Neurotrophic Factor Applications in Parkinson’s Disease Therapy
Summary
Neurotrophic factors are a class of proteins that support the survival, growth and differentiation of neurons. In Parkinson’s disease (PD), the progressive degeneration of dopaminergic neurons in the substantia nigra leads to motor and non-motor impairments. Among the most studied neurotrophic factors are glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF). These molecules act via high-affinity receptors to activate intracellular pathways that promote dopaminergic neuron viability, axonal outgrowth and synaptic plasticity. Early clinical efforts focused on direct infusion or gene delivery of GDNF to the striatum; however, challenges in achieving widespread distribution and sustained bioactivity have limited therapeutic efficacy. Advances in structural biology have elucidated the assembly and receptor interactions of GDNF complexes, offering insight into mechanisms of synaptic adhesion and trophic signalling. Parallel research on BDNF has underscored its role in modulating dopamine transmission and motor behaviour, as well as in mediating the benefits of physical exercise. Novel delivery platforms and precision targeting strategies are now emerging to overcome delivery barriers and enhance clinical translation, offering renewed optimism for neurotrophic therapies in PD.
Research from Nature Portfolio
Recent structural investigations have resolved the decameric assembly of the GDNF–GFRα1 complex at synaptic membranes, revealing how multiple GDNF dimers bridge co-receptor pentamers to stabilise cell adhesion and coordinate trophic signalling. High-resolution crystallography and cryo-electron tomography have shown that GFRα1 interfaces and heparan sulfate chains modulate RET receptor engagement and dynamically regulate adhesion complex formation. These insights provide a molecular framework for designing engineered GDNF variants with optimised receptor selectivity and enhanced tissue penetration, addressing longstanding challenges in achieving uniform neurotrophic support within the nigrostriatal pathway.
Neurotrophic Factor Applications in Parkinson’s Disease Therapy publication trend
The graph below shows the total number of articles in neurotrophic factor applications in parkinson’s disease therapy across all publications each year (not limited to Nature Index journals).
Technical terms
Neurotrophic factor: A protein that supports neuronal survival, growth and differentiation.
Glial cell line-derived neurotrophic factor (GDNF): A trophic protein promoting dopaminergic neuron viability via GFRα1 and RET receptors.
Brain-derived neurotrophic factor (BDNF): A growth factor that enhances synaptic plasticity and dopaminergic neurotransmission through TrkB activation.
GFRα1: A glycosylphosphatidylinositol-anchored co-receptor that binds GDNF and presents it to RET.
Cryogel microcarrier: A porous polymer particle engineered to load and release proteins in a controlled manner.
Convection-enhanced delivery: A technique using positive pressure to distribute therapeutics widely within brain tissue.
Blood–brain barrier (BBB): A selective endothelial interface that restricts passage of large molecules into the central nervous system.
References
- Architecture and regulation of a GDNF-GFRα1 synaptic adhesion assembly. Nature Communications (2023).
- Cryogel microcarriers for sustained local delivery of growth factors to the brain. Journal of Controlled Release (2024).
- BDNF as a Promising Therapeutic Agent in Parkinson’s Disease. International Journal of Molecular Sciences (2020).
- Randomized trial of intermittent intraputamenal glial cell line-derived neurotrophic factor in Parkinson’s disease. Brain (2019).
- Extended Treatment with Glial Cell Line-Derived Neurotrophic Factor in Parkinson’s Disease. Journal of Parkinson’s Disease (2019).
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