Inflammation kinase PKR phosphorylates α-synuclein and causes α-synuclein-dependent cell death

Reimer, Lasse; Vesterager, Louise Buur; Betzer, Cristine; Zheng, Jin; Nielsen, Lærke; Kofoed, Rikke Hahn; Lassen, Louise Berkhoudt; Bølcho, Ulrik; Paludan, Søren R.; Fog, Karina; Jensen, Poul Henning

doi:10.1016/j.nbd.2018.03.001

Cited by 30 publications

(33 citation statements)

References 64 publications

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“…Influenza virus H5N1 leads to microgliosis and a‐syn pathology (phosphorylation) in mouse (Jang et al., ). A recent report suggests that inflammation‐associated serine‐threonine kinase, PKR (EIF2AK2), which is involved in protection against viral infection, leads to phosphorylation of Ser129 in a‐syn, which is suggested to play a role in the disease phenotype (Reimer et al., ). Therefore, certain viral infections that lead to a‐syn pathology could contribute to the onset or progression of neurodegenerative disease.…”

Section: Infections As Putative Players In the Risk Of Developing Parmentioning

confidence: 99%

Immune system responses in Parkinson's disease: Early and dynamic

Tansey

Romero‐Ramos

2018

Eur J of Neuroscience

125

127

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The neuropathological hallmarks of Parkinson's disease (PD) are the degeneration and death of dopamine‐producing neurons in the ventral midbrain, the widespread intraneuronal aggregation of alpha‐synuclein (α) in Lewy bodies and neurites, neuroinflammation, and gliosis. Signs of microglia activation in the PD brain postmortem as well as during disease development revealed by neuroimaging, implicate immune responses in the pathophysiology of the disease. Intensive research during the last two decades has advanced our understanding of the role of these responses in the disease process, yet many questions remain unanswered. A transformative finding in the field has been the confirmation that in vivo microglia are able to respond directly to pathological a‐syn aggregates but also to neuronal dysfunction due to intraneuronal a‐syn toxicity well in advance of neuronal death. In addition, clinical research and disease models have revealed the involvement of both the innate and adaptive immune systems. Indeed, the data suggest that PD leads not only to a microglia response, but also to a cellular and humoral peripheral immune response. Together, these findings compel us to consider a more holistic view of the immunological processes associated with the disease. Central and peripheral immune responses aimed at maintaining neuronal health will ultimately have consequences on neuronal survival. We will review here the most significant findings that have contributed to the current understanding of the immune response in PD, which is proposed to occur early, involve peripheral and brain immune cells, evolve as neuronal dysfunction progresses, and is likely to influence disease progression.

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Section: Infections As Putative Players In the Risk Of Developing Parmentioning

confidence: 99%

Immune system responses in Parkinson's disease: Early and dynamic

Tansey

Romero‐Ramos

2018

Eur J of Neuroscience

125

127

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“…PTMs play crucial roles in almost every biological process. They consist of alterations that occur on a protein after it is translated by the ribosome, affecting its function, stability, localization, interaction with other proteins and degradation 10,[21][22][23][24] . The ability to modify existing proteins allows the cell to respond rapidly to stimuli, and this is particularly important in neurons, where neurotransmission typically occurs on the millisecond timescale.…”

Section: Phosphorylation Ubiquitination and Sumoylationmentioning

confidence: 99%

“…Recent insights have shown that this protein may also act like a prion, propagating from one neuron to another, therefore enhancing brain degeneration 33,35,36 . Phosphorylation of α-syn at Ser-129 exacerbates the formation of α-syn inclusions, with over 90% of α-syn in LBs being phosphorylated at this residue, resulting in increased toxicity and neuronal death 5,23,27,34 . In a study by Karampetsou and colleagues (2017), α-syn was injected into mouse striatum in its wild type form versus its phosphorylated form, and they observed that phosphorylated α-syn demonstrated enhanced pathology in the SN compared to WT α-syn, increasing dopaminergic neuronal loss 27 .…”

Section: Ptms Of α-Synmentioning

confidence: 99%

“…In a study by Karampetsou and colleagues (2017), α-syn was injected into mouse striatum in its wild type form versus its phosphorylated form, and they observed that phosphorylated α-syn demonstrated enhanced pathology in the SN compared to WT α-syn, increasing dopaminergic neuronal loss 27 . It is known that various kinases can contribute to this overphosphorylation at Ser-129, and one example is the inflammation kinase PKR, highlighting how neuroinflammation can play a role in PD progression through α-syn dysfunction 5,23 .…”

Section: Ptms Of α-Synmentioning

confidence: 99%

“…In PD it has been shown that all three PTMs play a role in protein aggregation, exocytosis, and degradation 5,[21][22][23]27,[32][33][34] . Therefore, comprehending how these modifications control the function of PD-related proteins, and how these PTMs are altered in disease, could bring new insights into the etiology of the disease, as well as identify potential targets for therapeutic intervention.…”

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confidence: 99%

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Post-translational modifications of Parkinson's disease-related proteins: Phosphorylation, SUMOylation and Ubiquitination

Junqueira

Centeno

Wilkinson

et al. 2019

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons in the nigrostriatal pathway. The etiology of PD remains unclear and most cases are sporadic, however genetic mutations in more than 20 proteins have been shown to cause inherited forms of PD. Many of these proteins are linked to mitochondrial function, defects in which are a central characteristic of PD. Post-translational modifications (PTMs) allow rapid and reversible control over protein function. Largely focussing on mitochondrial dysfunction in PD, here we review findings on the PTMs phosphorylation, SUMOylation and ubiquitination that have been shown to affect PDrelated proteins.

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A truncated PACT protein resulting from a frameshift mutation reported in movement disorder DYT16 triggers caspase activation and apoptosis

Burnett

Vaughn

Strom

et al. 2019

J of Cellular Biochemistry

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Protein Activator (PACT) activates the interferon (IFN)‐induced double‐stranded (ds) RNA‐activated protein kinase (PKR) in response to stress signals. Oxidative stress and endoplasmic reticulum (ER) stress causes PACT‐mediated PKR activation, which leads to phosphorylation of translation initiation factor eIF2α, inhibition of protein synthesis, and apoptosis. A dominantly inherited form of early‐onset dystonia 16 (DYT16) has been identified to arise due to a frameshift (FS) mutation in PACT. To examine the effect of the resulting truncated mutant PACT protein on the PKR pathway, we examined the biochemical properties of the mutant protein and its effect on mammalian cells. Our results indicate that the FS mutant protein loses its ability to bind dsRNA as well as its ability to interact with PKR while surprisingly retaining the ability to interact with PACT and PKR‐inhibitory protein TRBP. The truncated FS mutant protein, when expressed as a fusion protein with a N‐terminal fluorescent mCherry tag aggregates in mammalian cells to induce apoptosis via activation of caspases both in a PKR‐ and PACT‐dependent as well as independent manner. Our results indicate that interaction of FS mutant protein with PKR inhibitor TRBP can dissociate PACT from the TRBP‐PACT complex resulting in PKR activation and consequent apoptosis. These findings are relevant to diseases resulting from protein aggregation especially since the PKR activation is a characteristic of several neurodegenerative conditions.

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Inflammation kinase PKR phosphorylates α-synuclein and causes α-synuclein-dependent cell death

Cited by 30 publications

References 64 publications

Immune system responses in Parkinson's disease: Early and dynamic

Immune system responses in Parkinson's disease: Early and dynamic

Post-translational modifications of Parkinson's disease-related proteins: Phosphorylation, SUMOylation and Ubiquitination

A truncated PACT protein resulting from a frameshift mutation reported in movement disorder DYT16 triggers caspase activation and apoptosis

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