Role of the ubiquitin–proteasome system in nervous system function and disease: using C. elegans as a dissecting tool

Baptista, Márcio S.; Duarte, Carlos B.; Maciel, Patrı́cia

doi:10.1007/s00018-012-0946-0

Cited by 20 publications

(13 citation statements)

References 285 publications

(268 reference statements)

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“…The sequential action of these enzymes leads to conjugation of Ub to proteins. Different E3 ligase target specific substrates for degradation and its activity could be under local control depending on the presence of regulatory cofactors [ 1 , 3 – 5 ].…”

Section: Introductionmentioning

confidence: 99%

Tyrosine Hydroxylase Is Short-Term Regulated by the Ubiquitin-Proteasome System in PC12 Cells and Hypothalamic and Brainstem Neurons from Spontaneously Hypertensive Rats: Possible Implications in Hypertension

et al. 2015

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Aberrations in the ubiquitin-proteasome system (UPS) are implicated in the pathogenesis of various diseases. Tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamines biosynthesis, is involved in hypertension development. In this study we investigated whether UPS regulated TH turnover in PC12 cells and hypothalamic and brainstem neurons from spontaneously hypertensive rats (SHR) and whether this system was impaired in hypertension. PC12 cells were exposed to proteasome or lysosome inhibitors and TH protein level evaluated by Western blot. Lactacystin, a proteasome inhibitor, induced an increase of 86±15% in TH levels after 30 min of incubation, then it started to decrease up to 6 h to reach control levels and finally it rose up to 35.2±8.5% after 24 h. Bafilomycin, a lysosome inhibitor, did not alter TH protein levels during short times, but it increased TH by 92±22% above basal after 6 h treatment. Before degradation proteasome substrates are labeled by conjugation with ubiquitin. Efficacy of proteasome inhibition on TH turnover was evidenced by accumulation of ubiquitinylated TH after 30 min. Further, the inhibition of proteasome increased the quantity of TH phosphorylated at Ser40, which is essential for TH activity, by 2.7±0.3 fold above basal. TH protein level was upregulated in neurons from hypothalami and brainstem of SHR when the proteasome was inhibited during 30 min, supporting that neuronal TH is also short-term regulated by the proteasome. Since the increased TH levels reported in hypertension may result from proteasome dysfunction, we evaluate proteasme activity. Proteasome activity was significantly reduced by 67±4% in hypothalamic and brainstem neurons from SHR while its protein levels did not change. Present findings show that TH is regulated by the UPS. The impairment in proteasome activity observed in SHR neurons may be one of the causes of the increased TH protein levels reported in hypertension.

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Section: Introductionmentioning

confidence: 99%

Tyrosine Hydroxylase Is Short-Term Regulated by the Ubiquitin-Proteasome System in PC12 Cells and Hypothalamic and Brainstem Neurons from Spontaneously Hypertensive Rats: Possible Implications in Hypertension

et al. 2015

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“…D, E). This group contains several genes that encode ubiquitin specific peptidases (Usp), which play important roles in the development and the physiology of bilaterian nervous systems as well as in neurodegenerative diseases (Baptista et al , ). As an example, Usp8 is implicated in the clearance of protein aggregates (Alexopoulou et al , ) and might in Ho_CS be involved in the response of old persisting neurons to the proteomic stress.…”

Section: Resultsmentioning

confidence: 99%

Loss of Neurogenesis in Aging Hydra

Tomczyk

Buzgariu

Perruchoud

et al. 2019

Developmental Neurobiology

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In Hydra the nervous system is composed of neurons and mechanosensory cells that differentiate from interstitial stem cells (ISCs), which also provide gland cells and germ cells. The adult nervous system is actively maintained through continuous de novo neurogenesis that occurs at two distinct paces, slow in intact animals and fast in regenerating ones. Surprisingly Hydra vulgaris survive the elimination of cycling interstitial cells and the subsequent loss of neurogenesis if force‐fed. By contrast, H. oligactis animals exposed to cold temperature undergo gametogenesis and a concomitant progressive loss of neurogenesis. In the cold‐sensitive strain Ho_CS, this loss irreversibly leads to aging and animal death. Within four weeks, Ho_CS animals lose their contractility, feeding response, and reaction to light. Meanwhile, two positive regulators of neurogenesis, the homeoprotein prdl‐a and the neuropeptide Hym‐355, are no longer expressed, while the “old” RFamide‐expressing neurons persist. A comparative transcriptomic analysis performed in cold‐sensitive and cold‐resistant strains confirms the downregulation of classical neuronal markers during aging but also shows the upregulation of putative regulators of neurotransmission and neurogenesis such as AHR, FGFR, FoxJ3, Fral2, Jagged, Meis1, Notch, Otx1, and TCF15. The switch of Fral2 expression from neurons to germ cells suggests that in aging animals, the neurogenic program active in ISCs is re‐routed to germ cells, preventing de novo neurogenesis and impacting animal survival.

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“…The 26S proteasome complex of C. elegans is composed of a 20S “catalytic core” and 19S “regulatory caps”. 19S can be further separated into two distinct substructures containing a ring of six homologous ATPase subunits of the AAA family (Rpt-1-6), two α-helical solenoid structures (Rpn-1 and Rpn-2), eight essential RP non-ATPase subunits (Rpn-3, Rpn-5-9 and Rpn-11-12), and two Ub receptors (Rpn-10) [ 21 ]. The effect of irisflorentin may be linked with augmented expression of rpn3 , a subunit of the 19S proteasome.…”

Section: Discussionmentioning

confidence: 99%

Irisflorentin improves α-synuclein accumulation and attenuates 6-OHDA-induced dopaminergic neuron degeneration, implication for Parkinson’s disease therapy

Chen¹,

Liu²,

Lin³

et al. 2015

BioMed

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Parkinson’s disease (PD) is a degenerative disorder of the central nervous system that is characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta as well as motor impairment. Aggregation of α-synuclein in neuronal cells plays a key role in this disease. At present, therapeutics for PD provides moderate symptomatic benefits, but it is not able to delay the development of the disease. Current efforts toward the treatment of PD are to identify new drugs that slow or arrest the progressive course of PD by interfering with a disease-specific pathogenetic process in PD patients. Irisflorentin derived from the roots of Belamcanda chinensis (L.) DC. is an herb which has been used for the treatment of inflammatory disorders in traditional Chinese medicine. The purpose of the present study was to assess the potential for irisflorentin to ameliorate PD in Caenorhabditis elegans models. Our data reveal that irisflorentin prevents α-synuclein accumulation in the transgenic Caenorhabditis elegans model and also improves dopaminergic neuron degeneration, food-sensing behavior, and life-span in a 6-hydroxydopamine-induced Caenorhabditis elegans model, thus indicating its potential as a anti-parkinsonian drug candidate. Irisflorentin may exert its effects by promoting rpn-3 expression to enhance the activity of proteasomes and down-regulating egl-1 expression to block apoptosis pathways. These findings encourage further investigation on irisflorentin as a possible potent agent for PD treatment.

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Role of the ubiquitin–proteasome system in nervous system function and disease: using C. elegans as a dissecting tool

Cited by 20 publications

References 285 publications

Tyrosine Hydroxylase Is Short-Term Regulated by the Ubiquitin-Proteasome System in PC12 Cells and Hypothalamic and Brainstem Neurons from Spontaneously Hypertensive Rats: Possible Implications in Hypertension

Tyrosine Hydroxylase Is Short-Term Regulated by the Ubiquitin-Proteasome System in PC12 Cells and Hypothalamic and Brainstem Neurons from Spontaneously Hypertensive Rats: Possible Implications in Hypertension

Loss of Neurogenesis in Aging Hydra

Irisflorentin improves α-synuclein accumulation and attenuates 6-OHDA-induced dopaminergic neuron degeneration, implication for Parkinson’s disease therapy

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