üstündağ, Perihan S. Ateş, Ahmet A. Alturfan, Meric A. Altinoz, Ilhan Elmaci, Ebru Emekli-Alturfan
Synucleins are small proteins of 100–140 amino acids expressed in neuronal presynaptic terminals. The three members of the synuclein family, alpha, beta and gamma synuclein, are encoded by separate genes and are highly conserved throughout the vertebrates. In zebrafish, three genes, sncb, sncg1 and sncg2 (encode beta, gamma1 and gamma2 synuclein), and these genes show wide phylogenetic protection with human paralogs. Synucleins in zebrafish show intense sequence similarity with human synucleins [33]. In our study, the immunohistochemical expression of gamma synucleins increased compared to the control group in the sections of the brain tissues of zebrafish exposed to rotenone. Mitoquinone administration decreased synuclein accumulation in the rotenone group. This condition supports the importance of increased oxidative stress in the accumulation of synuclein and the potential of the mitoquinone as an antioxidant protector.