scholarly journals Intracellular delivery of Parkin rescues neurons from accumulation of damaged mitochondria and pathological α-synuclein

2020 ◽  
Vol 6 (18) ◽  
pp. eaba1193 ◽  
Author(s):  
Eunna Chung ◽  
Youngsil Choi ◽  
Jiae Park ◽  
Wonheum Nah ◽  
Jaehyung Park ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Dopaminergic Neurons ◽  
Neurodegenerative Disorder ◽  
E3 Ubiquitin Ligase ◽  
Intracellular Delivery ◽  
Motor Deficits ◽  
Motor Symptoms ◽  
Body Formation ◽  
Enhanced Solubility ◽  
A Cell

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by mitochondrial dysfunction, Lewy body formation, and loss of dopaminergic neurons. Parkin, an E3 ubiquitin ligase, is thought to inhibit PD progression by removing damaged mitochondria and suppressing the accumulation of α-synuclein and other protein aggregates. The present study describes a protein-based therapy for PD enabled by the development of a cell-permeable Parkin protein (iCP-Parkin) with enhanced solubility and optimized intracellular delivery. iCP-Parkin recovered damaged mitochondria by promoting mitophagy and mitochondrial biogenesis and suppressed toxic accumulations of α-synuclein in cells and animals. Last, iCP-Parkin prevented and reversed declines in tyrosine hydroxylase and dopamine expression concomitant with improved motor function induced by mitochondrial poisons or enforced α-synuclein expression. These results point to common, therapeutically tractable features in PD pathophysiology, and suggest that motor deficits in PD may be reversed, thus providing opportunities for therapeutic intervention after the onset of motor symptoms.

scholarly journals Distinct intracellular motifs of Delta mediate its ubiquitylation and activation by Mindbomb1 and Neuralized

2011 ◽  
Vol 195 (6) ◽  
pp. 1017-1031 ◽  
Author(s):  
Aikaterini Daskalaki ◽  
Nevine A. Shalaby ◽  
Kristina Kux ◽  
Giorgos Tsoumpekos ◽  
George D. Tsibidis ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Notch Receptor ◽  
Molecular Dissection ◽  
Excellent Correlation ◽  
New Gene ◽  
A Cell ◽  
Dsl Ligands ◽  
Signaling Activity

DSL proteins are transmembrane ligands of the Notch receptor. They associate with a RING (really interesting new gene) family E3 ubiquitin ligase, either Neuralized (Neur) or Mindbomb 1 (Mib1), as a prerequisite to signaling. Although Neur and Mib1 stimulate internalization of DSL ligands, it is not known how ubiquitylation contributes to signaling. We present a molecular dissection of the intracellular domain (ICD) of Drosophila melanogaster Delta (Dl), a prototype DSL protein. Using a cell-based assay, we detected ubiquitylation of Dl by both Neur and Mib1. The two enzymes use distinct docking sites and displayed different acceptor lysine preferences on the Dl ICD. We generated Dl variants that selectively perturb its interactions with Neur or Mib1 and analyzed their signaling activity in two in vivo contexts. We found an excellent correlation between the ability to undergo ubiquitylation and signaling. Therefore, ubiquitylation of the DSL ICD seems to be a necessary step in the activation of Notch.

Gene Therapy in the Management of Parkinson’s Disease: Potential of GDNF as a Promising Therapeutic Strategy

2020 ◽  
Vol 20 (3) ◽  
pp. 207-222
Author(s):  
Tapan Behl ◽  
Ishnoor Kaur ◽  
Arun Kumar ◽  
Vineet Mehta ◽  
Gokhan Zengin ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Gene Therapy ◽  
Parkinson's Disease ◽  
Neurotrophic Factor ◽  
Dopaminergic Neurons ◽  
Viral Vector ◽  
Neurodegenerative Disorder ◽  
Dopamine Synthesis ◽  
Motor Symptoms ◽  
Ligand Complex

: The limitations of conventional treatment therapies in Parkinson’s disorder, a common neurodegenerative disorder, lead to the development of an alternative gene therapy approach. Multiple treatment options targeting dopaminergic neuronal regeneration, production of enzymes linked with dopamine synthesis, subthalamic nucleus neurons, regulation of astrocytes and microglial cells and potentiating neurotrophic factors, were established. Viral vector-based dopamine delivery, prodrug approaches, fetal ventral mesencephalon tissue transplantation and dopamine synthesizing enzyme encoding gene delivery are significant therapies evidently supported by numerous trials. The review primarily elaborates on the significant role of glial cell-line derived neurotrophic factor in alleviating motor symptoms and the loss of dopaminergic neurons in Parkinson’s disease. Neuroprotective and neuroregenerative effects of GDNF were established via preclinical and clinical study outcomes. The binding of GDNF family ligands with associated receptors leads to the formation of a receptor-ligand complex activating Ret receptor of tyrosine kinase family, which is only expressed in dopaminergic neurons, playing an important role in Parkinson’s disease, via its association with the essential protein encoded genes. Furthermore, the review establishes delivery aspects, like ventricular delivery of recombinant GDNF, intraparenchymal and intraputaminal delivery using infusion catheters. The review highlights problems and challenges of GDNF delivery, and essential measures to overcome them, like gene therapy combinations, optimization of delivery vectors, newer targeting devices, motor symptoms curbing focused ultrasound techniques, modifications in patient selection criteria and development of novel delivery strategies based on liposomes and encapsulated cells, to promote safe and effective delivery of neurotrophic factor and establishment of routine treatment therapy for patients.

scholarly journals Nicotinamide mononucleotide treatment increases NAD+ levels in an iPSC Model of Parkinson’s Disease

2020 ◽  
Author(s):  
Brett K. Fulleylove-Krause ◽  
Samantha L. Sison ◽  
Allison D. Ebert
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Stem Cell ◽  
Mitochondrial Function ◽  
Dopaminergic Neurons ◽  
Neurodegenerative Disorder ◽  
Motor Deficits ◽  
Severe Motor ◽  
Underlying Mechanisms ◽  
Reduced Nicotinamide Adenine Dinucleotide

AbstractParkinson’s disease (PD) is a common neurodegenerative disorder caused by the loss of dopaminergic neurons in the substantia nigra that leads to severe motor and non-motor deficits. Although the underlying mechanisms of dopaminergic neuron loss is not entirely clear, increasing evidence suggests mitochondrial malfunction as a key contributor to disease pathogenesis. Recently, we found that human PD patient stem cell-derived dopaminergic neurons exhibit reduced nicotinamide adenine dinucleotide (NAD+) levels, an essential cofactor in mitochondrial function and cellular metabolism. In addition, we found that sirtuins, a group of NAD+-dependent deacetylase enzymes that participate in the regulation of mitochondrial function, energy production, and cell survival, displayed decreased activity in PD dopaminergic neurons, thereby suggesting a potential mechanism for dopaminergic loss in PD. Thus, here we tested whether treatment of PD stem cell-derived dopaminergic neurons with an NAD+ precursor could increase NAD+ levels and improve sirtuin activity.

Parkin: a multifaceted ubiquitin ligase

2006 ◽  
Vol 34 (5) ◽  
pp. 749-753 ◽  
Author(s):  
D.J. Moore
Keyword(s):  
Ubiquitin Ligase ◽  
Dopaminergic Neurons ◽  
Autosomal Recessive ◽  
E3 Ubiquitin Ligase ◽  
Gene Products ◽  
Biochemical Pathway ◽  
Leucine Rich Repeat ◽  
Parkin Gene ◽  
Protein Substrates ◽  
Phosphatase And Tensin Homologue

Mutations in the parkin gene are a common cause of autosomal recessive early-onset parkinsonism. Parkin functions as an E3 ubiquitin ligase where it can polyubiquitinate a number of its protein substrates, thus targeting them for degradation by the 26 S proteasomal complex. Recent studies have demonstrated that alternative modes of parkin-mediated ubiquitination may serve other non-degradative regulatory roles. In addition, parkin appears to function as a multipurpose neuroprotectant in a number of toxic paradigms. Coupled with these observations, parkin may integrate other gene products associated with parkinsonism, including α-synuclein, LRRK2 (leucine-rich repeat kinase 2), DJ-1 and PINK1 [PTEN (phosphatase and tensin homologue deleted on chromosome 10)-induced putative kinase 1], into a common biochemical pathway of potential relevance to disease pathogenesis. Parkin therefore represents a unique multifaceted ubiquitin ligase consistent with an important housekeeping role in maintaining the integrity or survival of dopaminergic neurons.

scholarly journals Huntingtin Ubiquitination Mechanisms and Novel Possible Therapies to Decrease the Toxic Effects of Mutated Huntingtin

2021 ◽  
Vol 11 (12) ◽  
pp. 1309
Author(s):  
Annarita Fiorillo ◽  
Veronica Morea ◽  
Gianni Colotti ◽  
Andrea Ilari
Keyword(s):  
Small Molecules ◽  
Ubiquitin Ligase ◽  
Neurodegenerative Disorder ◽  
E3 Ubiquitin Ligase ◽  
Ubiquitin Proteasome System ◽  
Aggregate Formation ◽  
Gene Encoding ◽  
Exon 1 ◽  
Ubiquitin Proteasome ◽  
Abnormal Expansion

Huntington Disease (HD) is a dominant, lethal neurodegenerative disorder caused by the abnormal expansion (>35 copies) of a CAG triplet located in exon 1 of the HTT gene encoding the huntingtin protein (Htt). Mutated Htt (mHtt) easily aggregates, thereby inducing ER stress that in turn leads to neuronal injury and apoptosis. Therefore, both the inhibition of mHtt aggregate formation and the acceleration of mHtt degradation represent attractive strategies to delay HD progression, and even for HD treatment. Here, we describe the mechanism underlying mHtt degradation by the ubiquitin–proteasome system (UPS), which has been shown to play a more important role than the autophagy–lysosomal pathway. In particular, we focus on E3 ligase proteins involved in the UPS and detail their structure–function relationships. In this framework, we discuss the possible exploitation of PROteolysis TArgeting Chimeras (PROTACs) for HD therapy. PROTACs are heterobifunctional small molecules that comprise two different ligands joined by an appropriate linker; one of the ligands is specific for a selected E3 ubiquitin ligase, the other ligand is able to recruit a target protein of interest, in this case mHtt. As a consequence of PROTAC binding, mHtt and the E3 ubiquitin ligase can be brought to a relative position that allows mHtt to be ubiquitinated and, ultimately, allows a reduction in the amount of mHtt in the cell.

scholarly journals A Cell-Based Target Engagement Assay for the Identification of Cereblon E3 Ubiquitin Ligase Ligands and Their Application in HDAC6 Degraders

2020 ◽  
Vol 27 (7) ◽  
pp. 866-876.e8 ◽  
Author(s):  
Ka Yang ◽  
Yu Zhao ◽  
Xueqing Nie ◽  
Hao Wu ◽  
Bo Wang ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Target Engagement ◽  
A Cell

scholarly journals State transitions in the substantia nigra reticulata predict the onset of motor deficits in models of progressive dopamine depletion in mice

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Amanda M Willard ◽  
Brian R Isett ◽  
Timothy C Whalen ◽  
Kevin J Mastro ◽  
Chris S Ki ◽  
...  
Keyword(s):  
Basal Ganglia ◽  
Substantia Nigra ◽  
Neurodegenerative Disorder ◽  
State Transitions ◽  
Motor Deficits ◽  
Motor Symptoms ◽  
Dopamine Depletion ◽  
Discrete State ◽  
Substantia Nigra Reticulata ◽  
Diseased State

Parkinson’s disease (PD) is a progressive neurodegenerative disorder whose cardinal motor symptoms are attributed to dysfunction of basal ganglia circuits under conditions of low dopamine. Despite well-established physiological criteria to define basal ganglia dysfunction, correlations between individual parameters and motor symptoms are often weak, challenging their predictive validity and causal contributions to behavior. One limitation is that basal ganglia pathophysiology is studied only at end-stages of depletion, leaving an impoverished understanding of when deficits emerge and how they evolve over the course of depletion. In this study, we use toxin- and neurodegeneration-induced mouse models of dopamine depletion to establish the physiological trajectory by which the substantia nigra reticulata (SNr) transitions from the healthy to the diseased state. We find that physiological progression in the SNr proceeds in discrete state transitions that are highly stereotyped across models and correlate well with the prodromal and symptomatic stages of behavior.

scholarly journals Mitochondrial E3 Ubiquitin Ligase Parkin: Relationships with Other Causal Proteins in Familial Parkinson’s Disease and Its Substrate-Involved Mouse Experimental Models

2020 ◽  
Vol 21 (4) ◽  
pp. 1202 ◽  
Author(s):  
Satoru Torii ◽  
Shuya Kasai ◽  
Tatsushi Yoshida ◽  
Ken-ichi Yasumoto ◽  
Shigeomi Shimizu
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Ubiquitin Ligase ◽  
Transcriptional Repression ◽  
Neurodegenerative Disorder ◽  
E3 Ubiquitin Ligase ◽  
Experimental Models ◽  
Dual Function ◽  
Key Factors ◽  
Post Translational Modifications

Parkinson’s disease (PD) is a common neurodegenerative disorder. Recent identification of genes linked to familial forms of PD has revealed that post-translational modifications, such as phosphorylation and ubiquitination of proteins, are key factors in disease pathogenesis. In PD, E3 ubiquitin ligase Parkin and the serine/threonine-protein kinase PTEN-induced kinase 1 (PINK1) mediate the mitophagy pathway for mitochondrial quality control via phosphorylation and ubiquitination of their substrates. In this review, we first focus on well-characterized PINK1 phosphorylation motifs. Second, we describe our findings concerning relationships between Parkin and HtrA2/Omi, a protein involved in familial PD. Third, we describe our findings regarding inhibitory PAS (Per/Arnt/Sim) domain protein (IPAS), a member of PINK1 and Parkin substrates, involved in neurodegeneration during PD. IPAS is a dual-function protein involved in transcriptional repression of hypoxic responses and the pro-apoptotic activities.

scholarly journals Herpes Simplex Virus Type 1 ICP0 Phosphorylation Mutants Impair the E3 Ubiquitin Ligase Activity of ICP0 in a Cell Type-Dependent Manner

2008 ◽  
Vol 82 (21) ◽  
pp. 10647-10656 ◽  
Author(s):  
Chris Boutell ◽  
Roger Everett ◽  
Joshua Hilliard ◽  
Priscilla Schaffer ◽  
Anne Orr ◽  
...  
Keyword(s):  
Herpes Simplex ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Transient Transfection ◽  
Dependent Manner ◽  
Cell Type ◽  
Ubiquitin Ligase Activity ◽  
A Cell ◽  
Simplex Virus

ABSTRACT Herpes simplex virus type 1 (HSV-1) infected cell protein 0 (ICP0) is a 110-kDa nuclear phosphoprotein that is required for both the efficient initiation of lytic infection and the reactivation of quiescent viral genomes from latency. The ability of ICP0 to act as a potent viral transactivator is mediated by its N-terminal zinc-binding RING finger domain. This domain confers E3 ubiquitin ligase activity to ICP0 and is required for the proteasome-dependent degradation of a number of cellular proteins during infection, including the major nuclear domain 10 (ND10) constituent protein promyelocytic leukemia. In previous work we mapped three phosphorylation regions within ICP0, two of which directly affected its transactivation capabilities in transient transfection assays (Davido et al., J. Virol. 79:1232-1243, 2005). Because ICP0 is a phosphoprotein, we initially sought to test the hypothesis that phosphorylation regulates the E3 ubiquitin ligase activity of ICP0. Although none of the mutations affected ICP0 E3 ligase activity in vitro, transient transfection analysis indicated that mutations within one or more of the phosphorylated regions impaired the ability of ICP0 to form foci with colocalizing conjugated ubiquitin and to disrupt ND10. Mutations within one of the regions also affected ICP0 stability, and all of these phenomena occurred in a cell type-dependent manner. In the context of viral infection, only one ICP0 phosphorylation mutant (P1) showed a significant defect in viral replication and enhanced protein stability compared to all the other viruses tested. This study suggests that specific cellular environments and context of expression (transfection versus infection) differentially regulate several activities of ICP0 related to its E3 ubiquitin ligase activity via phosphorylation.

Author response for "TAM receptors attenuate murine NK cell responses via E3 ubiquitin ligase Cbl‐b"

2019 ◽  
Author(s):  
Leilani M. Chirino ◽  
Suresh Kumar ◽  
Mariko Okumura ◽  
David E. Sterner ◽  
Michael Mattern ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Nk Cell ◽  
E3 Ubiquitin Ligase ◽  
Author Response ◽  
Cell Responses ◽  
Tam Receptors
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