Parkinsonâ€™s disease-implicated kinases in the brain; insights into disease pathogenesis

Dzamko, Nicolas; Zhou, Jinxia; Huang, Yue; Halliday, Glenda M.

doi:10.3389/fnmol.2014.00057

Cited by 73 publications

(70 citation statements)

References 193 publications

(248 reference statements)

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“…The characteristics of PD include a loss of dopaminergic neurons in the substantia nigra and accumulation of α-synuclein aggregates in Lewy bodies in the brain (Dzamko et al 2014). The symptoms of this disease include resting tremors, postural abnormalities, and akinesia due to the loss of dopaminergic neurons (Gandhi and Wood 2005).…”

Section: Parkinson's Diseasementioning

confidence: 99%

Compromised MAPK signaling in human diseases: an update

2015

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The mitogen-activated protein kinases (MAPKs) in mammals include c-Jun NH2-terminal kinase (JNK), p38 MAPK, and extracellular signal-regulated kinase (ERK). These enzymes are serine-threonine protein kinases that regulate various cellular activities including proliferation, differentiation, apoptosis or survival, inflammation, and innate immunity. The compromised MAPK signaling pathways contribute to the pathology of diverse human diseases including cancer and neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The JNK and p38 MAPK signaling pathways are activated by various types of cellular stress such as oxidative, genotoxic, and osmotic stress as well as by proinflammatory cytokines such as tumor necrosis factor-α and interleukin 1β. The Ras-Raf-MEK-ERK signaling pathway plays a key role in cancer development through the stimulation of cell proliferation and metastasis. The p38 MAPK pathway contributes to neuroinflammation mediated by glial cells including microglia and astrocytes, and it has also been associated with anticancer drug resistance in colon and liver cancer. We here summarize recent research on the roles of MAPK signaling pathways in human diseases, with a focus on cancer and neurodegenerative conditions.

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Section: Parkinson's Diseasementioning

confidence: 99%

Compromised MAPK signaling in human diseases: an update

2015

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“…First, while LRRK2 can be assayed as a kinase, the true substrate for LRRK2 remains uncertain with many proposed but few being proven unambiguously at physiological levels [45]. A convenient way to assay LRRK2 is to monitor autophosphorylation, and there is one site at S1292 that can be measured in vivo [25], so it remains possible if unlikely that there are no actual external substrates.…”

Section: Mutant Lrrk2 Alleles Produce Biochemically Active Proteinsmentioning

confidence: 99%

LRRK2 Pathways Leading to Neurodegeneration

Cookson

2015

Curr Neurol Neurosci Rep

121

106

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Mutations in LRRK2 are associated with inherited Parkinson’s disease (PD) in a large number of families, and the genetic locus containing the LRRK2 gene contains a risk factor for sporadic PD. The LRRK2 protein contains several domains that suggest a role in cellular signaling, including a kinase domain. It is also clear that LRRK2 interacts, either physically or genetically, with several other important proteins implicated in PD, suggesting that LRRK2 may be a central player in the pathways that underlie parkinsonism. As such, LRRK2 has been proposed to be a plausible target for therapeutic intervention, with kinase inhibition being pursued most actively. However, there are still several fundamental aspects of LRRK2 biology and function that remain unresolved at this time. This review will focus on the key questions of normal function of LRRK2 and how this might be related to the path-ophysiology of PD.

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“…Neurons have a particular reliance on mitochondria for energy production, calcium buffering, and managing ionic changes related to synaptic transmission . Furthermore, dysfunction of OMM signaling components can contribute to the pathophysiology of neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD) …”

Section: Introductionmentioning

confidence: 99%

Phosphoregulation on mitochondria: Integration of cell and organelle responses

2019

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Mitochondria are highly integrated organelles that are crucial to cell adaptation and mitigating adverse physiology. Recent studies demonstrate that fundamental signal transduction pathways incorporate mitochondrial substrates into their biological programs. Reversible phosphorylation is emerging as a useful mechanism to modulate mitochondrial function in accordance with cellular changes. Critical serine/threonine protein kinases, such as the c‐Jun N‐terminal kinase (JNK), protein kinase A (PKA), PTEN‐induced kinase‐1 (PINK1), and AMP‐dependent protein kinase (AMPK), readily translocate to the outer mitochondrial membrane (OMM), the interface of mitochondria‐cell communication. OMM protein kinases phosphorylate diverse mitochondrial substrates that have discrete effects on organelle dynamics, protein import, respiratory complex activity, antioxidant capacity, and apoptosis. OMM phosphorylation events can be tempered through the actions of local protein phosphatases, such as mitogen‐activated protein kinase phosphatase‐1 (MKP‐1) and protein phosphatase 2A (PP2A), to regulate the extent and duration of signaling. The central mediators of OMM signal transduction are the scaffold proteins because the relative abundance of these accessory proteins determines the magnitude and duration of a signaling event on the mitochondrial surface, which dictates the biological outcome of a local signal transduction pathway. The concentrations of scaffold proteins, such as A‐kinase anchoring proteins (AKAPs) and Sab (or SH3 binding protein 5—SH3BP5), have been shown to influence neuronal survival and vulnerability, respectively, in models of Parkinson's disease (PD), highlighting the importance of OMM signaling to health and disease. Despite recent progress, much remains to be discovered concerning the mechanisms of OMM signaling. Nonetheless, enhancing beneficial OMM signaling events and inhibiting detrimental protein‐protein interactions on the mitochondrial surface may represent highly selective approaches to restore mitochondrial health and homeostasis and mitigate organelle dysfunction in conditions such as PD.

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Parkinsonâ€™s disease-implicated kinases in the brain; insights into disease pathogenesis

Cited by 73 publications

References 193 publications

Compromised MAPK signaling in human diseases: an update

Compromised MAPK signaling in human diseases: an update

LRRK2 Pathways Leading to Neurodegeneration

Phosphoregulation on mitochondria: Integration of cell and organelle responses

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