Atuka is pleased to present the second entry in our Discovery Series on Emerging Targets in Parkinson’s Disease, examining the Brain-Derived Neurotrophic Factor (BDNF) and its receptor TrkB as a potential avenue for disease-modifying therapy in Parkinson’s disease (PD).
Authored by Dr. Patrick Howson, Atuka’s Chief Innovation Officer, this review surveys the historical development and current landscape of research into BDNF/TrkB signalling, outlining how advances in gene therapy, small-molecule and antibody TrkB agonists, and pathway-modulating approaches are reshaping possibilities for neuroprotective intervention.
Why BDNF/TrkB?
- Neuroprotective Signalling
Activation of TrkB by BDNF triggers three major intracellular cascades—PI3K/Akt, PLCγ, and MAPK/ERK—that together support neuronal survival, differentiation, and synaptic plasticity. In PD models, these pathways enhance dopaminergic survival and protect neurons from toxic insults. - Re-examining an Earlier Target
Although early protein-infusion studies were limited by delivery challenges, the field has been re-energized by progress in AAV-based gene therapy, and by new understanding of how α-synuclein may disrupt BDNF/TrkB signalling. This interaction appears bidirectional—α-synuclein can inhibit TrkB activity, while TrkB activation can reduce α-synuclein expression—making this pathway a compelling focus for renewed investigation. - Broader CNS Relevance
BDNF and TrkB are widely expressed throughout the brain, supporting not only dopaminergic but also cortical, hippocampal, and spinal neurons. Physical exercise is known to increase BDNF levels, which may contribute to its observed benefits in PD.
What You’ll Learn
- Mechanisms of Action
A clear summary of how BDNF/TrkB activation promotes neuronal survival and plasticity through its downstream pathways. - Therapeutic Landscape
An overview of gene-therapy, antibody, and small-molecule approaches in preclinical and early-phase testing, including AAV-based vectors, TrkB agonist mAbs (BI 754132), and small-molecule TrkB agonists such as 7,8-DHF and ACD856 (Trk PAM). - Challenges and Future Directions
Discussion of key barriers identified in the paper: the blood–brain barrier, delivery and distribution, complex receptor biology, α-synuclein interactions, and clinical-trial design for a heterogeneous disease. The review also highlights emerging strategies such as Shp2 and PTP1B inhibition, modulation of proBDNF conversion, and TrkB positive allosteric modulators. - Preclinical and Clinical Context
Comparative insights from BDNF and GDNF research, with examples of ongoing and completed studies across indications including ALS, Alzheimer’s disease, and cognitive disorders.
Download the Full Report
The Potential of BDNF/TrkB Pathway Modulation in Parkinson’s Disease
A detailed review of the biology, history, and therapeutic landscape of BDNF/TrkB, and the considerations required to translate its promise into effective treatment.
Related Reading
As world leaders in Parkinson’s research, with a proven track record evaluating over 300 potential therapeutics, Atuka’s scientists bring decades of experience in designing preclinical studies that deliver actionable results.
Explore our previous papers:
- Discovery Series #1: D1 Dopamine Receptor Positive Allosteric Modulators (D1 PAMs)
- Optimizing Preclinical Studies for Parkinson’s Disease Therapeutics
- The Future of Gene Therapy
Contact Us
To discuss how Atuka can help design and de-risk preclinical programs targeting BDNF/TrkB and other neurotrophic pathways, please reach out or schedule a conversation via our contact page.