Transcription factor EB overexpression prevents neurodegeneration in experimental synucleinopathies

Arotcarena, Marie-Laure; Bourdenx, Mathieu; Dutheil, Nathalie; Thiolat, Marie-Laure; Doudnikoff, Évelyne; Doveró, Sandra; Ballabio, Andrea; Fernagut, Pierre‐Olivier; Meissner, Wassilios G.; Bézard, Erwan; Dehay, Benjamin

doi:10.1172/jci.insight.129719

Cited by 61 publications

(53 citation statements)

References 69 publications

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“…No cytotoxicity was observed for E4 at the tested concentrations ( Figure S1). and therapeutic potential of TFEB in PD [10][11][12][13][14]. Defective ALP and decreased TFEB activity was found in postmortem PD midbrains [10].…”

Section: Compound E4 Promoted the Nuclear Translocation Of Endogenousmentioning

confidence: 95%

“…TFEB activation has been shown to be protective in the cellular and animal models of PD [10][11][12][13][14]. Therefore, we primarily tested whether compound E4 exerts neuroprotection in cellular models of PD.…”

Section: Compound E4 Reduces α-Syn Levels and Protects Against Mpp + mentioning

confidence: 99%

“…ALP, a cellular process for degrading misfolded cellular proteins and damaged organelles in lysosomes [6], has been proved to be tightly controlled by the transcription factor EB (TFEB) [9]. Several recent studies have investigated the roles and therapeutic potential of TFEB in PD [10][11][12][13][14]. Defective ALP and decreased TFEB activity was found in postmortem PD midbrains [10].…”

Section: Introductionmentioning

confidence: 99%

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A Curcumin Derivative Activates TFEB and Protects Against Parkinsonian Neurotoxicity in Vitro

Wang

Yang

Liu

et al. 2020

IJMS

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TFEB (transcription factor EB), which is a master regulator of autophagy and lysosome biogenesis, is considered to be a new therapeutic target for Parkinson’s disease (PD). However, only several small-molecule TFEB activators have been discovered and their neuroprotective effects in PD are unclear. In this study, a curcumin derivative, named E4, was identified as a potent TFEB activator. Compound E4 promoted the translocation of TFEB from cytoplasm into nucleus, accompanied by enhanced autophagy and lysosomal biogenesis. Moreover, TFEB knockdown effectively attenuated E4-induced autophagy and lysosomal biogenesis. Mechanistically, E4-induced TFEB activation is mainly through AKT-MTORC1 inhibition. In the PD cell models, E4 promoted the degradation of α-synuclein and protected against the cytotoxicity of MPP+ (1-methyl-4-phenylpyridinium ion) in neuronal cells. Overall, the TFEB activator E4 deserves further study in animal models of neurodegenerative diseases, including PD.

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Section: Compound E4 Promoted the Nuclear Translocation Of Endogenousmentioning

confidence: 95%

Section: Compound E4 Reduces α-Syn Levels and Protects Against Mpp + mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Curcumin Derivative Activates TFEB and Protects Against Parkinsonian Neurotoxicity in Vitro

Wang

Yang

Liu

et al. 2020

IJMS

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“…TFEB regulates the expression of autophagic genes through the Coordinated Lysosomal Expression and Regulation (CLEAR) signaling network, enhancing both lysosomal biogenesis and autophagy [313][314][315]. TFEB overexpression prevented motor deficits and induced dopaminergic neuroprotection associated with enhancement of α-syn clearance through MA activation in human WT and A53T α-syn overexpressing rats [306,316]. Similarly, TFEB overexpression in MPTP-intoxicated mice induced autophagosomal formation and lysosomal activity in addition to neurotrophic effects [317].…”

Section: Activation Of Ma and Lysosomal Functionmentioning

confidence: 99%

Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts

et al. 2020

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Parkinson’s Disease (PD) is characterized both by the loss of dopaminergic neurons in the substantia nigra and the presence of cytoplasmic inclusions called Lewy Bodies. These Lewy Bodies contain the aggregated α-synuclein (α-syn) protein, which has been shown to be able to propagate from cell to cell and throughout different regions in the brain. Due to its central role in the pathology and the lack of a curative treatment for PD, an increasing number of studies have aimed at targeting this protein for therapeutics. Here, we reviewed and discussed the many different approaches that have been studied to inhibit α-syn accumulation via direct and indirect targeting. These analyses have led to the generation of multiple clinical trials that are either completed or currently active. These clinical trials and the current preclinical studies must still face obstacles ahead, but give hope of finding a therapy for PD with time.

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“…The extent of mCherry staining within the GP (i.e., both the external and internal segments of the globus pallidus) was quantified with threshold surface analysis (Arotcarena et al, 2019) using Mercator software (Mercator V7.13.4, Explora Nova, France). The mCherry fluorescent protein tag was fused to the hM4Di DREADDs; therefore the extent of mCherry staining reliably reflected the expression of hM4Di DREADDs.…”

Section: Histology and Dreadd Extent Analysismentioning

confidence: 99%

In vivoelectrophysiological validation of DREADD-based inhibition of pallidal neurons in the non-human primate

Deffains

Nguyen

Orignac

et al. 2020

Preprint

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Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are widely used in rodents to manipulate neuronal activity and establish causal links between structure and function. Their utilization in non-human primates (NHPs) is however limited and their efficacy still debated. Here, we tested DREADD expression in the NHP external globus pallidus (GPe) and electrophysiologically validated DREADD-based inhibition of GPe neurons in the anesthetized monkey.To do so, we performed intracerebral injections of viral construct expressing hM4Di receptor under a neuron-specific promoter into the GPe. Then, we recorded the neuronal activity in the DREADD-transduced (test condition) and DREADD-free (control condition) GPe of two anesthetized animals following local intra-GPe microinjection of clozapine-N-oxide (CNO). In total, 19 and 8 well-isolated and stable units were recorded in the DREADD-transduced and DREADD-free GPe, respectively. Overall, we found that almost half (9/19) of the units modulated their activity following CNO injection in DREADDtransduced GPe. Surprisingly, neuronal activity of the GPe units exhibited diverse patterns in timing and polarity (increase/decrease) of firing rate modulations during and after CNO injection. Nevertheless, decreases were exclusive and stronger after CNO injection. In contrast, only one unit modulated its activity after CNO injection in DREADD-free GPe.Moreover, post-mortem histochemical analysis revealed that hM4Di DREADDs were expressed at high level in the GPe neurons located in the vicinity of the viral construct injection sites. Our results therefore show in vivo DREADD-based inhibition of pallidal neurons in the NHP model and reinforce the view that DREADD technology can be effective in NHPs.

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Transcription factor EB overexpression prevents neurodegeneration in experimental synucleinopathies

Cited by 61 publications

References 69 publications

A Curcumin Derivative Activates TFEB and Protects Against Parkinsonian Neurotoxicity in Vitro

A Curcumin Derivative Activates TFEB and Protects Against Parkinsonian Neurotoxicity in Vitro

Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts

In vivoelectrophysiological validation of DREADD-based inhibition of pallidal neurons in the non-human primate

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