Journal Article

Osmotin-derived 9-amino-acid peptide alleviates α-synuclein and MPTP-induced glial cell activation mediated neuroinflammation, protecting dopaminergic neurons in Parkinson’s disease mice brain

Park, Tae Ju, Kim, Myeong Ok, Tahir, Muhammad, Kang, Min Hwa, Ahmad, Riaz, Park, Hyun Young, Choe, Kyonghwan

2026

Overview

Background Parkinson’s disease (PD) is the second most common neurodegenerative disorder, categorized by the loss of dopaminergic neurons in the brain’s Substantia Nigra pars compacta (SNpc) due to α-synuclein (α-syn) aggregation, leading to reduced dopamine levels in the striatum. This research study evaluates the neuroprotective potential of the novel peptide osmotin-derived 9-amino-acid (Os_9aa, C-T-Q-G-P-C-G-P-T) against α-syn (neuron-specific enolase promoter human alpha-synuclein (NSE-hαSyn)) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD models. Methods Human neuroblastoma SH-SY5Y cells were employed as an in vitro model, while NSE-hαSyn (α-synuclein) transgenic mice and MPTP-treated mice were used as in vivo models of PD. MPTP was administered intraperitoneally (30 mg/kg) once daily for five consecutive days. Mice were immunized with Os_9aa (15 mg/kg, i.p., twice weekly for five weeks), followed by behavioral assessments including open field test, wire hang test, pole test, and rotarod test, and biochemical analysis using the Triplex Assay, western blotting, and confocal microscopy. Results Our study demonstrated that the novel peptide Os_9aa enhanced cell viability, reduced cytotoxicity, and apoptosis in SH-SY5Y neuroblastoma cells. Os_9aa attenuated synucleinopathy-related pathology in NSE-hαSyn transgenic mice and MPTP-induced PD mouse models. Current findings also highlighted the therapeutic potential of Os_9aa in mitigating behavioral deficits observed in NSE-hαSyn and MPTP mouse models of PD. Furthermore, Os_9aa administration effectively restored key dopaminergic markers, including tyrosine hydroxylase (TH), vesicular monoamine transporter 2 (VMAT2), and dopamine transporter (DAT). Additionally, it reduced neuroinflammation by decreasing the activation of glial cells—ionized calcium-binding adaptor molecule 1 (Iba-1) and glial fibrillary acidic protein (GFAP), as well as pro-inflammatory cytokines, such as phosphorylated nuclear factor-κB (p-NF-кB), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β), in the striatum and SNpc regions. Furthermore, Os_9aa mitigated oxidative stress (OS) by upregulating the expression of nuclear factor erythroid-related factor 2 (Nrf-2) and heme oxygenase 1 (HO-1), and improved cognitive performance. Conclusion Collectively, these findings highlight the neuroprotective potential of the Os_9aa, which counteracts α-synuclein– and MPTP-induced neurotoxicity by reducing oxidative stress, glial activation, and neuroinflammation. This multifaceted protection preserves neuronal integrity in both the NSE-hαSyn transgenic and MPTP-induced PD mouse models, underscoring Os_9aa as a promising therapeutic candidate for modifying PD pathogenesis.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) / alpha-Synuclein - genetics / alpha-Synuclein - metabolism / Amino acids / Animal models / Animals / Apoptosis / Biochemical analysis / Biocompatibility / Biomedical and Life Sciences / Biomedicine / Brain / Brain research / Cell activation / Cell Line, Tumor / Cell viability / Cognitive ability / Confocal microscopy / Cytokines / Cytotoxicity / Disease / Dopamine / Dopamine receptors / Dopamine transporter / Dopaminergic neuron / Dopaminergic Neurons - drug effects / Dopaminergic Neurons - metabolism / Drug dosages / Field tests / GA-binding protein / Gene therapy / Glial cells / Homeostasis / Humans / Immunization / In vivo methods and tests / Inflammation / Male / Mice / Mice, Inbred C57BL / Mice, Transgenic / Movement disorders / Neostriatum / Nervous system / Neuroblasts / Neurodegeneration / Neurodegenerative diseases / Neuroglia / Neuroglia - drug effects / Neuroglia - metabolism / Neuroinflammation / Neuroinflammatory Diseases - drug therapy / Neuronal-glial interactions / Neurons / Neuroprotective Agents - pharmacology / Neurotoxicity / Osmotin / Oxidative stress / Parkinson Disease - drug therapy / Parkinson's disease / Parkinson’s disease (PD) / Pathogenesis / Peptide osmotin-derived 9-amino-acid (Os_9aa) / Peptides / Peptides - chemistry / Peptides - pharmacology / Proteins / Substantia nigra / Tumor necrosis factor-TNF / Tumor necrosis factor-α / Tyrosine / Western blotting / α-synuclein (α-syn)