WNT-β Catenin Signaling as a Potential Therapeutic Target for Neurodegenerative Diseases: Current Status and Future Perspective

Kakarla, Ramesh; Nalla, Lakshmi Vineela; Naresh, D.; Venkateswarlu, Kojja; Viswanadh, Matte Kasi; Nalluri, Buchi N.; Chakravarthy, G Kalyana; Duguluri, Sajusha; Singh, Payal; Nand, Sachchida; Kumar, Ashish; Singh, Veer; Singh, Santosh Kumar

doi:10.3390/diseases11030089

Cited by 49 publications

(15 citation statements)

References 262 publications

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“…As previously reported, [35][36][37] sporadic PD accounts for approximately 85%-95% of all PD cases. It may result from a complex interplay of genetic susceptibility, environmental factors, age-related changes, oxidative stress, mitochondrial dysfunction, protein misfolding and aggregation, and neuroinflammation.…”

Section: Discussionsupporting

confidence: 63%

Leucine‐rich repeat kinase 2 (LRRK2) inhibition upregulates microtubule‐associated protein 1B to ameliorate lysosomal dysfunction and parkinsonism

Chen,

Tang,

et al. 2023

MedComm

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Mutations in LRRK2 (encoding leucine‐rich repeat kinase 2 protein, LRRK2) are the most common genetic risk factors for Parkinson's disease (PD), and increased LRRK2 kinase activity was observed in sporadic PD. Therefore, inhibition of LRRK2 has been tested as a disease‐modifying therapeutic strategy using the LRRK2 mutant mice and sporadic PD. Here, we report a newly designed molecule, FL090, as a LRRK2 kinase inhibitor, verified in cell culture and animal models of PD. Using the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine mice and SNCA A53T transgenic mice, FL090 ameliorated motor dysfunctions, reduced LRRK2 kinase activity, and rescued loss in the dopaminergic neurons in the substantia nigra. Notably, by RNA‐Seq analysis, we identified microtubule‐associated protein 1 (MAP1B) as a crucial mediator of FL090's neuroprotective effects and found that MAP1B and LRRK2 co‐localize. Overexpression of MAP1B rescued 1‐methyl‐4‐phenylpyridinium induced cytotoxicity through rescuing the lysosomal function, and the protective effect of FL090 was lost in MAP1B knockout cells. Further studies may be focused on the in vivo mechanisms of MAP1B and microtubule function in PD. Collectively, these findings highlight the potential of FL090 as a therapeutic agent for sporadic PD and familial PD without LRRK2 mutations.

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Section: Discussionsupporting

confidence: 63%

Leucine‐rich repeat kinase 2 (LRRK2) inhibition upregulates microtubule‐associated protein 1B to ameliorate lysosomal dysfunction and parkinsonism

Chen,

Tang,

et al. 2023

MedComm

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“…3 Current treatment strategies for PD only provide symptomatic relief to patients, with limited effects on modifying the disease course. 4,5 Therefore, searching for neuroprotective agents for preventing neuronal loss in PD is necessary and urgent.…”

Section: ■ Introductionmentioning

confidence: 99%

“…According to the Global Burden of Disease Study (GBD), the prevalence of PD is increasing in the first place among the disabling neurological diseases, leading to an incremental demand for PD diagnosis, treatment, and rehabilitation . Current treatment strategies for PD only provide symptomatic relief to patients, with limited effects on modifying the disease course. , Therefore, searching for neuroprotective agents for preventing neuronal loss in PD is necessary and urgent.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of GluN2D-Containing NMDA Receptors Protects Dopaminergic Neurons against 6-OHDA-Induced Neurotoxicity via Activating ERK/NRF2/HO-1 Signaling

Zhang,

Wang,

Tang

et al. 2024

ACS Chem. Neurosci.

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Abnormal glutamate signaling is implicated in the heightened vulnerability of dopaminergic neurons in Parkinson's disease (PD). NMDA receptors are ion-gated glutamate receptors with high calcium permeability, and their GluN2D subunits are prominently distributed in the basal ganglia and brainstem nuclei. Previous studies have reported that dopamine depletion led to the dysfunctions of GluN2D-containing NMDA receptors in PD animal models. However, it remains unknown whether selective modulation of GluN2D could protect dopaminergic neurons against neurotoxicity in PD. In this study, we found that allosteric activation of GluN2D-containing NMDA receptors decreased the cell viability of MES23.5 dopaminergic cells and the GluN2D inhibitor, QNZ46, showed antioxidant effects and significantly relieved apoptosis in 6-OHDA-treated cells. Meanwhile, we demonstrated that QNZ46 might act via activation of the ERK/NRF2/HO-1 pathway. We also verified that QNZ46 could rescue abnormal behaviors and attenuate dopaminergic cell loss in a 6-OHDA-lesioned rat model of PD. Although the precise mechanisms underlying the efficacy of QNZ46 in vivo remain elusive, the inhibition of the GluN2D subunit should be a considerable way to treat PD. More GluN2D-selective drugs, which present minimal side effects and broad therapeutic windows, need to be developed for PD treatment in future studies.

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“…However, there is not any neuroprotective therapy available, although significant development has been made in the treatment of symptomatic PD, since the discovery of L-dopa in the middle of the 20th century (1960s). 10 Therefore, it is of great importance to seek effective drugs with high BBB permeability for delaying the onset or for forestalling the progression of PD.…”

Section: ■ Introductionmentioning

confidence: 99%

“…DAT and VMAT2 are important reference indexes for exploring the pathogenesis of PD, which is supported by that the reduced expression levels of DAT and VMAT2 are obtained in the nigrostriatal pathway of PD patients. , Previous studies have reported that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration to mice results in a severe loss of dopaminergic neurons and a dramatic reduction in striatal DA levels, which is similar to those in PD patients. , The expression levels of DAT and VMAT2 are also decreased in vivo and in vitro models of MPTP/MPP + injury. , Based on the depletion of dopamine in the striatum, most of the current drugs focus on clinical symptom relief to improve the quality of life in PD patients. However, there is not any neuroprotective therapy available, although significant development has been made in the treatment of symptomatic PD, since the discovery of l -dopa in the middle of the 20th century (1960s) . Therefore, it is of great importance to seek effective drugs with high BBB permeability for delaying the onset or for forestalling the progression of PD.…”

Section: Introductionmentioning

confidence: 99%

(+)-Borneol Protects Dopaminergic Neuronal Loss in Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Induced Parkinson’s Disease Mice: A Study of Dopamine Level using In Vivo Brain Microdialysis

Ding,

Wang,

Yang

et al. 2024

ACS Chem. Neurosci.

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Considerable research efforts have been directed toward the symptom relief of Parkinson’s disease (PD) by attenuating dopamine (DA) depletion. One common feature of these existing therapies is their unavailability of preventing the neurodegenerative process of dopaminergic neurons. (+)-Borneol, a natural highly lipid-soluble bicyclic monoterpene, has been reported to regulate the levels of monoamine neurotransmitters in the central nervous system and exhibit neuroprotective effects. However, the effect of (+)-borneol on the dopaminergic neuronal loss of methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice is not defined. Herein, we first report that 30 mg/kg (+)-borneol significantly attenuated the motor deficits of PD mice, which benefits from markedly increasing the level of DA and decreasing the metabolic rate of DA in the striatum of conscious and freely moving mouse detected by ultraperformance liquid chromatography tandem mass spectrometry online combined with in vivo brain microdialysis sampling. It is worth noting that the enhanced level of DA by (+)-borneol was enabled by the reduction in loss of tyrosine hydroxylase-immunoreactive dopaminergic neurons in the substantia nigra and striatum and promotion of reserpine- or nomifensine-induced DA release in PD mice. Interestingly, (+)-borneol evidently inhibited the decreased expression levels of DA transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) on the MPTP mouse model of PD. Moreover, (+)-borneol suppressed the neuroinflammation by inhibiting the production of IL-1β, IL-6, and TNF-α and attenuated oxidative stress by decreasing the level of MDA and increasing the activities of SOD and GSH-px in PD mice. These findings demonstrate that (+)-borneol protects DA neurons by inhibiting neuroinflammation and oxidative stress. Further research work for the neuroprotection mechanism of (+)-borneol will focus on reactive oxygen species-mediated apoptosis. Therefore, (+)-borneol is a potential therapeutic candidate for retarding the neurodegenerative process of PD.

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WNT-β Catenin Signaling as a Potential Therapeutic Target for Neurodegenerative Diseases: Current Status and Future Perspective

Cited by 49 publications

References 262 publications

Leucine‐rich repeat kinase 2 (LRRK2) inhibition upregulates microtubule‐associated protein 1B to ameliorate lysosomal dysfunction and parkinsonism

Leucine‐rich repeat kinase 2 (LRRK2) inhibition upregulates microtubule‐associated protein 1B to ameliorate lysosomal dysfunction and parkinsonism

Inhibition of GluN2D-Containing NMDA Receptors Protects Dopaminergic Neurons against 6-OHDA-Induced Neurotoxicity via Activating ERK/NRF2/HO-1 Signaling

(+)-Borneol Protects Dopaminergic Neuronal Loss in Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Induced Parkinson’s Disease Mice: A Study of Dopamine Level using In Vivo Brain Microdialysis

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