Genetic Activity Offers Neuroprotection Against ALS in Specific Motor Neurons

Recent research conducted by Stockholm University, in collaboration with the Paris Brain Institute and Örebro University, has illuminated why some nerve cells exhibit resistance to Amyotrophic Lateral Sclerosis (ALS). By analyzing millions of messenger RNA (mRNA) molecules during ALS progression, scientists have identified key genetic factors that contribute to this resistance. The study, published in Genome Research, centers on a hereditary form of ALS linked to mutations in the SOD1 gene.

The findings reveal that certain motor neurons, such as those controlling eye muscles, are less affected by the disease. These resistant neurons maintain high levels of protective factors like Engrailed-1 (En1), Parvalbumin (Pvalb), Cd63, and Galanin (Gal). For instance, En1, a transcription factor that influences gene expression, appears to shield these neurons from degeneration. Interestingly, resistant neurons produce these protective molecules at levels significantly higher than vulnerable neurons, which typically regulate lower baseline levels.

Further analysis demonstrated that sensitive motor neurons actively respond to ALS by triggering both harmful and protective gene programs. They attempt to self-protect by activating genes usually high in resistant neurons, such as En1, Pvalb, Cd63, and Gal. Simultaneously, they try to regenerate lost connections by activating genes like Atf3 and Sprr1a; however, these efforts often fail, leading to cell death.

This research underscores distinct basal and induced gene activity patterns in different nerve cell types, offering new avenues for therapy development. By stimulating these protective responses or suppressing harmful ones, future treatments might help prolong neuron survival. The team employed machine learning techniques to identify specific genes—VGF, INA, and PENK—as reliable indicators of disease across various mutations and in human samples. These could serve as biomarkers for early diagnosis and prognosis.

Eva Hedlund, a neurochemistry professor and lead researcher, emphasizes that understanding these genetic mechanisms opens potential for targeted therapies that enhance nerve cell resilience in ALS. This study adds crucial insights into the molecular pathways involved in nerve degeneration and resistance, providing hope for the development of more effective treatments.