Is DARPP-32 a potential therapeutic target?

Reis, Helton José; Rosa, Daniela V.; Guimarães, Melissa Monteiro; Souza, Bruno R.; Barros, A.G.A.; Pimenta, Flávio Juliano; Souza, Renan Pedra de; Torres, Karen; Romano-Silva, Marco Aurélio

doi:10.1517/14728222.11.12.1649

Cited by 28 publications

(10 citation statements)

References 104 publications

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“…Furthermore, beside confirming the potential of pridopidine to represent a symptomatic treatment in HD, our findings highlight a neuroprotective action of the drug; administration of pridopidine increased the expression of both BDNF and DARPP32, proteins normally implicated in neuronal health and reduced in animal models of HD and post‐mortem samples of HD patients , and ameliorated mHtt aggregation, commonly linked to mHtt toxicity Consistently, pridopidine protected HD cells from apoptosis and promoted the activation of pro‐survival kinase ERK. Similar to (‐)‐OSU6162, another dopaminergic stabilizer recently reported in a HD study , pridopidine exerted its antiapoptotic effect only at concentrations of 150 μM.…”

Section: Discussionsupporting

confidence: 71%

Pridopidine, a dopamine stabilizer, improves motor performance and shows neuroprotective effects in Huntington disease R6/2 mouse model

Squitieri

Pardo

Favellato

et al. 2015

J Cellular Molecular Medi

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Huntington disease (HD) is a neurodegenerative disorder for which new treatments are urgently needed. Pridopidine is a new dopaminergic stabilizer, recently developed for the treatment of motor symptoms associated with HD. The therapeutic effect of pridopidine in patients with HD has been determined in two double-blind randomized clinical trials, however, whether pridopidine exerts neuroprotection remains to be addressed. The main goal of this study was to define the potential neuroprotective effect of pridopidine, in HD in vivo and in vitro models, thus providing evidence that might support a potential disease-modifying action of the drug and possibly clarifying other aspects of pridopidine mode-of-action. Our data corroborated the hypothesis of neuroprotective action of pridopidine in HD experimental models. Administration of pridopidine protected cells from apoptosis, and resulted in highly improved motor performance in R6/2 mice. The anti-apoptotic effect observed in the in vitro system highlighted neuroprotective properties of the drug, and advanced the idea of sigma-1-receptor as an additional molecular target implicated in the mechanism of action of pridopidine. Coherent with protective effects, pridopidine-mediated beneficial effects in R6/2 mice were associated with an increased expression of pro-survival and neurostimulatory molecules, such as brain derived neurotrophic factor and DARPP32, and with a reduction in the size of mHtt aggregates in striatal tissues. Taken together, these findings support the theory of pridopidine as molecule with disease-modifying properties in HD and advance the idea of a valuable therapeutic strategy for effectively treating the disease.

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Section: Discussionsupporting

confidence: 71%

Pridopidine, a dopamine stabilizer, improves motor performance and shows neuroprotective effects in Huntington disease R6/2 mouse model

Squitieri

Pardo

Favellato

et al. 2015

J Cellular Molecular Medi

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“…2). Treatment with GM1 also restored normal levels of DARPP-32 phoshorylation at threonine 34 in the striatum of YAC128 mice, suggesting overall normalization of cell signaling and/or dopaminergic pathways in medium spiny neurons (41,42).…”

Section: Chronic Infusion Of Gm1 Restores Normal Motor Behavior In Yamentioning

confidence: 86%

“…DARPP-32 plays a crucial role at the crossroad of dopaminergic and other signaling pathways, which converge to determine overall expression level and phosphorylation state (resulting in specific protein functions) of DARPP-32 in medium spiny neurons. In turn, DARPP-32 integrates neuronal responses to a variety of neurotransmitters and stimuli and modulates striatum output pathways (41,42,45).…”

Section: Discussionmentioning

confidence: 99%

Ganglioside GM1 induces phosphorylation of mutant huntingtin and restores normal motor behavior in Huntington disease mice

Pardo

Maglione

Alpaugh

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

146

143

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Huntington disease (HD) is a progressive neurodegenerative monogenic disorder caused by expansion of a polyglutamine stretch in the huntingtin (Htt) protein. Mutant huntingtin triggers neural dysfunction and death, mainly in the corpus striatum and cerebral cortex, resulting in pathognomonic motor symptoms, as well as cognitive and psychiatric decline. Currently, there is no effective treatment for HD. We report that intraventricular infusion of ganglioside GM1 induces phosphorylation of mutant huntingtin at specific serine amino acid residues that attenuate huntingtin toxicity, and restores normal motor function in already symptomatic HD mice. Thus, our studies have identified a potential therapy for HD that targets a posttranslational modification of mutant huntingtin with critical effects on disease pathogenesis.H untington disease (HD) is an inherited neurodegenerative monogenic disorder caused by the expansion of a polyglutamine stretch beyond 36 residues in the amino-terminal domain of huntingtin (Htt), a protein expressed in most tissues and cells. The mutation causes huntingtin to acquire toxic conformation/s and to affect neuronal function and viability. Medium-sized spiny neurons in the corpus striatum are most affected, but neurodegeneration also occurs in the cerebral cortex and, to a minor extent, in other brain areas, resulting in motor and psychiatric symptoms, as well as cognitive decline.The cellular and molecular mechanisms underlying HD pathogenesis are complex. Both loss and gain of function of mutant huntingtin contribute to cause a wide array of neuronal dysfunctions affecting cell signaling, gene transcription, axonal transport, cell and mitochondrial metabolism as well as neurotransmission (1).In recent years, a breakthrough in HD research has been the discovery that posttranslational modifications of mutant Htt are crucial modulators of mutant Htt toxicity (2-4). Phosphorylation at various serine residues prevents cleavage of mutant huntingtin into more toxic fragments, decreases neural cell death in vitro (5-10), and/or restores Htt functions that are compromised by the mutation (8, 11). The most dramatic effects have been described for huntingtin phosphorylation at serine 13 and serine 16. These two amino acid residues are part of the highly conserved amino-terminal "N17" domain of huntingtin, a domain that regulates huntingtin intracellular localization and association to cellular membranes (12, 13), as well as kinetics of mutant huntingtin aggregation (14,15). Phosphomimetic mutations of serine 13 and serine 16 by aspartic or glutamic acid substitution (S13D and S16D or S13E and S16E) decrease the toxicity of mutant huntingtin fragments in vitro (10, 16). In line with these studies, expression of a phosphomimetic (S13D and S16D) mutant form of expanded full-length huntingtin in a BACHD transgenic mouse model was shown to result in a normal phenotype, with no detectable signs of HD pathology by 12 mo (17).These findings suggest that pharmacological interventions that modulate cell sig...

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“…When phosphorylated at threonine 34 by protein kinase A (PKA), it becomes a potent inhibitor of protein phosphatase‐1 (PP‐1), a major multifunctional serine/threonine protein phosphatase in brain (Viggiano et al, 2003). The DARPP‐32/PP‐1 pathway integrates information from a variety of neurotransmitters and produces a coordinated response involving numerous downstream physiological effectors (Souza et al, 2006; Reis et al, 2007). Although there are data showing DARPP‐32 association with ADHD‐like behaviors, such as hyperlocomotion presented by DARPP‐32 mice knockout (Nally et al, 2003), and PKA‐specific site phosphorylation after administration of psychotomimetics, such as dextroamphetamine (Svenningsson et al, 2003); DARPP‐32 potential role on the psychostimulants effects remains to be fully understood.…”

Section: Methodsmentioning

confidence: 99%

Cerebral DARPP‐32 expression after methylphenidate administration in young and adult rats

Souza

Soares

Rosa

et al. 2008

Intl J of Devlp Neuroscience

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Dopamine may alter the phosphorylation state of DARPP-32 that plays a central role in the dopaminergic neurons biology. Studies have shown that DARPP-32/protein phosphatase 1 cascade is a major target for psychostimulants drugs. Methylphenidate is a psychostimulant that acts blocking the dopamine transporter has been used as an effective treatment for Attention Deficit Hyperactivity Disorder. We investigated if methylphenidate could alter DARPP-32 expression in five brain regions (striatum, hippocampus, prefrontal cortex, cortex and cerebellum) in young and adult rats. Our results showed that methylphenidate treatment is able to alter DARPP-32 expression in rat brain. Acute methylphenidate treatment has reduced hippocampal DARPP-32 protein levels in old rats, while chronic methylphenidate treatment has decreased them in old rat hippocampus and young rat cerebellum. It was found an increased cortical expression after chronic methylphenidate administration in old rats. Our results provide the first experimental demonstration that methylphenidate induces changes in total DARPP-32 expression that are posology- and age-related in some rat brain areas, although further studies are needed to shed more light on the mechanisms behind these findings.

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Is DARPP-32 a potential therapeutic target?

Cited by 28 publications

References 104 publications

Pridopidine, a dopamine stabilizer, improves motor performance and shows neuroprotective effects in Huntington disease R6/2 mouse model

Pridopidine, a dopamine stabilizer, improves motor performance and shows neuroprotective effects in Huntington disease R6/2 mouse model

Ganglioside GM1 induces phosphorylation of mutant huntingtin and restores normal motor behavior in Huntington disease mice

Cerebral DARPP‐32 expression after methylphenidate administration in young and adult rats

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