Scientists discover a potential new way to slow ALS disease progression

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that causes the progressive loss of motor neurons, which in most cases leads to respiratory failure within three to five years after diagnosis. In this context, a team from the Institute for Neurosciences (IN), a joint centre of the Miguel Hernández University (UMH) and the Spanish National Research Council (CSIC), has identified that a cellular 'selective cleaning system' for proteins: chaperone-mediated autophagy, is significantly reduced in patients, making it a potential therapeutic target to slow disease progression.

The study, published in Acta Neuropathologica Communications, involved the participation of the UMH Sports Research Centre and the Pascual Parrilla Murcia Institute for Biosanitary Research (IMIB). In this work, the team explored in greater depth the role of this cellular mechanism, which is responsible for the selective removal of damaged proteins. Its proper function is essential to maintain neuronal homeostasis, and its dysfunction may promote the accumulation of toxic proteins, one of the hallmark features of the disease.

ALS is a devastating disease whose cause remains unknown in the vast majority of patients, which greatly hampers the development of effective treatments."

Professor Salvador Martínez, director of the Neurobiology of Mental, Neurodegenerative, and Neuro-oncological Diseases Laboratory at the IN UMH-CSIC

He adds that "identifying cellular mechanisms directly involved in neuron survival is a key step towards advancing new therapeutic strategies".

An essential system for neuronal survival

Motor neurons are particularly vulnerable cells in ALS. In more than 90% of cases, these cells accumulate a protein called TDP-43 outside its normal location, forming toxic aggregates. The body has mechanisms to prevent this accumulation, including autophagy, a cellular 'cleaning and recycling' system. However, not all types of autophagy work in the same way. While macroautophagy acts as a general waste disposal system, chaperone-mediated autophagy is highly selective and is responsible for degrading specific proteins, such as TDP-43.

To analyze this process, the researchers used spinal cord tissue from patients enrolled in clinical trials conducted by the IN UMH-CSIC and IMIB teams, as well as control samples from donors without the disease. Using immunohistochemistry and immunofluorescence techniques, they assessed the presence of LAMP2A, a key protein that serves as an indicator of the activity of this type of autophagy.

The results show that healthy motor neurons display high activity of this system, whereas in patients with ALS, this activity is markedly reduced. "These findings indicate that chaperone-mediated autophagy activity is clearly decreased in motor neurons from ALS patients", explains Daniel Garrigós García, first author of the paper. In this regard, Martínez highlights: "In our study, we have shown that motor neurons require very high levels of chaperone-mediated autophagy to survive. When this mechanism declines, as occurs in ALS, these are precisely the cells that are first affected and eventually die".

Donations that drive research

This study also shows that the observed alterations are specific to cellular protein clearance and recycling processes and that they present significant differences between patients and controls. "We have been able to observe this mechanism directly in human tissue, something we had not achieved in animal models", says Martínez, who highlights that the study was made possible thanks to the altruistic donation of tissue by patients and their families, which is essential for advancing ALS research.

Based on these findings, the researchers suggest that this mechanism could become a new therapeutic target. "Our goal is to try to modulate this pathway to increase its activity", explains the professor, adding that this discovery opens the door to the development of strategies aimed at slowing disease progression, although they are still in the early stages of research.

Este trabajo ha sido posible gracias a la financiación de la Agencia Estatal de Investigación, a través del programa "Severo Ochoa" para Centros de Excelencia en I+D, el Ministerio de Ciencia, Innovación y Universidades, el programa Prometeo de la Generalitat Valenciana, el Instituto de Salud Carlos III (Red de Terapias Avanzadas-TERAV) y el programa Next Generation EU en el marco del Plan de Recuperación, Transformación y Resiliencia y, muy especialmente, a la Catedra sobre ELA Gragoria Ramos Gil de la UMH.

This work has been made possible thanks to funding from the Spanish State Research Agency, through the "Severo Ochoa" Programme for Centres of Excellence in R&D; the Ministry of Science, Innovation and Universities; the Prometeo Programme of the Generalitat Valenciana; the Instituto de Salud Carlos III (Advanced Therapies Network – TERAV); and the Next Generation EU programme within the framework of the Recovery, Transformation and Resilience Plan. It also received key support from the UMH Chair Gregoria Ramos Gil on ALS.