Recent research shows that the Parkinson’s disease (PD) protein, alpha-synuclein, blocks pro-survival signals from an important brain growth factor. These findings provide new reasons why neurons degenerate and are lost in patients with PD.
The finding, “TrkB neurotrophic activities are blocked by α-synuclein, triggering dopaminergic celldeath in Parkinson’s disease,” was published by Keqiang Ye, PhD, and his team of researchers in the journal PNAS.
Two features characterize PD: The selective loss of neurons that respond to dopamine, and the accumulation of protein clumps called Lewy bodies. Alpha-synuclein is a major component of Lewy bodies.
Brain-derived neurotrophic factor (BDNF) is a type of neurotrophin (NT), or growth factor, that promotes the growth and survival of neurons within the peripheral and central nervous systems. Previous studies have shown that PD patients have significantly less BDNF.
Like other growth factors, BDNF functions by binding and activating proteins on the surface of cells that can then relay pro-survival messages into the cell. TrkB is a receptor that sits on the surface of neurons and can be activated by BDNF.
In the current paper, Ye and his team show that alpha-synuclein interacts with TrkB in cell culture models as well as in human brain samples. They also show, using cell culture and mouse models, that this interaction interferes with BDNF-mediated activation of TrkB and its ability to promote survival.
Dopamine can stimulate the interaction between these molecules. DOPAL is a metabolic byproduct of dopamine. The drug rasagiline, which inhibits the generation of DOPAL, was shown to block the alpha-synuclein/TrkB interaction.
On the other side, BDNF binding to the cell surface receptor can block alpha-synuclein binding to TrkB. In this way, BDNF and alpha-synuclein are in constant competition, fighting over which protein will dominate TrkB.
The key finding in this research — of the ability to disrupt the alpha-synuclein association and promote neuron survival — should have implications for the use of existing therapeutics to treat PD, as well as for the development of future therapeutics.
Other studies have shown that overabundant alpha-synuclein can affect neuron function, such as neurotransmitter synthesis and remodeling synapses. In addition, “oligomeric” alpha-synuclein (multiple protein molecules stuck together) is thought to be more toxic than a single molecule. The current research does not address whether oligomeric alpha-synuclein associates more robustly with TrkB than single molecules.
However, Ye concluded that his team’s “discovery provides a model for the underlying molecular etiology of α-Syn–mediated neurotoxicity and [dopamine-mediated] neuronal loss in PD.”
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