MTOR Pathway-Based Discovery of Genetic Susceptibility to L-DOPA-Induced Dyskinesia in Parkinson’s Disease Patients

Martín‐Flores, Núria; Fernández‐Santiago, Rubén; Antonelli, Francesa; Cerquera-Cleves, Catalina; Moreno, Verónica; Martí, María Josep; Ezquerra, Mario; Malagelada, Cristina

doi:10.1007/s12035-018-1219-1

Cited by 20 publications

(13 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, with long-term L-DOPA treatment, most patients start to experience motor response fluctuations or dyskinesia [79,80]. By using a genetic association approach, Martin-Flores et al have detected genetic variability in the mTOR pathway and found it involved in the development of L-DOPA-induced dyskinesia [81]. Persistent activation of mTOR signaling in the striatum has been found in L-DOPA-induced dyskinesia [82].…”

Section: Potential Pd Treatment By Targeting Mtormentioning

confidence: 99%

Balancing mTOR Signaling and Autophagy in the Treatment of Parkinson’s Disease

Zhu

Yang

Iyaswamy

et al. 2019

IJMS

199

133

View full text Add to dashboard Cite

The mammalian target of rapamycin (mTOR) signaling pathway plays a critical role in regulating cell growth, proliferation, and life span. mTOR signaling is a central regulator of autophagy by modulating multiple aspects of the autophagy process, such as initiation, process, and termination through controlling the activity of the unc51-like kinase 1 (ULK1) complex and vacuolar protein sorting 34 (VPS34) complex, and the intracellular distribution of TFEB/TFE3 and proto-lysosome tubule reformation. Parkinson’s disease (PD) is a serious, common neurodegenerative disease characterized by dopaminergic neuron loss in the substantia nigra pars compacta (SNpc) and the accumulation of Lewy bodies. An increasing amount of evidence indicates that mTOR and autophagy are critical for the pathogenesis of PD. In this review, we will summarize recent advances regarding the roles of mTOR and autophagy in PD pathogenesis and treatment. Further characterizing the dysregulation of mTOR pathway and the clinical translation of mTOR modulators in PD may offer exciting new avenues for future drug development.

show abstract

Section: Potential Pd Treatment By Targeting Mtormentioning

confidence: 99%

Balancing mTOR Signaling and Autophagy in the Treatment of Parkinson’s Disease

Zhu

Yang

Iyaswamy

et al. 2019

IJMS

199

133

View full text Add to dashboard Cite

show abstract

“…49 Based on the high heritability of antipsychotics-induced side effects (0.60-0.80), a recent study developed a model based on genetic data to predict extrapyramidal symptoms induced by antipsychotics, 52 which represented a refinement of a previous model proposed by the same authors. 53 In light of the evidence implicating the mTOR signaling pathway in antipsychotics-induced extrapyramidal symptoms 53 as well as in L-DOPA-induced dyskinesia, 54 Boloc et al evaluated 12 functional SNPs located in four genes of the mTOR signaling pathway (AKT1, FCHSD1, RPTOR and DDIT4). Four of these SNPs (rs33925946 and rs1130214 in the AKT1 gene; rs3476568 and rs9915667 in the RPTOR gene) were selected on the basis of their nominal association with extrapyramidal symptoms in a discovery sample including 131 patients treated with risperidone (of which 48 with and 83 without extrapyramidal symptoms).…”

Section: Biological Predictive Models In Precision Psychiatrymentioning

confidence: 99%

<p>Challenges and Future Prospects of Precision Medicine in Psychiatry</p>

Manchia¹,

Pisanu²,

Squassina³

et al. 2020

PGPM

View full text Add to dashboard Cite

Precision medicine is increasingly recognized as a promising approach to improve disease treatment, taking into consideration the individual clinical and biological characteristics shared by specific subgroups of patients. In specific fields such as oncology and hematology, precision medicine has already started to be implemented in the clinical setting and molecular testing is routinely used to select treatments with higher efficacy and reduced adverse effects. The application of precision medicine in psychiatry is still in its early phases. However, there are already examples of predictive models based on clinical data or combinations of clinical, neuroimaging and biological data. While the power of single clinical predictors would remain inadequate if analyzed only with traditional statistical approaches, these predictors are now increasingly used to impute machine learning models that can have adequate accuracy even in the presence of relatively small sample size. These models have started to be applied to disentangle relevant clinical questions that could lead to a more effective management of psychiatric disorders, such as prediction of response to the mood stabilizer lithium, resistance to antidepressants in major depressive disorder or stratification of the risk and outcome prediction in schizophrenia. In this narrative review, we summarized the most important findings in precision medicine in psychiatry based on studies that constructed machine learning models using clinical, neuroimaging and/or biological data. Limitations and barriers to the implementation of precision psychiatry in the clinical setting, as well as possible solutions and future perspectives, will be presented.

show abstract

“…Thus, we think that LID is also related to intrinsic factors that are possibly genetic [14]. Remarkably, this notion is supported by very recent studies that have demonstrated genetic features as major factors influencing susceptibility to dyskinesias in patients with Parkinson´s disease [49,50].…”

Section: Discussionmentioning

confidence: 81%

Severity of Dyskinesia and D3R Signaling Changes Induced by L-DOPA Treatment of Hemiparkinsonian Rats Are Features Inherent to the Treated Subjects

et al. 2019

View full text Add to dashboard Cite

Extensive damage to nigrostriatal dopaminergic neurons leads to Parkinson’s disease (PD). To date, the most effective treatment has been administration of levodopa (L-DOPA) to increase dopaminergic tone. This treatment leads to responses that vary widely among patients, from predominantly beneficial effects to the induction of disabling, abnormal movements (L-DOPA induced dyskinesia (LID)). Similarly, experimental studies have shown animals with widely different degrees of LID severity. In this study, unilateral injections of 6-hydroxydopamine (6-OHDA) in the medial forebrain bundle (MFB) produced more than 90% depletion of dopamine in both the striatum and the substantia nigra reticulata (SNr) of rats. Population analysis showed that dopamine depletion levels were clustered in a single population. In contrast, analysis of abnormal involuntary movements (AIMs) induced by L-DOPA treatment of 6-OHDA-lesioned animals yielded two populations: one with mild LID, and the other with severe LID, which are also related to different therapeutic responses. We examined whether the severity of LID correlated with changes in dopamine 3 receptor (D3R) signaling because of the following: (a) D3R expression and the induction of LID are strongly correlated; and (b) dopaminergic denervation induces a qualitative change in D3R signaling in the SNr. We found that the effects of D3R activation on cAMP accumulation and depolarization-induced [3H]-gamma-aminobutyric acid ([3H]-GABA) release were switched. L-DOPA treatment normalized the denervation-induced changes in animals with mild LID. The D3R activation caused depression of both dopamine 1 receptor (D1R)-induced increases in cAMP production and depolarization-induced [3H]-GABA release, which were reversed to their pre-denervation state. In animals with severe LID, none of the denervation-induced changes were reversed. The finding that in the absence of identifiable differences in 6-OHDA and L-DOPA treatment, two populations of animals with different D3R signaling and LIDs severity implies that mechanisms intrinsic to the treated subject determine the segregation.

show abstract

MTOR Pathway-Based Discovery of Genetic Susceptibility to L-DOPA-Induced Dyskinesia in Parkinson’s Disease Patients

Cited by 20 publications

References 54 publications

Balancing mTOR Signaling and Autophagy in the Treatment of Parkinson’s Disease

Balancing mTOR Signaling and Autophagy in the Treatment of Parkinson’s Disease

<p>Challenges and Future Prospects of Precision Medicine in Psychiatry</p>

Severity of Dyskinesia and D3R Signaling Changes Induced by L-DOPA Treatment of Hemiparkinsonian Rats Are Features Inherent to the Treated Subjects

Contact Info

Product

Resources

About