7 research outputs found
ΠΠ»ΡΡΠ°-ΡΠΈΠ½ΡΠΊΠ»Π΅ΠΈΠ½ ΠΈ Π΄ΠΈΡΡΡΠ½ΠΊΡΠΈΡ ΠΌΠΈΡΠΎΡ ΠΎΠ½Π΄ΡΠΈΠΉ ΠΏΡΠΈ Π±ΠΎΠ»Π΅Π·Π½ΠΈ ΠΏΠ°ΡΠΊΠΈΠ½ΡΠΎΠ½Π°
ΠΠΎΠ»Π΅Π·Π½Ρ ΠΠ°ΡΠΊΠΈΠ½ΡΠΎΠ½Π° (ΠΠ) - ΠΎΠ΄Π½ΠΎ ΠΈΠ· ΡΠ°ΠΌΡΡ
ΡΠ°ΡΠΏΡΠΎΡΡΡΠ°Π½Π΅Π½Π½ΡΡ
Π½Π΅ΠΉΡΠΎΠ΄Π΅Π³Π΅Π½Π΅ΡΠ°ΡΠΈΠ²Π½ΡΡ
Π·Π°Π±ΠΎΠ»Π΅Π²Π°Π½ΠΈΠΉ. Π Π°Π·Π²ΠΈΡΠΈΠ΅ ΠΏΠ°ΡΠΎΠ»ΠΎΠ³ΠΈΠΈ ΡΠ²ΡΠ·Π°Π½ΠΎ Ρ Π³ΠΈΠ±Π΅Π»ΡΡ Π΄ΠΎΡΠ°ΠΌΠΈΠ½Π΅ΡΠ³ΠΈΡΠ΅ΡΠΊΠΈΡ
Π½Π΅ΠΉΡΠΎΠ½ΠΎΠ², Π³Π»Π°Π²Π½ΡΠΌ ΠΎΠ±ΡΠ°Π·ΠΎΠΌ, Π² ΡΠ΅ΡΠ½ΠΎΠΉ ΡΡΠ±ΡΡΠ°Π½ΡΠΈΠΈ Π³ΠΎΠ»ΠΎΠ²Π½ΠΎΠ³ΠΎ ΠΌΠΎΠ·Π³Π°. ΠΠ΅Π΄ΠΎΡΡΠ°ΡΠΎΡΠ½ΠΎΡΡΡ Π΄ΠΎΡΠ°ΠΌΠΈΠ½Π° Π²ΡΠ·ΡΠ²Π°Π΅Ρ ΡΠ΅Π»ΡΠΉ Π½Π°Π±ΠΎΡ ΡΡΠΆΠ΅Π»ΡΡ
ΡΠΈΠΌΠΏΡΠΎΠΌΠΎΠ², ΡΡΠ΅Π΄ΠΈ ΠΊΠΎΡΠΎΡΡΡ
Π±ΡΠ°Π΄ΠΈΠΊΠΈΠ½Π΅Π·ΠΈΡ, ΠΏΠΎΡΡΡΡΠ°Π»ΡΠ½Π°Ρ Π½Π΅ΡΡΡΠΎΠΉΡΠΈΠ²ΠΎΡΡΡ, ΡΠΈΠ³ΠΈΠ΄Π½ΠΎΡΡΡ ΠΌΡΡΡ ΠΈ ΡΡΠ΅ΠΌΠΎΡ. ΠΠ΅Π½Π΅ΡΠΈΡΠ΅ΡΠΊΠΈΠ΅ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΡ ΠΏΠΎΠΊΠ°Π·Π°Π»ΠΈ, ΡΡΠΎ Π²Π΅Π΄ΡΡΡΡ ΡΠΎΠ»Ρ Π² ΠΏΠ°ΡΠΎΠ³Π΅Π½Π΅Π·Π΅ ΠΠ ΠΈΠ³ΡΠ°Π΅Ρ Π±Π΅Π»ΠΎΠΊ Π°Π»ΡΡΠ°-ΡΠΈΠ½ΡΠΊΠ»Π΅ΠΈΠ½ (?-Π‘ΠΈΠ½). ΠΠΎΠ»ΡΡΠΎΠ΅ ΠΊΠΎΠ»ΠΈΡΠ΅ΡΡΠ²ΠΎ Π΄Π°Π½Π½ΡΡ
ΡΠ²ΠΈΠ΄Π΅ΡΠ΅Π»ΡΡΡΠ²ΡΠ΅Ρ ΠΎ ΡΠ°Π·Π»ΠΈΡΠ½ΡΡ
ΠΌΠ΅Ρ
Π°Π½ΠΈΠ·ΠΌΠ°Ρ
ΡΠΎΠΊΡΠΈΡΠ΅ΡΠΊΠΎΠ³ΠΎ Π΄Π΅ΠΉΡΡΠ²ΠΈΡ ?-Π‘ΠΈΠ½. ΠΡΠΎΠΌΠ΅ ΡΠΎΠ³ΠΎ, ΡΡΠ΅Π΄ΠΈ ΠΊΠ»ΡΡΠ΅Π²ΡΡ
ΡΠ°ΠΊΡΠΎΡΠΎΠ², ΡΠΏΠΎΡΠΎΠ±ΡΡΠ²ΡΡΡΠΈΡ
ΡΠ°Π·Π²ΠΈΡΠΈΡ Π½Π΅ΠΉΡΠΎΠ΄Π΅Π³Π΅Π½Π΅ΡΠ°ΡΠΈΠΈ ΠΏΡΠΈ ΠΠ, Π²ΡΠ΄Π΅Π»ΡΡΡ ΡΡΡΠ΅ΡΡΠ²Π΅Π½Π½ΡΠ΅ Π½Π°ΡΡΡΠ΅Π½ΠΈΡ ΡΡΠ½ΠΊΡΠΈΠΉ ΠΌΠΈΡΠΎΡ
ΠΎΠ½Π΄ΡΠΈΠΉ ΠΈ/ΠΈΠ»ΠΈ ΠΌΡΡΠ°ΡΠΈΠΈ. Π ΡΠΈΡΠ»ΠΎ ΠΌΡΡΠΈΡΡΠ΅ΠΌΡΡ
Π³Π΅Π½ΠΎΠ² ΠΏΡΠΈ Π½Π°ΡΠ»Π΅Π΄ΡΡΠ²Π΅Π½Π½ΠΎΠΉ ΠΈ ΡΠΏΠΎΡΠ°Π΄ΠΈΡΠ΅ΡΠΊΠΎΠΉ ΡΠΎΡΠΌΠ°Ρ
ΠΠ Π²Ρ
ΠΎΠ΄ΡΡ Π³Π΅Π½Ρ, ΠΊΠΎΠ΄ΠΈΡΡΡΡΠΈΠ΅ PINK1 ΠΈ Parkin, ΠΎΡΠ½ΠΎΠ²Π½ΡΠ΅ ΠΊΠΎΠΌΠΏΠΎΠ½Π΅Π½ΡΡ ΡΠΈΡΡΠ΅ΠΌΡ βΠΊΠΎΠ½ΡΡΠΎΠ»Ρ ΠΊΠ°ΡΠ΅ΡΡΠ²Π°β ΠΌΠΈΡΠΎΡ
ΠΎΠ½Π΄ΡΠΈΠΉ. Π‘Π°ΠΌΡΠ΅ ΡΠ°Π½Π½ΠΈΠ΅ Π±ΠΈΠΎΡ
ΠΈΠΌΠΈΡΠ΅ΡΠΊΠΈΠ΅ ΠΏΡΠΈΠ·Π½Π°ΠΊΠΈ Π·Π°Π±ΠΎΠ»Π΅Π²Π°Π½ΠΈΡ ΠΏΡΠΎΡΠ²Π»ΡΡΡΡΡ Π² Π½Π°ΡΡΡΠ΅Π½ΠΈΡΡ
Π²Π·Π°ΠΈΠΌΠΎΠ΄Π΅ΠΉΡΡΠ²ΠΈΡ ΠΌΠΈΡΠΎΡ
ΠΎΠ½Π΄ΡΠΈΠΉ ΠΈ ΡΠ½Π΄ΠΎΠΏΠ»Π°Π·ΠΌΠ°ΡΠΈΡΠ΅ΡΠΊΠΎΠ³ΠΎ ΡΠ΅ΡΠΈΠΊΡΠ»ΡΠΌΠ°, ΠΌΠΈΡΠΎΡ
ΠΎΠ½Π΄ΡΠΈΠ°Π»ΡΠ½ΠΎΠΉ Π΄ΠΈΠ½Π°ΠΌΠΈΠΊΠΈ, Π³ΠΎΠΌΠ΅ΠΎΡΡΠ°Π·Π° ΠΊΠ°Π»ΡΡΠΈΡ ΠΈ ΠΏΠΎΠ²ΡΡΠ΅Π½ΠΈΠΈ ΡΡΠΎΠ²Π½Ρ ΠΌΠΈΡΠΎΡ
ΠΎΠ½Π΄ΡΠΈΠ°Π»ΡΠ½ΡΡ
Π°ΠΊΡΠΈΠ²Π½ΡΡ
ΡΠΎΡΠΌ ΠΊΠΈΡΠ»ΠΎΡΠΎΠ΄Π°. ΠΡΠ΅ ΡΡΠΈ ΡΠ°ΠΊΡΠΎΡΡ ΡΡΠ°ΡΡΠ²ΡΡΡ Π² ΠΏΠΎΠ²ΡΠ΅ΠΆΠ΄Π΅Π½ΠΈΠΈ Π΄ΠΎΡΠ°ΠΌΠΈΠ½Π΅ΡΠ³ΠΈΡΠ΅ΡΠΊΠΈΡ
Π½Π΅ΠΉΡΠΎΠ½ΠΎΠ²
Dopamine controls neuronal spontaneous calcium oscillations via astrocytic signal
Dopamine is a neuromodulator and neurotransmitter responsible for a number of physiological processes. Dysfunctions of the dopamine metabolism and signalling are associated with neurological and psychiatric diseases. Here we report that in primary co-culture of neurons and astrocytes dopamine-induces calcium signal in astrocytes and suppress spontaneous synchronous calcium oscillations (SSCO) in neurons. Effect of dopamine on SSCO in neurons was dependent on calcium signal in astrocytes and could be modified by inhibition of dopamine-induced calcium signal or by stimulation of astrocytic calcium rise with ATP. Ability of dopamine to suppress SSCO in neurons was independent on D1- or D2- like receptors but dependent on GABA and alpha-adrenoreceptors. Inhibitor of monoaminoxidase bifemelane blocked effect of dopamine on astrocytes but also inhibited the effect dopamine on SSCO in neurons. These findings suggest that dopamine-induced calcium signal may stimulate release of neuromodulators such as GABA and adrenaline and thus suppress spontaneous calcium oscillations in neurons
Alpha-Synuclein and Mitochondrial Dysfunction in Parkinson Disease
Parkinsonβs disease (PD) is one of the most common neurodegenerative diseases. The development of pathology is associated with the loss of dopaminergic neurons, mainly in substantia nigra pars compacta. Dopamine deficiency causes a whole range of severe motor symptoms, including bradykinesia, postural instability, muscle rigidity, and tremor. Studies have shown the primary role of the alpha-synuclein protein in this neurodegenerative disease. A large amount of data indicates different mechanisms of the toxic effect of alpha-synuclein. The process of neurodegeneration in PD is the result of significant disturbances in mitochondrial functions and/or genetic mutations. The number of mutated genes in hereditary and sporadic forms of Parkinsonβs disease includes genes encoding PINK1 and Parkin, which are the main participants in the mitochondrial βquality controlβ system. The earliest biochemical hallmarks of the disease are disturbances of the mitochondrial interaction with endoplasmic reticulum, mitochondrial dynamics, Ca2+ homeostasis, and an increase in the level of mitochondrial reactive oxygen species. All these factors exert damaging effects on dopaminergic neurons
Intracellular pH Modulates Autophagy and Mitophagy
The specific autophagic elimination of mitochondria (mitophagy) plays the role of quality control for this organelle. Deregulation of mitophagy leads to an increased number of damaged mitochondria and triggers cell death. The deterioration of mitophagy has been hypothesized to underlie the pathogenesis of several neurodegenerative diseases, most notably Parkinson disease. Although some of the biochemical and molecular mechanisms of mitochondrial quality control are described in detail, physiological or pathological triggers of mitophagy are still not fully characterized. Here we show that the induction of mitophagy by the mitochondrial uncoupler FCCP is independent of the effect of mitochondrial membrane potential but dependent on acidification of the cytosol by FCCP. The ionophore nigericin also reduces cytosolic pH and induces PINK1/PARKIN-dependent and -independent mitophagy. The increase of intracellular pH with monensin suppresses the effects of FCCP and nigericin on mitochondrial degradation. Thus, a change in intracellular pH is a regulator of mitochondrial quality control
Role of DJ-1 in the mechanism of pathogenesis of Parkinson's disease
DJ-1 protein has multiple specific mechanisms to protect dopaminergic neurons against neurodegeneration in Parkinson's disease. Wild type DJ-1 can acts as oxidative stress sensor and as an antioxidant. DJ-1 exhibits the properties of molecular chaperone, protease, glyoxalase, transcriptional regulator that protects mitochondria from oxidative stress. DJ-1 increases the expression of two mitochondrial uncoupling proteins (UCP 4 and UCP5), that decrease mitochondrial membrane potential and leads to the suppression of ROS production, optimizes of a number of mitochondrial functions, and is regarded as protection for the neuronal cell survival. We discuss also the stabilizing interaction of DJ-1 with the mitochondrial Bcl-xL protein, which regulates the activity of (Inositol trisphosphate receptor) IP3R, prevents the cytochrome c release from mitochondria and inhibits the apoptosis activation. Upon oxidative stress DJ-1 is able to regulate various transcription factors including nuclear factor Nrf2, PI3K/PKB, and p53 signal pathways. Stress-activated transcription factor Nrf2 regulates the pathways to protect cells against oxidative stress and metabolic pathways initiating the NADPH and ATP production. DJ-1 induces the Nrf2 dissociation from its inhibitor Keap1 (Kelch-like ECH-associated protein 1), promoting Nrf2 nuclear translocation and binding to antioxidant response elements. DJ-1 is shown to be a co-activator of the transcription factor NF-kB. Under nitrosative stress, DJ-1 may regulate PI3K/PKB signaling through PTEN transnitrosylation, which leads to inhibition of phosphatase activity. DJ-1 has a complex modulating effect on the p53 pathway: one side DJ-1 directly binds to p53 to restore its transcriptional activity and on the other hand DJ-1 can stimulate deacylation and suppress p53 transcriptional activity. The ability of the DJ-1 to induce activation of different transcriptional factors and change redox balance protect neurons against aggregation of Ξ±-synuclein and oligomer-induced neurodegeneration
Interaction of misfolded proteins and mitochondria in neurodegenerative disorders
The number of the people affected by neurodegenerative disorders is growing dramatically due to the ageing of population. The major neurodegenerative diseases share some common pathological features including the involvement of mitochondria in the mechanism of pathology and misfolding and the accumulation of abnormally aggregated proteins. Neurotoxicity of aggregated Ξ²-amyloid, tau, Ξ±-synuclein and huntingtin is linked to the effects of these proteins on mitochondria. All these misfolded aggregates affect mitochondrial energy metabolism by inhibiting diverse mitochondrial complexes and limit ATP availability in neurones. Ξ²-Amyloid, tau, Ξ±-synuclein and huntingtin are shown to be involved in increased production of reactive oxygen species, which can be generated in mitochondria or can target this organelle. Most of these aggregated proteins are capable of deregulating mitochondrial calcium handling that, in combination with oxidative stress, lead to opening of the mitochondrial permeability transition pore. Despite some of the common features, aggregated Ξ²-amyloid, tau, Ξ±-synuclein and huntingtin have diverse targets in mitochondria that can partially explain neurotoxic effect of these proteins in different brain regions