ArticleNeurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics2019
Tetramethylpyrazine Analogue T-006 Promotes the Clearance of Alpha-synuclein by Enhancing Proteasome Activity in Parkinson's Disease Models.
Article in Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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19 citing papers in PubMed, 35 citations in OpenAlex.
- Interactions Between Nutraceuticals and α-Synuclein Conformational States: Molecular Mechanisms and Neuroprotective Implications in Parkinson's Disease.International journal of molecular sciences · 2026Review
- Mitochondrial Dysfunction in Neurodegenerative Diseases: Mechanisms and Corresponding Therapeutic Strategies.Biomedicines · 2025Review
- Tetramethylpyrazine Analogue T-006 Protects Neuronal and Endothelial Cells Against Oxidative Stress via PI3K/AKT/mTOR and Nrf2 Signaling.Antioxidants (Basel, Switzerland) · 2024Article
- 20S proteasome enhancers prevent cytotoxic tubulin polymerization-promoting protein induced α-synuclein aggregation.iScience · 2024Article
- Tetramethylpyrazine Nitrone Promotes the Clearance of Alpha-Synuclein via Nrf2-Mediated Ubiquitin-Proteasome System Activation.Neuromolecular medicine · 2024Article
- Interactions Between the Ubiquitin-Proteasome System, Nrf2, and the Cannabinoidome as Protective Strategies to Combat Neurodegeneration: Review on Experimental Evidence.Neurotoxicity research · 2024Review
- Neuroprotection by tetramethylpyrazine and its synthesized analogues for central nervous system diseases: a review.Molecular biology reports · 2024Review
- Mechanisms of ubiquitin-independent proteasomal degradation and their roles in age-related neurodegenerative disease.Frontiers in cell and developmental biology · 2024Review
- Inhibition of Protein Aggregation and Endoplasmic Reticulum Stress as a Targeted Therapy for α-Synucleinopathy.Pharmaceutics · 2023Review
- Determining the Potential Roles of Branched-Chain Amino Acids in the Regulation of Muscle Growth in Common Carp (Aquaculture nutrition · 2023Article
- Chinese Herbal Medicine in the Treatment of Depression in Parkinson's Disease: From Molecules to Systems.Frontiers in pharmacology · 2022Review
- Autophagy and apoptosis cascade: which is more prominent in neuronal death?Cellular and molecular life sciences : CMLS · 2021Review
- The Roles of Tetramethylpyrazine During Neurodegenerative Disease.Neurotoxicity research · 2021Review
- Review
- The Tetramethylpyrazine Analogue T-006 Alleviates Cognitive Deficits by Inhibition of Tau Expression and Phosphorylation in Transgenic Mice Modeling Alzheimer's Disease.Journal of molecular neuroscience : MN · 2021Article
- Alpha-Synuclein Post-translational Modifications: Implications for Pathogenesis of Lewy Body Disorders.Frontiers in aging neuroscience · 2021Review
- Targeting α-synuclein for PD Therapeutics: A Pursuit on All Fronts.Biomolecules · 2020Review
- Novel approaches to counter protein aggregation pathology in Parkinson's disease.Progress in brain research · 2020Review
- Proteasome, a Promising Therapeutic Target for Multiple Diseases Beyond Cancer.Drug design, development and therapy · 2020Review
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Authors and funding
14 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide and is characterized in part by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). The main pathological hallmark of PD is the intraneuronal accumulation of misfolded α-synuclein (α-syn) aggregates. Mutations in the SNCA gene (encoding α-syn) and variations in its copy number are associated with some forms of familial PD. In the present study, T-006, a new tetramethylpyrazine (TMP) derivative with recently reported anti-Alzheimer activity, is shown to significantly promote α-syn degradation in a cellular PD model. Moreover, we illustrate that T-006 inhibits the accumulation of both Triton-soluble and -insoluble forms of α-syn and protects against α-syn-induced neurotoxicity in A53T-α-syn transgenic mice. The mechanism of action of T-006 was verified by evaluation of a potential protein degradation pathway. We found that T-006 promotes α-syn degradation in a proteasome-dependent and autophagy-independent manner. We further confirmed that T-006 enhances proteasome activity by upregulating 20S proteasome subunit β5i (LMP7) protein expression. A functional study revealed that T-006 activates the PKA/Akt/mTOR/p70S6K pathway to trigger LMP7 expression and enhance chymotrypsin-like proteasomal activity. These findings indicate that T-006 is a potent proteasome activator and a potential therapeutic agent for the prevention and treatment of PD and related diseases.
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