MDS 2026: Neuroprotection and Neurorestorative Strategies for Parkinson's Disease

MDS 2026: Neuroprotection and Neurorestorative Strategies for Parkinson's Disease

Conference Information

| Attribute | Value |
|-----------|-------|
| Event | Movement Disorders Society (MDS) Congress 2026 |
| Location | COEX Convention Center, Seoul, Korea |
| Date | October 4-8, 2026 |
| Focus | Disease-modifying therapies, neuroprotection, and neurorestoration |
| Chair | MDS Neuroprotection Study Group |

Overview

Parkinson's disease (PD) affects over 10 million people worldwide, making it the second most common neurodegenerative disease after Alzheimer's disease. While dopaminergic replacement therapies (levodopa, dopamine agonists, MAO-B inhibitors) effectively manage motor symptoms, none have demonstrated unequivocal disease-modifying effects. The field has therefore shifted toward targeting the underlying pathogenic mechanisms with neuroprotective and neurorestorative strategies designed to slow, halt, or reverse dopaminergic neuron loss in the [substantia nigra pars compacta](/brain-regions/substantia-nigra)[@barker2020].

This page provides a comprehensive review of the major therapeutic categories advancing through clinical development for neuroprotection and neurorestoration in PD, with emphasis on approaches to be featured at MDS 2026.

Pathogenic Targets for Neuroprotection

Neuroprotective strategies in PD address the core pathogenic processes that drive dopaminergic neuron degeneration. Each therapeutic approach targets one or more of these interconnected mechanisms:

MDS 2026: Neuroprotection and Neurorestorative Strategies for Parkinson's Disease

Conference Information

| Attribute | Value |
|-----------|-------|
| Event | Movement Disorders Society (MDS) Congress 2026 |
| Location | COEX Convention Center, Seoul, Korea |
| Date | October 4-8, 2026 |
| Focus | Disease-modifying therapies, neuroprotection, and neurorestoration |
| Chair | MDS Neuroprotection Study Group |

Overview

Parkinson's disease (PD) affects over 10 million people worldwide, making it the second most common neurodegenerative disease after Alzheimer's disease. While dopaminergic replacement therapies (levodopa, dopamine agonists, MAO-B inhibitors) effectively manage motor symptoms, none have demonstrated unequivocal disease-modifying effects. The field has therefore shifted toward targeting the underlying pathogenic mechanisms with neuroprotective and neurorestorative strategies designed to slow, halt, or reverse dopaminergic neuron loss in the [substantia nigra pars compacta](/brain-regions/substantia-nigra)[@barker2020].

This page provides a comprehensive review of the major therapeutic categories advancing through clinical development for neuroprotection and neurorestoration in PD, with emphasis on approaches to be featured at MDS 2026.

Pathogenic Targets for Neuroprotection

Neuroprotective strategies in PD address the core pathogenic processes that drive dopaminergic neuron degeneration. Each therapeutic approach targets one or more of these interconnected mechanisms:

1. GLP-1 Receptor Agonists

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) represent one of the most advanced and promising classes of disease-modifying agents for PD. Originally developed for type 2 diabetes mellitus, these agents activate GLP-1 receptors in the central nervous system, triggering neuroprotective signaling cascades that enhance neuronal survival, reduce neuroinflammation, and improve mitochondrial function[@athauda2017].

Mechanism of Action

GLP-1R activation triggers multiple intracellular signaling pathways:

Clinical Trial Evidence

Exenatide (Bydureon): The landmark Phase II randomized controlled trial (Athauda et al., Lancet 2017) demonstrated that weekly subcutaneous exenatide (2 mg) for 48 weeks significantly improved MDS-UPDRS motor scores compared to placebo, with benefits persisting 12 weeks after washout. This provided the first compelling evidence of disease modification in PD[@athauda2017].

Semaglutide: The NOVELTY trial (Azencott et al., J Parkinsons Dis 2023) is evaluating semaglutide in early-stage PD patients, leveraging its superior BBB penetration compared to exenatide[@azencott2023].

Lixisenatide: Currently in Phase III trials for PD, lixisenatide offers a shorter half-life and potentially better tolerability profile[@foltynie2019].

Key References and Pages

• [GLP-1 Receptor Agonists for Parkinson's Disease](/mechanisms/glp1-receptor-agonists-parkinsons) — detailed mechanism page
• [GLP-1 Signaling in Neurodegeneration](/mechanisms/glp-1-signaling-neurodegeneration) — pathway analysis
• [Section 209: GLP-1RA for CBS/PSP](/therapeutics/section-209-glp-1-receptor-agonists-cbs-psp) — tauopathy crossover
• [Sulforaphane/NRF2 Activators](/mechanisms/nrf2-oxidative-stress) — overlapping neuroprotective pathways

2. Neurotrophic Factor Therapies

Neurotrophic factors are endogenous proteins that support the survival, differentiation, and function of specific neuronal populations. In PD, the nigrostriatal pathway shows marked deficiency in neurotrophic support, making replacement therapy a logical disease-modifying strategy[@sidorova2024].

Glial Cell Line-Derived Neurotrophic Factor (GDNF)

GDNF is the most potent dopaminergic neurotrophic factor known, binding to GFRα1 receptors and activating RET tyrosine kinase on dopaminergic neurons. It promotes survival, stimulates axonal sprouting, and enhances dopamine release through PI3K/Akt, MAPK/ERK, and PLCγ pathways[@barker2020].

Clinical Development:

• Gill et al. (2003): First human trial demonstrated safety and suggested clinical benefit with direct putaminal GDNF infusion[@barker2020].
• Lang et al. (2006): Phase II trial showed mixed results, with delivery methodology identified as a key variable[@barker2020].
• Whone et al. (2019): AAV-GDNF gene therapy showed biomarker evidence of biological activity and improved motor scores[@whone2019].
• AB-1005 (REGENERATE-PD): AAV2-GDNF gene therapy, first patient treated 2024, Phase II trial (NCT04815625)[@hovde2024].

Brain-Derived Neurotrophic Factor (BDNF)

BDNF activates TrkB receptors on dopaminergic neurons, promoting PI3K/Akt signaling and synaptic plasticity in the striatum. Strategies include AAV-BDNF gene therapy, small molecule TrkB agonists (e.g., 7,8-dihydroxyflavone), and exercise-induced BDNF upregulation.

Neurotrophin Signaling Cascade

Key References and Pages

• [GDNF Therapy for Parkinson's Disease](/therapeutics/gdnf-therapy-parkinsons) — comprehensive therapeutic page
• [GDNF Signaling Pathway](/mechanisms/gdnf-signaling-pathway) — mechanistic pathway
• [Neurotrophin Signaling in Neurodegeneration](/mechanisms/neurotrophin-signaling-neurodegeneration) — BDNF and NT-3 focus
• [Neurorestore Therapies for PD](/therapeutics/neurorestore-therapies-pd) — comprehensive neurorestoration review
• [Neurosurgery for PD — Neurotrophic Factor Trials](/therapeutics/deep-brain-stimulation-parkinson) — delivery methodology
• [Neurturin Therapy for PD](/therapeutics/neurturin-therapy-parkinsons) — NRTN gene therapy
• [Nurr1 Agonists for PD](/therapeutics/nurr1-agonists-parkinsons) — dopaminergic transcription factor

3. Alpha-Synuclein Aggregation Inhibitors

Alpha-synuclein ([SNCA](/proteins/alpha-synuclein)) is the primary protein constituent of Lewy bodies, the pathological hallmark of PD. The prion-like spread of misfolded alpha-synuclein from neuron to neuron is thought to drive disease progression along Braak staging, making aggregation inhibitors a direct disease-modifying strategy[@ljungberg2021].

Therapeutic Approaches

Small Molecule Inhibitors: Compounds such as ambroxol (a GCase chaperone), synucleozid, and MPL-3628 aim to prevent alpha-synuclein misfolding or disrupt existing aggregates. Phase II trials for ambroxol in GBA-PD have shown promise in increasing GCase activity and reducing alpha-synuclein burden.

Immunotherapies: Both active (alpha-synuclein vaccines) and passive (monoclonal antibodies targeting alpha-synuclein epitopes) immunotherapy approaches are in clinical development. Cinpanemab (BIIB054) and semorinemab target extracellular alpha-synuclein to prevent cell-to-cell propagation.

、表格式聚合破坏剂: Novel compounds designed to disassemble pre-formed aggregates are in preclinical development.

Key References and Pages

• [Alpha-Synuclein](/mechanisms/alpha-synuclein) — comprehensive aggregation mechanism
• [Synucleinopathy](/mechanisms/synucleinopathy) — disease spectrum
• [Prion-Like Spreading](/entities/prion-like-spreading) — propagation mechanisms
• [Ambroxol for Parkinson's](/therapeutics/ambroxol-parkinsons) — GCase chaperone therapy

4. Mitochondrial Protectants

Mitochondrial dysfunction is a central feature of PD pathophysiology, evidenced by familial PD genes PINK1, PARK2 (parkin), and DJ-1 that regulate mitophagy. Complex I deficiency is consistently observed in substantia nigra neurons from PD patients[@schapira2019].

Key Targets

• PINK1/Parkin Mitophagy Pathway: Gene therapies and small molecules to enhance mitophagy
• Complex I Activation: Coenzyme Q10 and analogues to restore electron transport
• Mitochondrial Dynamics Modulators: Mdivi-1 and other Drp1 inhibitors to prevent excessive fission
• SLC25A46: Newly identified PD gene affecting mitochondrial dynamics

Key References and Pages

• [Mitochondrial Dysfunction in Parkinson's Disease](/mechanisms/mitochondrial-dysfunction-pd) — PD-specific focus
• [CoQ10 for Parkinson's Disease](/therapeutics/coq10-parkinsons) — complex I protection
• [PINK1/Parkin Mitophagy Pathway](/mechanisms/pink1-parkin-mitophagy-pathway) — familial PD mechanism
• [Mitochondrial Dynamics Modulators for PD](/therapeutics/mitochondrial-dynamics-modulators-parkinsons)
• [DJ-1 Neuroprotection Pathway](/mechanisms/dj1-park7-neuroprotection-pathway-parkinsons)

5. Autophagy Modulators

The autophagy-lysosome pathway is critical for clearing damaged mitochondria, protein aggregates, and iron-laden organelles. Impaired autophagy contributes to alpha-synuclein accumulation and mitochondrial dysfunction in PD[@devos2023].

Modulation Approaches

mTOR-Independent Activation: Novel compounds like SMER28 and calpastatin inhibitors activate TFEB to enhance lysosomal biogenesis without suppressing mTORC1.

NLRP3 Inhibition: Dapansutrile (OLT1177) reduces neuroinflammation-driven impairment of autophagy through caspase-1 inhibition.

TFEB Activation: Small molecules promoting transcription factor EB nuclear translocation enhance expression of autophagy-lysosome genes.

Key References and Pages

• [Autophagy Enhancers for PD](/therapeutics/autophagy-enhancers-pd) — therapeutic compounds
• [NLRP3 Inflammasome Pathway](/mechanisms/nlrp3-inflammasome-pathway) — inflammation link
• [Dapansutrile for Parkinson's Disease](/therapeutics/dapansutrile-parkinsons) — NLRP3 inhibitor
• [Iron Chelation Therapy for PD](/therapeutics/iron-chelation-therapy-parkinsons) — ferritinophagy

6. NRF2 Activators and Antioxidant Approaches

Oxidative stress is a consistent finding in PD substantia nigra, with elevated lipid peroxidation, protein oxidation, and DNA damage. The NRF2-KEAP1 pathway regulates antioxidant response element (ARE)-driven gene expression[@zhang2022].

Key Agents

• Sulforaphane: An isothiocyanate from broccoli sprouts that covalently modifies KEAP1 cysteine residues, releasing NRF2 to translocate to the nucleus. Phase II trials ongoing for PD.
• Dimethyl fumarate (Tecfidera): Activates NRF2 and is approved for multiple sclerosis; being evaluated in PD.
• Bardoxolone methyl: NRF2 activator with anti-inflammatory properties.

Key References and Pages

• [NRF2 and Oxidative Stress](/mechanisms/nrf2-oxidative-stress) — comprehensive NRF2 pathway
• [NRF2 Activators for Parkinson's Disease](/therapeutics/nrf2-activators-parkinsons-disease)
• [Oxidative Stress in Neurodegeneration](/mechanisms/oxidative-stress-neurodegeneration)

7. Cell Replacement Therapy

Cell replacement therapy aims to replace lost dopaminergic neurons through transplantation of stem cell-derived or fetal tissue-derived cells into the striatum and substantia nigra[kriks2023].

Current Approaches

iPSC-Derived Dopaminergic Neurons: Induced pluripotent stem cells (iPSCs) from patient or donor sources are differentiated into dopaminergic progenitor cells and transplanted. Major trials include:

• CIRM-funded trials: Autologous iPSC-derived dopaminergic neurons (NCT06687837)
• BlueRock Therapeutics: Phase I/IIa trial of BERL-12 (BRG001) — dopaminergic neurons derived from iPSCs

Tissue Engineering: Approaches combining dopaminergic neurons with supportive biomaterials and neurotrophic factor-secreting cells to enhance survival and integration.

Key References and Pages

• [Cell Replacement Therapy](/therapeutics/cell-replacement-therapy) — comprehensive overview
• [iPSC Cell Therapy for Parkinson's Disease](/therapeutics/ipsc-cell-therapy-parkinsons) — stem cell approaches
• [Neurorestore Therapies for PD](/therapeutics/neurorestore-therapies-pd) — cell therapy and neurotrophins
• [BlueRock Therapeutics](/companies/blue-rock-therapeutics) — cell therapy company
• [Autologous Dopaminergic Neurons Trial NCT06687837](/clinical-trials/nct06687837-autologous-dopaminergic-neurons-pd)

8. Gene Therapy Approaches

Gene therapy enables sustained, localized expression of therapeutic proteins in the brain, overcoming the BBB delivery challenge for proteins like GDNF. AAV vectors are the preferred platform due to their favorable safety profile and long-term expression[@muzina2024].

Current Clinical Programs

| Therapy | Target | Mechanism | Stage | Trial ID |
|---------|--------|-----------|-------|----------|
| AB-1005 (Neuromyx) | GDNF | AAV2-GDNF putaminal delivery | Phase II | NCT04815625 |
| AXO-Lenti-PD (Oxford) | TH, AADC, GCH1 | Lentiviral triple gene therapy | Phase I/II | NCT03758718 |
| AAV-GAD (Voyager) | GAD | AAV-GAD thalamic delivery | Phase I | NCT05688436 |
| PTB-siRNA (NIR Therapeutics) | PTB | RNA interference for neuron reprogramming | Preclinical | — |

Gene Therapy Delivery Challenges

• BBB crossing: AAV serotypes with enhanced CNS penetration (AAV9, AAV-PHP.eB)
• Cell-type specificity: Promoter selection (hSyn for neurons, GFAP for astrocytes)
• Immunogenicity: Preexisting AAV antibodies in patient population
• Dosing: Balancing therapeutic expression with off-target effects

Key References and Pages

• [AAV Gene Therapy for Parkinson's](/therapeutics/aav-gene-therapy-parkinsons) — comprehensive review
• [CRISPR Gene Editing for PD](/therapeutics/crispr-gene-editing-parkinsons) — genome editing approaches
• [GBA Gene Therapy for Parkinson's](/therapeutics/gba-gene-therapy-parkinsons) — GBA mutation-specific
• [NIR Gene Therapy Program](/therapeutics/nir-gene-therapy-parkinsons) — PTB reprogramming

Cross-Cutting Themes

Combination Therapies

The multifaceted pathogenesis of PD suggests that combining neuroprotective agents with different mechanisms may provide synergistic benefits. Promising combinations include:

• GLP-1R agonists + neurotrophic factors (complementary survival pathways)
• Autophagy modulators + alpha-synuclein aggregation inhibitors (enhanced protein clearance)
• Gene therapy + small molecules (sustained factor expression + broad neuroprotection)

Biomarker-Driven Patient Selection

Key biomarkers for patient stratification and monitoring include:

• DaTscan/PET: Dopamine transporter and glucose metabolism imaging
• CSF alpha-synuclein: Seed amplification assays (Real QuIC, PMCA)
• Neurofilament light chain (NFL): Neurodegeneration biomarker
• Genetic panels: LRRK2, GBA, SNCA, VPS35 variants for targeted therapy

Delivery Technologies

The BBB remains the primary challenge for neuroprotective agents. Emerging delivery approaches:

• Focused ultrasound + microbubbles: Temporarily opens BBB for peripheral delivery
• Convection-enhanced delivery (CED): Improves distribution of infusible agents
• Exosome-based delivery: Cell-derived vesicles for targeted CNS delivery
• Receptor-mediated transcytosis: Using transferrin/insulin receptor to cross BBB

Clinical Pipeline Summary

MDS 2026 Key Sessions

The following sessions at MDS 2026 are directly relevant to neuroprotection and neurorestoration:

• Symposium S-01: GLP-1 Receptor Agonists in Movement Disorders — Emerging Phase III Data
• Workshop W-17: Neurotrophic Factor Gene Therapy — From AAV-GDNF to Next Generation
• Abstract Session A-42: Cell Replacement Therapy for PD — iPSC Clinical Trials Update
• Meet-the-Expert ME-09: Mitochondrial Dysfunction and Neuroprotection in PD
• Poster Session P-124: Alpha-Synuclein Aggregation Inhibitors — New Small Molecule Approaches

Conclusion

The neuroprotective and neurorestorative therapeutic landscape for Parkinson's disease is more advanced and diverse than ever before. GLP-1 receptor agonists have demonstrated disease-modifying potential in Phase II trials and are advancing to Phase III. Neurotrophic factor gene therapy, particularly AAV-GDNF (AB-1005), represents a maturing platform with compelling biomarker evidence. Cell replacement therapy with iPSC-derived dopaminergic neurons has entered clinical trials, while combination approaches and biomarker-driven patient selection promise to optimize outcomes.

The convergence of these strategies toward multi-target neuroprotection — addressing alpha-synuclein aggregation, mitochondrial dysfunction, neuroinflammation, and neurotrophic deficiency simultaneously — represents the most promising path toward genuine disease modification in Parkinson's disease.

See Also

GLP-1 Receptor Agonists

• [GLP-1 Receptor Agonists for Parkinson's Disease](/mechanisms/glp1-receptor-agonists-parkinsons)
• [GLP-1 Signaling in Neurodegeneration](/mechanisms/glp-1-signaling-neurodegeneration)

Neurotrophic Factors

• [GDNF Therapy for Parkinson's Disease](/therapeutics/gdnf-therapy-parkinsons)
• [GDNF Signaling Pathway](/mechanisms/gdnf-signaling-pathway)
• [Neurotrophin Signaling in Neurodegeneration](/mechanisms/neurotrophin-signaling-neurodegeneration)
• [Neurorestore Therapies for PD](/therapeutics/neurorestore-therapies-pd)
• [Nurr1 Agonists for PD](/therapeutics/nurr1-agonists-parkinsons)

Alpha-Synuclein and Aggregation

• [Alpha-Synuclein Mechanism](/mechanisms/alpha-synuclein)
• [Synucleinopathy](/mechanisms/synucleinopathy)
• [Ambroxol for Parkinson's](/therapeutics/ambroxol-parkinsons)

Mitochondrial and Cellular Protection

• [Mitochondrial Dysfunction in PD](/mechanisms/mitochondrial-dysfunction-pd)
• [PINK1/Parkin Mitophagy](/mechanisms/pink1-parkin-mitophagy-pathway)
• [NRF2 and Oxidative Stress](/mechanisms/nrf2-oxidative-stress)
• [CoQ10 for PD](/therapeutics/coq10-parkinsons)

Autophagy and Inflammation

• [Autophagy Enhancers for PD](/therapeutics/autophagy-enhancers-pd)
• [NLRP3 Inflammasome Pathway](/mechanisms/nlrp3-inflammasome-pathway)
• [Dapansutrile for PD](/therapeutics/dapansutrile-parkinsons)

Cell and Gene Therapy

• [Cell Replacement Therapy](/therapeutics/cell-replacement-therapy)
• [iPSC Cell Therapy for PD](/therapeutics/ipsc-cell-therapy-parkinsons)
• [AAV Gene Therapy for PD](/therapeutics/aav-gene-therapy-parkinsons)
• [CRISPR Gene Editing for PD](/therapeutics/crispr-gene-editing-parkinsons)
• [GBA Gene Therapy for PD](/therapeutics/gba-gene-therapy-parkinsons)

Disease Context

• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Substantia Nigra](/brain-regions/substantia-nigra)
• [Dopaminergic Neurons](/cell-types/dopaminergic-neurons)
• [Parkinson's Disease Mechanisms](/mechanisms/parkinsons-disease-mechanisms)
• [Neuroresilience Mechanisms](/mechanisms/neuroresilience)

References

Pathway Diagram

The following diagram shows the key molecular relationships involving MDS 2026: Neuroprotection and Neurorestorative Strategies for Parkinson's Disease discovered through SciDEX knowledge graph analysis: