REST Protects Dopaminergic Neurons from Mitochondrial and α-Synuclein Oligomer Pathology in an Alpha Synuclein Overexpressing BAC-Transgenic Mouse Model

Ryan, Brent J.; Bengoa-Vergniory, Nora; Williamson, Matthew G; Kirkiz, Ecem; Roberts, Rosalind F.; Corda, Gabriele; Sloan, Maximilian; Saqlain, Saba; Cherubini, Marta; Poppinga, Josse; Bogtofte, Helle; Cioroch, Milena; Hester, Svenja; Wade‐Martins, Richard

doi:10.1523/jneurosci.1478-20.2021

Cited by 22 publications

(13 citation statements)

References 59 publications

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“…In agreement with recent results obtained in dopaminergic neurons (Ryan et al, 2021 ), we show that REST deficiency contributes to cellular dysfunction by blocking autophagic protein clearance. We provide data for this blockade at both structural and functional levels.…”

Section: Discussionsupporting

confidence: 94%

REST/NRSF deficiency impairs autophagy and leads to cellular senescence in neurons

et al. 2021

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During aging, brain performances decline. Cellular senescence is one of the aging drivers and a key feature of a variety of human age‐related disorders. The transcriptional repressor RE1‐silencing transcription factor (REST) has been associated with aging and higher risk of neurodegenerative disorders. However, how REST contributes to the senescence program and functional impairment remains largely unknown. Here, we report that REST is essential to prevent the senescence phenotype in primary mouse neurons. REST deficiency causes failure of autophagy and loss of proteostasis, increased oxidative stress, and higher rate of cell death. Re‐establishment of autophagy reverses the main hallmarks of senescence. Our data indicate that REST has a protective role in physiological aging by regulating the autophagic flux and the senescence program in neurons, with implications for neurological disorders associated with aging.

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Section: Discussionsupporting

confidence: 94%

REST/NRSF deficiency impairs autophagy and leads to cellular senescence in neurons

et al. 2021

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“…Growing evidence shows that REST is neuroprotective, and its dysfunction may contribute to the neuropathology of multiple neurological disorders, such as PD, dementia with Lewy body ( 39 , 53 ), and AD ( 38 ). Decreased REST levels were correlated with higher oxidative stress and apoptotic events with dementia in AD brains compared with normal healthy brains ( 38 ).…”

Section: Discussionmentioning

confidence: 99%

“…Growing evidence has shown that REST exerts neuroprotective effects against several neurodegenerative diseases, including AD ( 38 ), PD ( 39 ) and experimental 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)–induced PD models ( 52 ). Reduced REST levels exacerbated mitochondrial dysfunction and correlated with α-synuclein accumulation in an α-synuclein-overexpressed PD mouse model ( 53 ). Mn decreased REST expression in dopaminergic neuronal cells, leading to a decrease in tyrosine hydroxylase expression, resulting in neuronal toxicity ( 50 ).…”

mentioning

confidence: 99%

Astrocytic transcription factor REST upregulates glutamate transporter EAAT2, protecting dopaminergic neurons from manganese-induced excitotoxicity

Pajarillo

Digman

Nyarko-Danquah

et al. 2021

Journal of Biological Chemistry

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Chronic exposure to high levels of manganese (Mn) leads to manganism, a neurological disorder with similar symptoms to those inherent to Parkinson's disease. However, the underlying mechanisms of this pathological condition have yet to be established. Since the human excitatory amino acid transporter 2 (EAAT2) (glutamate transporter 1 in rodents) is predominantly expressed in astrocytes and its dysregulation is involved in Mn-induced excitotoxic neuronal injury, characterization of the mechanisms that mediate the Mn-induced impairment in EAAT2 function is crucial for the development of novel therapeutics against Mn neurotoxicity. Repressor element 1-silencing transcription factor (REST) exerts protective effects in many neurodegenerative diseases. But the effects of REST on EAAT2 expression and ensuing neuroprotection are unknown. Given that the EAAT2 promoter contains REST binding sites, the present study investigated the role of REST in EAAT2 expression at the transcriptional level in astrocytes and Mn-induced neurotoxicity in an astrocyte–neuron coculture system. The results reveal that astrocytic REST positively regulates EAAT2 expression with the recruitment of an epigenetic modifier, cAMP response element-binding protein–binding protein/p300, to its consensus binding sites in the EAAT2 promoter. Moreover, astrocytic overexpression of REST attenuates Mn-induced reduction in EAAT2 expression, leading to attenuation of glutamate-induced neurotoxicity in the astrocyte–neuron coculture system. Our findings demonstrate that astrocytic REST plays a critical role in protection against Mn-induced neurotoxicity by attenuating Mn-induced EAAT2 repression and the ensuing excitotoxic dopaminergic neuronal injury. This indicates that astrocytic REST could be a potential molecular target for the treatment of Mn toxicity and other neurological disorders associated with EAAT2 dysregulation.

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“…Indeed, recent data showed that CRISPR-mediated REST KO induced mitochondrial dysfunction and impaired mitophagy in vitro. Furthermore, REST overexpression impedes mitochondrial toxicity and mitochondrial morphology disruption through the transcription factor PGC-1α [41].…”

Section: Discussionmentioning

confidence: 99%

Cell Stress Induces Mislocalization of Transcription Factors with Mitochondrial Enrichment

Rossi

Fernàndez

Torres

et al. 2021

IJMS

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Previous evidence links the formation of extranuclear inclusions of transcription factors, such as ERK, Jun, TDP-43, and REST, with oxidative, endoplasmic-reticulum, proteasomal, and osmotic stress. To further characterize its extranuclear location, we performed a high-content screening based on confocal microscopy and automatized image analyses of an epithelial cell culture treated with hydrogen peroxide, thapsigargin, epoxomicin, or sorbitol at different concentrations and times to recreate the stresses mentioned above. We also performed a subcellular fractionation of the brain from transgenic mice overexpressing the Q331K-mutated TARDBP, and we analyzed the REST-regulated mRNAs. The results show that these nuclear proteins exhibit a mitochondrial location, together with significant nuclear/extranuclear ratio changes, in a protein and stress-specific manner. The presence of these proteins in enriched mitochondrial fractions in vivo confirmed the results of the image analyses. TDP-43 aggregation was associated with alterations in the mRNA levels of the REST target genes involved in calcium homeostasis, apoptosis, and metabolism. In conclusion, cell stress increased the mitochondrial translocation of nuclear proteins, increasing the chance of proteostasis alterations. Furthermore, TDP-43 aggregation impacts REST target genes, disclosing an exciting interaction between these two transcription factors in neurodegenerative processes.

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REST Protects Dopaminergic Neurons from Mitochondrial and α-Synuclein Oligomer Pathology in an Alpha Synuclein Overexpressing BAC-Transgenic Mouse Model

Cited by 22 publications

References 59 publications

REST/NRSF deficiency impairs autophagy and leads to cellular senescence in neurons

REST/NRSF deficiency impairs autophagy and leads to cellular senescence in neurons

Astrocytic transcription factor REST upregulates glutamate transporter EAAT2, protecting dopaminergic neurons from manganese-induced excitotoxicity

Cell Stress Induces Mislocalization of Transcription Factors with Mitochondrial Enrichment

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