Cellular Proteostasis in Neurodegeneration

Kurtishi, Alberim; Rosen, Ben; Patil, Ketan S.; Alves, Guido; Møller, Simon Geir

doi:10.1007/s12035-018-1334-z

Cited by 173 publications

(112 citation statements)

References 149 publications

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“…Currently, how αS abnormalities cause neuronal dysfunction and degeneration is not fully understood. However, studies have implicated oxidative stress in the pathogenesis of PD [8][9][10] and dysfunction in proteostasis [11,12]. While oxidative stress in neurons has complex and multifaceted effects, recent reports suggest that activation of c-Abl, a non-receptor tyrosine kinase, can be stimulated by oxidative stress.…”

Section: Introductionmentioning

confidence: 99%

α-Synucleinopathy associated c-Abl activation causes p53-dependent autophagy impairment

Karim

Liao

Kim

et al. 2020

Mol Neurodegeneration

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Background: Studies link c-Abl activation with the accumulation of pathogenic α-synuclein (αS) and neurodegeneration in Parkinson's disease (PD). Currently, c-Abl, a tyrosine kinase activated by cellular stress, is thought to promote αS pathology by either directly phosphorylating αS or by causing autophagy deficits. Methods: αS overexpressing transgenic (Tg) mice were used in this study. A53T Tg mice that express high levels of human mutant A53TαS under the control of prion protein promoter. Two different approaches were used in this study. Natural aging and seeding model of synucleinopathy. In seeding model, intracortical/intrastriatal (IC/IS) stereotaxic injection of toxic lysates was done using tissue lysates from end-stage symptomatic mice. In this study, nilotinib and pifithrin-α was used as a c-Abl and p53 inhibitor, respectively. Both Tg and non-transgenic (nTg) mice from each group were subjected to nilotinib (10 mg/kg) or vehicle (DMSO) treatment. Frozen brain tissues from PD and control human cases were analyzed. In vitro cells study was implied for c-Abl/p53 genetic manipulation to uncover signal transduction. Results: Herein, we show that the pathologic effects of c-Abl in PD also involve activation of p53, as c-Abl activation in a transgenic mouse model of α-synucleinopathy (TgA53T) and human PD cases are associated with the increased p53 activation. Significantly, active p53 in TgA53T neurons accumulates in the cytosol, which may lead to inhibition of autophagy. Thus, we hypothesized that c-Abl-dependent p53 activation contributes to autophagy impairment in α-synucleinopathy. In support of the hypothesis, we show that c-Abl activation is sufficient to inhibit autophagy in p53-dependent manner. Moreover, inhibition of either c-Abl, using nilotinib, or p53, using pifithrin-α, was sufficient to increase autophagic flux in neuronal cells by inducing phosphorylation of AMP-activated kinase (AMPK), ULK1 activation, and down-regulation of mTORC1 signaling. Finally, we show that pharmacological attenuation of c-Abl activity by nilotinib treatment in the TgA53T mouse model reduces activation of p53, stimulates autophagy, decreases accumulation αS pathology, and delays disease onset. Conclusion: Collectively, our data show that c-Abl activation by α-synucleinopathy causes p53 dependent autophagy deficits and both c-Abl and p53 represent therapeutic target for PD.

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Section: Introductionmentioning

confidence: 99%

α-Synucleinopathy associated c-Abl activation causes p53-dependent autophagy impairment

Karim

Liao

Kim

et al. 2020

Mol Neurodegeneration

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“…Activation of the ER stress response and the subsequent cell death is a major contributor to the pathogenesis of a number of human diseases. Degenerative diseases are commonly caused or complicated by the accumulation of misfolded proteins in the ER and stress-induced cell death (2,(32)(33)(34)(35). In order to treat these degenerative diseases, it is essential to specifically target stressassociated cell death without inhibiting the beneficial stress-induced pathways that restore homeostasis.…”

Section: Discussionmentioning

confidence: 99%

“…Endoplasmic reticulum (ER) stress-induced apoptosis is a primary or contributing cause of degeneration in a wide variety of diseases such as type 2 diabetes and Alzheimer's Disease (1)(2)(3). Reducing stress-induced apoptosis could be the key to slowing the progression of these diseases, and indeed a major focus of therapeutic development is to identify compounds that can inhibit apoptosis.…”

Section: Introductionmentioning

confidence: 99%

The Drosophila metallopeptidase superdeath decouples apoptosis from the activation of the ER stress response

Palu

Chow

2019

Preprint

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Endoplasmic reticulum (ER) stress-induced apoptosis is a primary cause and modifier of degeneration in a number of genetic disorders. Understanding how genetic variation between individuals influences the ER stress response and subsequent activation of apoptosis could improve individualized therapies and predictions of outcomes for patients. In this study, we find that the uncharacterized, membrane-bound metallopeptidase CG14516 in Drosophila melanogaster, which we rename as SUPpressor of ER stress-induced DEATH (superdeath), plays a role in modifying ER stress-induced apoptosis. We demonstrate that loss of superdeath reduces apoptosis and degeneration in the Rh1 G69D model of ER stress through the JNK signaling cascade. This effect on apoptosis occurs without altering the activation of the unfolded protein response (IRE1 and PERK), suggesting that the beneficial pro-survival effects of this response are intact. Furthermore, we show that superdeath functions epistatically upstream of CDK5, a known JNK-activated pro-apoptotic factor in this model of ER stress. We demonstrate that superdeath is not only a modifier of this particular model, but functions as a general modifier of ER stress-induced apoptosis across different tissues and ER stresses. Finally, we present evidence of Superdeath localization to the endoplasmic reticulum membrane. While similar in sequence to a number of human metallopeptidases found in the plasma membrane and ER membrane, its localization suggests that superdeath is orthologous to ERAP1/2 in humans.Together, this study provides evidence that superdeath is a link between stress in the ER and activation of cytosolic apoptotic pathways. KEYWORDS ER stress, apoptosis, metallopeptidase, modifier genes SIGNIFICANCE STATEMENTGenetic diseases display a great deal of variability in presentation, progression, and overall outcomes. Much of this variability is caused by differences in genetic background among patients.One process that commonly modifies degenerative disease is the endoplasmic reticulum (ER) stress response. Understanding the genetic sources of variation in the ER stress response could improve individual diagnosis and treatment decisions. In this study, we characterized one such modifier in Drosophila melanogaster, the membrane-bound metallopeptidase CG14516 (superdeath). Loss of this enzyme suppresses a model of ER stress-induced degeneration by reducing cell death without altering the beneficial activation of the unfolded protein response. Our findings make superdeath and its orthologues attractive therapeutic targets in degenerative disease.

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“…Taking into account the high rate of demand and energy consumption of the brain, the majority of mitochondrial mutations can affect the functioning of the CNS and have been associated with neurodegenerative diseases (Angelova and Abramov, 2018). Thus, mitochondrial dysfunction is currently seen as a "convergence point" in neurodegeneration Bennett et al, 2014;Arun et al, 2016;Kurtishi et al, 2018).…”

Section: Oxidative Stress and Neurodegenerative Diseasesmentioning

confidence: 99%

Antioxidant Alternatives in the Treatment of Amyotrophic Lateral Sclerosis: A Comprehensive Review

et al. 2020

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that produces a selective loss of the motor neurons of the spinal cord, brain stem and motor cortex. Oxidative stress (OS) associated with mitochondrial dysfunction and the deterioration of the electron transport chain has been shown to be a factor that contributes to neurodegeneration and plays a potential role in the pathogenesis of ALS. The regions of the central nervous system affected have high levels of reactive oxygen species (ROS) and reduced antioxidant defenses. Scientific studies propose treatment with antioxidants to combat the characteristic OS and the regeneration of nicotinamide adenine dinucleotide (NAD +) levels by the use of precursors. This review examines the possible roles of nicotinamide riboside and pterostilbene as therapeutic strategies in ALS.

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Cellular Proteostasis in Neurodegeneration

Cited by 173 publications

References 149 publications

α-Synucleinopathy associated c-Abl activation causes p53-dependent autophagy impairment

α-Synucleinopathy associated c-Abl activation causes p53-dependent autophagy impairment

The Drosophila metallopeptidase superdeath decouples apoptosis from the activation of the ER stress response

Antioxidant Alternatives in the Treatment of Amyotrophic Lateral Sclerosis: A Comprehensive Review

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