Progressive Parkinsonism by acute dysfunction of excitatory amino acid transporters in the rat substantia nigra

Assous, Maxime; Had‐Aissouni, Laurence; Gubellini, Paolo; Melon, Christophe; Nafia, Imane; Salin, Pascal; Goff, Lydia Kerkerian‐Le; Kachidian, Philippe

doi:10.1016/j.nbd.2014.01.011

Cited by 45 publications

(42 citation statements)

References 63 publications

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“…Furthermore, dysfunction of the excitatory amino acid transporters (EAATs) through acute stimulation with their substrates has been shown to cause degeneration in rat striatal neurons, leading to Parkinsonism-like phenotype in vivo (Assous et al 2014). …”

Section: Neurodegenerationmentioning

confidence: 99%

Amino acids and autophagy: cross-talk and co-operation to control cellular homeostasis

2014

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Maintenance of amino acid homeostasis is important for healthy cellular function, metabolism and growth. Intracellular amino acid concentrations are dynamic; the high demand for protein synthesis must be met with constant dietary intake, followed by cellular influx, utilization and recycling of nutrients. Autophagy is a catabolic process via which superfluous or damaged proteins and organelles are delivered to the lysosome and degraded to release free amino acids into the cytoplasm. Furthermore, autophagy is specifically activated in response to amino acid starvation via two key signaling cascades: the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) and the general control nonderepressible 2 (GCN2) pathways. These pathways are key regulators of the integration between anabolic (amino acid depleting) and catabolic (such as autophagy which is amino acid replenishing) processes to ensure intracellular amino acid homeostasis. Here, we discuss the key roles that amino acids, along with energy (ATP, glucose) and oxygen, are playing in cellular growth and proliferation. We further explore how sophisticated methods are employed by cells to sense intracellular amino acid concentrations, how amino acids can act as a switch to dictate the temporal and spatial activation of anabolic and catabolic processes and how autophagy contributes to the replenishment of free amino acids, all to ensure cell survival. Relevance of these molecular processes to cellular and organismal physiology and pathology is also discussed.

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Section: Neurodegenerationmentioning

confidence: 99%

Amino acids and autophagy: cross-talk and co-operation to control cellular homeostasis

2014

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“…[7] In this study, the authors found that excitotoxicity was significantly enhanced in the dopaminergic neurons selectively via NMDA receptors, and that raising glutathione levels using N-acetyl-L-cysteine was protective, again emphasizing a dual role of the EAAT glutamate transporter in both glutamate reuptake and transfer of glutathione precursors into the dopaminergic neuron.…”

Section: B Inflammation and Parkinson’s Diseasementioning

confidence: 89%

“…[5721224969160167176254] There is a considerable amount of evidence for excitotoxicity in Parkinson's disease brains, but is it a critical player in the process or is the progressive destruction primarily dependent on inflammation? In an article published in 2008, I coined the term immunoexcitotoxicity to call attention to a previously described interrelationship between inflammatory mechanisms and excitotoxicity.…”

Section: B Inflammation and Parkinson’s Diseasementioning

confidence: 99%

“…[2549143157228244253] Over the past 10 years, evidence has accumulated that these two processes are intimately linked and probably never occur independently in the pathological nervous system. In the majority of cases, the source of the inflammation and excitotoxicity is the resident immune cells of the central nervous system (CNS), the microglia, and under certain conditions, invading macrophages[125148251] [Figure 1].…”

Section: Introductionmentioning

confidence: 99%

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Parkinson's disease: Microglial/macrophage-induced immunoexcitotoxicity as a central mechanism of neurodegeneration

Blaylock¹

2017

Surg Neurol Int

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Parkinson's disease is one of the several neurodegenerative disorders that affects aging individuals, with approximately 1% of those over the age of 60 years developing the disorder in their lifetime. The disease has the characteristics of a progressive disorder in most people, with a common pattern of pathological change occurring in the nervous system that extends beyond the classical striatal degeneration of dopaminergic neurons. Earlier studies concluded that the disease was a disorder of alpha-synuclein, with the formation of aggregates of abnormal alpha-synuclein being characteristic. More recent studies have concluded that inflammation plays a central role in the disorder and that the characteristic findings can be accounted for by either mutation or oxidative damage to alpha-synuclein, with resulting immune reactions from surrounding microglia, astrocytes, and macrophages. What has been all but ignored in most of these studies is the role played by excitotoxicity and that the two processes are intimately linked, with inflammation triggered cell signaling enhancing the excitotoxic cascade. Further, there is growing evidence that it is the excitotoxic reactions that actually cause the neurodegeneration. I have coined the name immunoexcitotoxicity to describe this link between inflammation and excitotoxicity. It appears that the two processes are rarely, if ever, separated in neurodegenerative diseases.

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“…Even though an exact conclusion for the role of glutamate transporters in the pathogenesis of the disease is not found, some studies do clearly demonstrate a link between disturbed glutamatergic neurotransmission and glutamate transporter functioning in the striatum of an animal model for PD (Massie et al, 2010). Dopamine neurons express the neuronal transporter EAAC1 (EAAT3) at high levels (Plaitakis and Shashidharan, 2000), and during pathological conditions which lead to excessive neuronal depolarization, it can affect or even reverse EAAT function by altering the transport driving force (Danbolt, 2001;Assous et al, 2014). In a few studies, a time-dependent bilateral effect of unilateral 6-hydroxydopamine lesioning on the expression as well as activity of GLT-1 was found in animal models of PD (Carbone et al, 2012).…”

Section: Parkinson's Disease (Pd)mentioning

confidence: 99%

GLT-1 transporter: An effective pharmacological target for various neurological disorders

Soni

Reddy

Kumar

2014

Pharmacology Biochemistry and Behavior

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Progressive Parkinsonism by acute dysfunction of excitatory amino acid transporters in the rat substantia nigra

Cited by 45 publications

References 63 publications

Amino acids and autophagy: cross-talk and co-operation to control cellular homeostasis

Amino acids and autophagy: cross-talk and co-operation to control cellular homeostasis

Parkinson's disease: Microglial/macrophage-induced immunoexcitotoxicity as a central mechanism of neurodegeneration

GLT-1 transporter: An effective pharmacological target for various neurological disorders

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