A long-lived cell is like a house where, instead of turning off the lights to save money, you switch them to emergency lighting: the bulbs dim, but life still glows. In amyotrophic lateral sclerosis (ALS), such house-neurons show up in the spinal cord, and scientists have now seen for the first time exactly how they shift into this mode.
Researchers took frozen samples from three regions: the motor cortex, the cervical spinal cord, and the lumbar spinal cord. First, they measured the activity of hundreds of genes using NanoString panels. Then, on adjacent sections, they applied GeoMx spatial proteomics: a laser cut out areas around individual motor neurons labeled with fluorescent antibodies, and proteins were collected from each such area for quantitative analysis. In total, about 3500 neurons were processed.
In the motor cortex, ALS with TDP-43 activated immune response genes and suppressed synapse genes. In the spinal cord, ALS without TDP-43 altered genes of immune receptors and metabolism, while ALS with TDP-43 additionally switched on genes of the cell cycle and aging. Spatial proteomics confirmed it: in the spinal cord, both forms of ALS made neurons behave like senescent cells, although the cortex showed nothing of the kind.
Senescent neurons are rare: in the human brain they make up just 2–3% of all cells. To catch such isolated cells, proteins had to be measured in individual neurons rather than in a piece of tissue where their signal gets lost among thousands of other cells. The work shows that motor neuron aging may be a common denominator for different forms of ALS, even when pathological TDP-43 is absent. This sets it apart from neighboring studies, which mostly link brain changes to the accumulation of specific proteins. Here, for the first time at the level of individual neurons, it is clear that the aging program switches on in the spinal cord regardless of TDP-43, while in the cortex only when it is present. Such a regional contrast hints that the disease may follow different scenarios in different parts of the nervous system.
If neuronal aging really does make neurons vulnerable, one could try to slow the disease by clearing out senescent cells or suppressing their inflammatory signals. In models of Alzheimer's and Parkinson's diseases, such approaches have already improved the condition of animals. For ALS this is still a hypothesis, but a testable one: it is enough to compare how senolytics (drugs that kill senescent cells) affect motor neurons in culture or in mice with ALS-causing mutations. A house with emergency lighting can either be rebuilt or left as it is, but if we learn to bring back bright light, its residents will have a chance.
Senescent neurons are rare: in the human brain they make up just 2–3% of all cells. To catch such one-of-a-kind cells, the team had to measure proteins in individual neurons rather than in a chunk of tissue, where their signal gets lost among thousands of other cells.
Not published on arXiv. Here are its page, the PDF and the formalization: you can check it yourself, not only read our account.