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Parkinson's Affects What Part Of The Brain

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Parkinson's Affects What Part Of The Brain – Parkinson’s disease (PD), the second most common neurodegenerative disease, is characterized by motor symptoms of bradykinesia, rigidity and tremors, and non-motor symptoms such as sleep disturbances, anorexia, and depression. Pathological features include neuroinflammation, degeneration of dopaminergic neurons in the substantia nigra pars compacta, and accumulation of protein α-synuclein as Lewy bodies and neurites. Microglia and astrocytes are important for maintaining homeostasis in the central nervous system (CNS), including protection through the process of gliosis. However, disruption of homeostasis due to glial cell dysfunction leads to chronic disease, which is the target of many CNS diseases. Recent evidence suggests a role for immune cells, particularly T lymphocytes, in the pathogenesis of PD. These cells enter the CNS, and accumulate in the substantia nigra, where they release inflammatory cytokines, stimulate peripheral nerve cells, and cause the death of dopaminergic neurons. In fact, a better understanding of the communication channels between cells and the immune system may improve our understanding of disease pathogenesis and thus provide new therapeutic approaches.

Parkinson’s disease (PD) is the second most common neurodegenerative disease affecting 1–2% of the population over 65 years of age (1), and the number of cases is expected to exceed 12 million by 2040 (2). PD is characterized by the degeneration of dopamine neurons in the substantia nigra (SN) of the midbrain, with the loss of their axons projecting to the striatum along the nigrostriatal pathway. This results in the loss of the neurotransmitter dopamine leading to the primary motor symptoms of PD, first reported as a disorder by James Parkinson in 1817 (3). These include bradykinesia, ataxia, tremors, rigidity, and behavioral disturbances, which are clinically apparent after striatal dopamine depletion of 70%. Another important feature of PD disease is the presence of Lewy body-containing proteins (5). The protein α-synuclein (α-syn) is a major component of Lewy bodies ( 6 ), and its mutant form can cause familial PD ( 7 – 10 ).

Parkinson's Affects What Part Of The Brain

The dysfunctional interaction of the central nervous system (CNS), neurons, glia, and the microenvironment is key to maintaining homeostasis, and failure in this homeostasis leads to neurodegenerative conditions such as PD. In recent years, the role of the inflammatory process in the death of dopamine neurons has come to light and is now considered to be important in this process (11-13). Gliosis is a common pathology in many neurodegenerative diseases, and emerging evidence suggests that the dysfunction of microglia and astrocytes remains at the root of dopaminergic impairment in PD ( 14 ). Indeed, the activation of microglia in people with PD was first described in 1988 (15) and this phenomenon has also been described in animal models (16, 17). Wilson et al. PET ligands have recently been described

Substantia Nigra Integrity Correlates With Sequential Working Memory In Parkinson’s Disease

C. Astrocyte studies have also been observed in the SN of patients with this disease [for review see (19)] and postmortem studies of nigral tissue homogenates have shown significant changes in biochemical parameters due to astrocyte dysfunction, including a global decrease in glutathione levels and mitochondrial damage. , and accumulation of rare toxins (20). Furthermore, clinical and basic studies have demonstrated the role of the innate and adaptive immune system in PD [for review see ( 21 , 22 )]. Indeed, available data indicate that in PD there is a response of immune cells and not only glial cells, suggesting that interactions between different types are involved in pathophysiology. We review the role of astrocytes and microglia in PD, taking into account the role of these immune cells and their impact on disease pathogenesis.

Astrocytes and many other non-brain cell types have an important function in maintaining structural support and homeostasis in the reproductive system (23). Their roles include metabolic support, neuron synapse (24), synapse development (25), and regulation of the blood-brain barrier (BBB) ​​(26). They are generally known for their ability to secrete several neurotrophic factors such as glial derived neurotrophic factor (GDNF) and mesencephalic astrocyte derived neurotrophic factor (MANF); Both have been shown to provide some degree of neuroprotection for dopamine neurons both in vitro and in vivo (27-29). However, in addition to this, there is a growing appreciation of the role that astrocytes play in neuroinflammation (30) in many neurodegenerative conditions, including PD. It has recently been shown that astrocytes become reactive in response to secreted microglial signals, such as IL-1α, TNF-α, and C1q, thereby adopting an inflammatory phenotype ( 31 , 32 ). Indeed, this astrocyte phenotype has been shown to be present in postmortem brain sections from individuals with PD ( 31 ). In addition, astrocytes can also adopt an inflammatory phenotype by endocytosis of α-syn released by neurons; They secrete IL-1α, IL-1β, and IL-6, cytokines associated with α-syn load ( 33 ). In addition, accumulation of α-syn in human astrocytes induced severe cellular disturbances including mitochondrial, lysosomal, and endoplasmic reticulum deficulum ( 34 , 35 ). In fact, these astrocytes respond to this stress by sending nanotubes that behave like tunnels and activate the transfer of α-syn binding to surrounding cells, indicating that astrocytes are very important in the pathogenesis of PD (35). NLY101, a GLP-1R agonist, has been shown to be neuroprotective in an α-syn fibril model first performed by PD and Yun et al. It acts to protect astrocyte-induced microglia activation and thus protects dopamine neurons and protects against behavioral deficits (36). Taken together, these findings suggest that astrocyte dysfunction is an important contributor to the pathogenesis of PD.

There are monogenic mutations identified in 20 genes involved in the pathogenesis of PD (37). Interestingly, a study by Zhang et al. . This would strongly support a possible role of astrocytes in the pathogenesis of this familial model of PD. Altered levels of these genes lead to many changes in astrocyte function, including impaired glutamate uptake, liposomal homeostasis, lysosomal and mitochondrial dysfunction, and inflammatory responses (Table 1).

Table 1. Involvement of Parkinson’s disease-causing genes and their pathology in astrocytes.

Pdf) Genes Involved In The Development Of Parkinson

Some of these genes have been studied more than others because of their role in astrobiology. DJ-1, encoded by the PARK7 gene, causes early-onset autosomal recessive PD (54) and is the most studied. Mullett and Hinkle used neuron-astrocyte cultures to show that siRNA knockdown of DJ-1 in mouse astrocytes impaired their ability to resist neurotoxins such as rotenone compared to wild-type astrocytes ( 55 ). In addition, studies using astrocytes from day 1 brains of DJ-1 knockout mice showed that loss of this gene can cause changes in cholesterol levels and glutamate uptake through regulation of the expression of flotillin-1 and caveolin-1 (40) . . Furthermore, Choi et al. Using astrocytes from DJ-1 knockout mice, it was shown that astrocytes lack prostaglandin D2 synthase expression and prostaglandin D2 secretion, suggesting that DJ-1 plays a role in regulating the anti-inflammatory role of astrocytes through prostaglandin expression. ) induced by lentiviral reactivation. and that the beginning has been replaced. response to LPS (56). Taken together, these studies demonstrate that DJ-1 is a critical regulator of the inflammatory response and that its knockdown in astrocytes does not regulate inflammation-induced damage.

Both PARK2 and PINK1 are expressed at the same level in astrocytes and neurons ( 38 , 39 , 57 ). Interestingly, astrocytic downregulation of Parkin, encoded by the PARK2 gene, reflects a stress-induced increase in NOD2 expression; The receptor binds to ER stress and inflammation and these astrocytes show an increase in cytokines and a decrease in the secretion of neurotrophic factors (42). Parkin has also been implicated in the astrocyte response to an inflammatory signal; Interaction with TNF-α leads to inhibition, while activation with IL-1β leads to inhibition of inhibition (58). Expression of PINK1, which encodes the protein PTEN-induced putase kinase 1 (PINK1), is a loss-of-function mutation in PD (59). Its expression increases during embryonic development and has been shown to affect the growth of GFAP-positive astrocytes ( 43 ). Indeed, when PINK1 is knocked down in astrocytes, this results in reduced differentiation (43), reduced release of neurotrophic factors, endoplasmic reticulum (ER) stress, JNK activation (42) and production of high levels of iNOS, NO, and TNF-α. is , and IL-1β through NF-κB signaling (44). Interestingly, even the steady-state level of PINK1 protein is very low

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