Boosting TFE3 in Parkinson’s may be neuroprotective: Study
Increasing protein in mice helped reduce damage, improve motor function
Boosting levels of a protein called TFE3 helped reduce nerve cell degeneration and improve motor function in a mouse model of Parkinson’s disease, a study found.
Increased levels of this protein helped clear toxic alpha-synuclein clumps, a hallmark of Parkinson’s, as well as restore the function of mitochondria, the cell’s powerhouses whose dysfunction is known to play a key role in the disease.
“These findings further underscore the neuroprotective role of TFE3 in [Parkinson’s disease] and provide insights into its underlying mechanisms, suggesting TFE3 as a potential therapeutic target,” researchers wrote.
The study, “TFE3-mediated neuroprotection: Clearance of aggregated a-synuclein and accumulated mitochondria in the AAV-a-synuclein model of Parkinson’s disease,” was published in Genes & Diseases.
Parkinson’s disease is characterized by the gradual loss of dopamine-producing neurons in the substantia nigra, a brain region responsible for controlling muscle movement and coordination. This neuronal loss is driven in part by the toxic buildup of alpha-synuclein protein.
Breaking alpha-synuclein clumps
The neurons depend on high levels of energy supplied by mitochondria to function properly. When mitochondria become impaired, energy production fails, worsening the energy shortage and further accelerating the death of these nerve cells.
Cells usually get rid of harmful waste and toxic materials such as alpha-synuclein clumps through a process called autophagy. A key regulator of this process is the TFE3 protein (transcription factor binding to IGHM enhancer 3). Studies have shown that activating this protein can protect nerve cells in models of Parkinson’s disease, Alzheimer’s disease, and spinal cord injury. Evidence also suggests that TFE3 may boost nerve cell survival by promoting the formation of new mitochondria.
However, it is unclear whether activating the protein can help break down alpha-synuclein in dopamine-producing neurons.
To know more, researchers in China tested whether increasing TFE3 levels could protect dopamine neurons in a mouse model of Parkinson’s. Mice were divided into three groups: a control group, a group injected with alpha-synuclein, and a group injected with both alpha-synuclein and TFE3. Three months later, researchers analyzed their brains and motor function.
As expected, alpha-synuclein alone caused a 46.1% loss of dopamine neurons and a 56% reduction in nerve terminals. However, when TFE3 was also added, neuron loss dropped to 1.2%, and nerve terminals were largely preserved.
Behavioral tests showed that mice injected with alpha-synuclein had trouble with motor tasks, but those also given TFE3 performed better.
Boosting TFE3 levels reversed autophagy defects observed in dopamine-producing neurons as a consequence of alpha-synuclein accumulation. This increase in TFE3 also promoted the clearance of alpha-synuclein clumps and inhibited their spread throughout the brain.
Increasing levels of the protein helped remove damaged mitochondria from nerve cells by restoring the function of parkin, a key protein involved in mitophagy, the process that clears out defective mitochondria. This process is often disrupted in Parkinson’s disease.
TFE3 boosted mitochondrial production in dopamine neurons, as shown by increased levels of PGC-1alpha, a protein that supports mitochondrial creation and protection; TFAM, essential for maintaining mitochondrial health; and Tom20, a key mitochondrial marker, in mice with higher TFE3 levels.
“In this study, we report that TFE3 exerts neuroprotective effects by regulating autophagy to facilitate the degradation of aggregated [alpha-synuclein] and damaged mitochondria, as well as promoting mitochondrial biogenesis,” the researchers wrote.
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