Protein recycling system may be treatment target in ALS
Study found reduced cleanup activity in vulnerable motor neurons
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- A cellular recycling system called CMA was found to be impaired in ALS motor neurons.
- Reduced CMA activity was linked to TDP-43 protein clumps, a hallmark of most ALS cases.
- Boosting CMA may be a promising future strategy for protecting motor neurons in ALS.
A cellular recycling system that degrades damaged or unwanted proteins is impaired in motor neurons from people with amyotrophic lateral sclerosis (ALS), suggesting it could be a target for future therapies aimed at slowing disease progression, according to a new study.
The research also showed that motor neurons in which this system, called chaperone-mediated autophagy (CMA), was deficient had abnormal clumps of the TDP-43 protein, a hallmark of ALS.
“We have shown that motor neurons require very high levels of chaperone-mediated autophagy to survive,” Salvador Martínez, MD, PhD, study lead author and director at the Institute for Neurosciences, in Spain, said in an institute press release. “When this mechanism declines, as occurs in ALS, these are precisely the cells that are first affected and eventually die.”
The study, “Chaperone mediated autophagy is deficient in spinal motoneurons of ALS patients with TDP-43 proteinopathy,” was published in Acta Neuropathologica Communications.
Protein cleanup system may help protect motor neurons
ALS is a progressive disease marked by the loss of motor neurons, the nerve cells that control muscle movement. This leads to worsening muscle weakness and symptoms such as difficulty moving, speaking, swallowing, and breathing.
In most cases, a hallmark feature is the buildup of misfolded TDP-43 clumps inside motor neurons, which are thought to contribute to motor neuron damage and disease progression.
TDP-43 can be broken down through CMA. In this process, certain proteins called chaperones identify damaged or unwanted proteins and deliver them for degradation. But whether CMA functions normally in sporadic ALS, the most common form of the disease, had not been studied previously.
“ALS is a devastating disease whose cause remains unknown in the vast majority of patients, which greatly hampers the development of effective treatments,” Martínez said. “Identifying cellular mechanisms directly involved in neuron survival is a key step towards advancing new therapeutic strategies.”
To learn more, Martínez’s team examined spinal cord tissue from deceased human donors with sporadic ALS and from donors without neurological disease. They measured levels of LAMP2A, a protein receptor that serves as a marker of CMA activity.
In control samples, the team found high LAMP2A levels in motor neurons across all spinal cord regions examined, while other nearby neuronal populations showed considerably lower LAMP2A levels, “suggesting heightened CMA activity” in motor neurons, the team wrote.
In ALS samples, however, most motor neurons showed weak LAMP2A levels, indicating that these nerve cells had low CMA recycling activity. Only about 5% to 10% of motor neurons retained a normal or near-normal distribution of LAMP2A.
“These findings indicate that chaperone-mediated autophagy activity is clearly decreased in motor neurons from ALS patients,” said Daniel Garrigós García, PhD, first author of the paper.
Low cleanup activity linked to TDP-43 buildup
Notably, low CMA activity coincided with signs of TDP-43 protein clumping in most motor neurons in the spinal tissue.
A particular observation involved Onuf’s nucleus, a small group of motor neurons in the spinal cord that are known to be resistant to degeneration in ALS. In ALS cases, these neurons maintained normal LAMP2A levels and showed no TDP-43 clumps, compared with affected motor neurons elsewhere in the spinal cord.
Researchers also measured LC3, a marker of a separate cellular recycling process called macroautophagy. They found no significant difference in its expression between ALS and control motor neurons, suggesting the impaired recycling was specific to CMA.
“We have been able to observe this mechanism directly in human tissue, something we had not achieved in animal models,” said Martínez, who expressed his gratitude for the donation of tissue by patients and their families.
“These findings strongly implicate CMA impairment as a key determinant of selective [motor neuron] vulnerability in ALS,” the researchers concluded. The results “highlight CMA enhancement as a promising therapeutic strategy to restore [protein balance] and prevent neurodegeneration in ALS.”
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