The role of alpha-synuclein in the development of the dopaminergic neurons in the substantia nigra and ventral tegmental area

Тарасова, Т. В.; Лыткина, О. А.; Roman, Andrei; Bachurin, S. O.; Ustyugov, A. A.

doi:10.1134/s0012496616010117

Cited by 5 publications

(3 citation statements)

References 14 publications

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“…And similarly Connor-Robson et al reported that stabilization of the striatal DA level depends on the presence of α-syn and cannot be compensated by other family members. [36] α-syn modulates dopaminergic neuron development, DA reuptake and stabilizes striatal DA level [35–37] . 5) α-syn modulates microglial phenotype and neuroinflammation.…”

Section: Discussionmentioning

confidence: 99%

SNCA Deletion Induced Aberrant Projection of Olfactory Sensory Neurons via NCK2-EphA4 Pathway

Ren

Yue

et al. 2022

Preprint

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Synucleinopathies such as Parkinson’s disease, dementia with Lewy bodies and multiple system atrophy are characteristic forα-synuclein aggregates in neurons or glia, and are always manifested olfaction deficits at their primary onsets. It remains elusive why aggregation ofα-synuclein predominantly affect the olfactory system. Employing the knockout mice, we investigate the physiological function of α-synuclein in olfactory system. We found that deletion of α-synuclein primarily interferes the projection of olfactory sensory neurons. iTRAQ based LC-MS identified that 188 proteins are differentially expressed, including 9 that were associated with axon guidance. Among them, NCK2 is most significantly down-regulated, which was indicated to be involved a PPI network of 21 proteins, including 11 players of the Ephrin receptor signaling pathway. Either α-synuclein deletion or NCK2 deficiency can inactivate Eph A4 receptor. Re-expressing α-synuclein in the α-synuclein knockout neurons reverse the NCK2, as well as the phosphorylated Eph A4 (the activated Eph A4). Thus, α-synuclein regulates axon guidance through NCK2-Eph A4 signaling pathway. Malfunction of α-synuclein, whether because of deletion or aggregation, may cause aberrant olfactory neurons projection and subsequent olfaction deficits. This extended our knowledge of effects of α-synuclein in olfactory system, which may explain why olfaction is usually impaired in some synucleinopathy related disorders such as Parkinson’s disease.

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Section: Discussionmentioning

confidence: 99%

SNCA Deletion Induced Aberrant Projection of Olfactory Sensory Neurons via NCK2-EphA4 Pathway

Ren

Yue

et al. 2022

Preprint

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“…Hippocampal levels of the major brain fatty acid docosahexaenoic acid (DHA) decrease with age in rats [40], which is associated with learning and memory deficits [41]. PD is characterized by the progressive loss of dopaminergic neurons, particularly in the substantia nigra, leading to significant dopamine depletion in the striatum, which is responsible for the motor symptoms of PD [42]. The concentration of O3FA decreases in the substantia nigra of patients with PD, whereas the concentration of malondialdehyde, a lipid oxidation marker, increases.…”

Section: Neurodegenerative Disordersmentioning

confidence: 99%

Omega-3 Fatty Acids as Druggable Therapeutics for Neurodegenerative Disorders

Chitre

Moniri

Murnane

2020

CNSNDDT

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: Neurodegenerative disorders are commonly associated with a complex pattern of pathophysiological hallmarks, including increased oxidative stress and neuroinflammation, which makes their treatment challenging. Omega-3 Fatty Acids (O3FA) are natural products with reported neuroprotective, anti-inflammatory, and antioxidant effects. These effects have been attributed to their incorporation into neuronal membranes or through the activation of intracellular or recently discovered cell-surface receptors (i.e., Free-Fatty Acid Receptors; FFAR). Molecular docking studies have investigated the roles of O3FA as agonists of FFAR and have led to the development of receptor-specific targeted agonists for therapeutic purposes. Moreover, novel formulation strategies for targeted delivery of O3FA to the brain have supported their development as therapeutics for neurodegenerative disorders. Despite the compelling evidence of the beneficial effects of O3FA for several neuroprotective functions, they are currently only available as unregulated dietary supplements, with only a single FDA-approved prescription product, indicated for triglyceride reduction. This review highlights the relative safety and efficacy of O3FA, their drug-like properties, and their capacity to be formulated in clinically viable drug delivery systems. Interestingly, the presence of cardiac conditions such as hypertriglyceridemia is associated with brain pathophysiological hallmarks of neurodegeneration, such as neuroinflammation, thereby further suggesting potential therapeutic roles of O3FA for neurodegenerative disorders. Taken together, this review article summarizes and integrates the compelling evidence regarding the feasibility of developing O3FA and their synthetic derivatives as potential drugs for neurodegenerative disorders.

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“…[ 207 , 208 ]. For example, in Parkinson’s disease, the SNCA gene encoding α-synuclein, a short cytoplasmic protein (140 amino acids in humans), is predominantly synthesized in the nervous system and localized in presynaptic terminals [ 209 , 210 , 211 ]. The most typical histopathological signs of Parkinson’s are the Lewy bodies found in the dopaminergic neurons of substantia nigra and dystrophic neuritis in the tract leading from substantia nigra to the striatum containing aggregates of various proteins [ 212 , 213 ].…”

Section: Problems and Targets In The Treatment Of Neurodegeneative DImentioning

confidence: 99%

Promising molecular targets for pharmacological therapy of neurodegenerative pathologies

et al. 2020

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Drug development for the treatment of neurodegenerative diseases has to confront numerous problems occurring, in particular, because of attempts to address only one of the causes of the pathogenesis of neurological disorders. Recent advances in multitarget therapy research are gaining momentum by utilizing pharmacophores that simultaneously affect different pathological pathways in the neurodegeneration process. The application of such a therapeutic strategy not only involves the treatment of symptoms, but also mainly addresses prevention of the fundamental pathological processes of neurodegenerative diseases and the reduction of cognitive abilities. Neuroinflammation and oxidative stress, mitochondrial dysfunction, dysregulation of the expression of histone deacetylases, and aggregation of pathogenic forms of proteins are among the most common and significant pathological features of neurodegenerative diseases. In this review, we focus on the molecular mechanisms and highlight the main aspects, including reactive oxygen species, the cell endogenous antioxidant system, neuroinflammation triggers, metalloproteinases, -synuclein, tau proteins, neuromelanin, histone deacetylases, presenilins, etc. The processes and molecular targets discussed in this review could serve as a starting point for screening leader compounds that could help prevent or slow down the development of neurodegenerative diseases.

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The role of alpha-synuclein in the development of the dopaminergic neurons in the substantia nigra and ventral tegmental area

Cited by 5 publications

References 14 publications

SNCA Deletion Induced Aberrant Projection of Olfactory Sensory Neurons via NCK2-EphA4 Pathway

SNCA Deletion Induced Aberrant Projection of Olfactory Sensory Neurons via NCK2-EphA4 Pathway

Omega-3 Fatty Acids as Druggable Therapeutics for Neurodegenerative Disorders

Promising molecular targets for pharmacological therapy of neurodegenerative pathologies

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