Pramipexole reduces soluble mutant huntingtin and protects striatal neurons through dopamine D3 receptors in a genetic model of Huntington's disease

Luis-Ravelo, Diego; Estévez-Silva, Héctor; Barroso‐Chinea, Pedro; Afonso-Oramas, Domingo; Salas-Hernández, Josmar; Rodríguez-Núñez, Julia; Acevedo-Arozena, Abraham; Marcellino, Daniel; González‐Hernández, Tomás

doi:10.1016/j.expneurol.2017.10.019

Cited by 17 publications

(13 citation statements)

References 98 publications

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“…The anti-ALS actions of ROPI can be interpreted from both its D2R-dependent and -independent mechanisms. Recent reports suggest that autophagy may be activated by D2R/D3R agonists, possibly through a Beclin-1dependent pathway [24,25]. It would be interesting to determine whether ROPI-induced D2R/D3R activation induces autophagy leading to degradation or disassembly of abnormal RNA-protein complexes in ALS MNs.…”

Section: Bosutinibmentioning

confidence: 99%

Ropinirole, a New ALS Drug Candidate Developed Using iPSCs

Okano

Yasuda

Fujimori

et al. 2020

Trends in Pharmacological Sciences

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Induced pluripotent stem cells (iPSCs) are increasingly used in the study of disease mechanisms and the development of effective disease-modifying therapies for neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Recently, three candidate anti-ALS drugsropinirole (ROPI), retigabine, and bosutinibhave been identified in iPSC-based drug screens and are now being evaluated in clinical trials for safety and effectiveness. We review the preclinical data, clinical research design, and rationale for ROPI as an anti-ALS drug candidate compared with those of the other two drugs. We also discuss the use of iPSCs for understanding and monitoring treatment response as well as for new insights into the development of new drugs and therapeutic interventions for major neurodegenerative diseases.

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Section: Bosutinibmentioning

confidence: 99%

Ropinirole, a New ALS Drug Candidate Developed Using iPSCs

Okano

Yasuda

Fujimori

et al. 2020

Trends in Pharmacological Sciences

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“…RNAi knock-down of calpain in rodents showed reduced mHTT aggregate bur-www.chinaphar.com Harding RJ et al Acta Pharmacologica Sinica den [117] and similar results were observed in transgenic mice which overexpressed calpastatin (CAST), the endogenous inhibitor of calpain. Pramipexole is a dopamine receptor agonist which activates autophagy probably by modulating cAMP signally pathways in R6/1 HD mouse model, resulting in reduced levels of soluble mHTT [118] . Inhibition of PIP4Kγ by NCT-504 modulates phosphoinositide levels in HD patient fibroblasts and activates basal autophagy, thus reducing the mHTT levels [119] .…”

Section: Therapeutic Approaches In Hd Targeting Upsmentioning

confidence: 99%

Proteostasis in Huntington's disease: disease mechanisms and therapeutic opportunities

Harding

Tong

2018

Acta Pharmacol Sin

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Many neurodegenerative diseases are characterized by impairment of protein quality control mechanisms in neuronal cells. Ineffective clearance of misfolded proteins by the proteasome, autophagy pathways and exocytosis leads to accumulation of toxic protein oligomers and aggregates in neurons. Toxic protein species affect various cellular functions resulting in the development of a spectrum of different neurodegenerative proteinopathies, including Huntington's disease (HD). Playing an integral role in proteostasis, dysfunction of the ubiquitylation system in HD is progressive and multi-faceted with numerous biochemical pathways affected, in particular, the ubiquitin-proteasome system and autophagy routes for protein aggregate degradation. Unravelling the molecular mechanisms involved in HD pathogenesis of proteostasis provides new insight in disease progression in HD as well as possible therapeutic avenues. Recent developments of potential therapeutics are discussed in this review.

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“…However, PPX has been shown to reverse rotenoneinduced SNCA/α-synuclein accumulations in PC12 cells and in midbrain dopaminergic neurons [12], where DRD3 levels are significantly lower than in the ventral striatum. On the other hand, in R6/1 mice, a genetic model of Huntington disease in which DRD2 expression virtually disappears but DRD3 is preserved [57], PPX induces autophagy and reduces the levels of soluble mutated huntingtin in both the ventral and dorsal striatum [57]. Confirming their DRD3 dependence, the effects were inhibited by the DRD3 selective antagonist NGB2904, and not detected in the somatosensory cortex where DRD3 is virtually absent.…”

Section: Discussionmentioning

confidence: 96%

“…Several studies in the last decades indicate that DRD2-DRD3 agonists have neuroprotective effects on dopaminergic neurons, and that these effects can be mediated by both dopaminergic and dopamine-independent actions [15,21]. Recently, neuroprotection of DRD2-DRD3 agonists has been associated with their ability to induce autophagy and reduce protein aggregation [12,27,57]. However, relevant aspects of this effect are still unknown.…”

Section: Discussionmentioning

confidence: 99%

DRD3 (dopamine receptor D3) but not DRD2 activates autophagy through MTORC1 inhibition preserving protein synthesis

et al. 2019

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Growing evidence shows that autophagy is deficient in neurodegenerative and psychiatric diseases, and that its induction may have beneficial effects in these conditions. However, as autophagy shares signaling pathways with cell death and interferes with protein synthesis, prolonged use of autophagy inducers available nowadays is considered unwise. The search for novel autophagy inducers indicates that DRD2 (dopamine receptor 2)-DRD3 ligands may also activate autophagy, though critical aspects of the action mechanisms and effects of dopamine ligands on autophagy are still unknown. In order to shed light on this issue, DRD2and DRD3-overexpressing cells and drd2 KO, drd3 KO and wild-type mice were treated with the DRD2-DRD3 agonist pramipexole. The results revealed that pramipexole induces autophagy through MTOR inhibition and a DRD3-dependent but DRD2-independent mechanism. DRD3 activated AMPK followed by inhibitory phosphorylation of RPTOR, MTORC1 and RPS6KB1 inhibition and ULK1 activation. Interestingly, despite RPS6KB1 inhibition, the activity of RPS6 was maintained through activation of the MAPK1/3-RPS6KA pathway, and the activity of MTORC1 kinase target EIF4EBP1 along with protein synthesis and cell viability, were also preserved. This pattern of autophagy through MTORC1 inhibition without suppression of protein synthesis, contrasts with that of direct allosteric and catalytic MTOR inhibitors and opens up new opportunities for G protein-coupled receptor ligands as autophagy inducers in the treatment of neurodegenerative and psychiatric diseases.

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Pramipexole reduces soluble mutant huntingtin and protects striatal neurons through dopamine D3 receptors in a genetic model of Huntington's disease

Cited by 17 publications

References 98 publications

Ropinirole, a New ALS Drug Candidate Developed Using iPSCs

Ropinirole, a New ALS Drug Candidate Developed Using iPSCs

Proteostasis in Huntington's disease: disease mechanisms and therapeutic opportunities

DRD3 (dopamine receptor D3) but not DRD2 activates autophagy through MTORC1 inhibition preserving protein synthesis

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