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Updated: Jan 11, 2026
08:59
Real-Time Fluorescent Measurement of Synaptic Functions in Models of Amyotrophic Lateral Sclerosis
Published on: July 16, 2021
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Does Amyotrophic Lateral Sclerosis (ALS) Have Metabolic Causes from Human Evolution?
1Spedding Research Solutions SAS, 78110 Le Vesinet, France.
Cells
|November 13, 2025
Summary
Recent human genetic variants, like CMAH loss, may drive ALS by altering metabolism and neuromuscular junctions. This evolutionary change impacts brain development and lactate utilization, offering new therapeutic avenues.
Area of Science:
- Neuroscience
- Human Evolution
- Metabolic Disorders
Background:
- Amyotrophic lateral sclerosis (ALS) treatments have seen limited success, necessitating novel therapeutic strategies.
- Human evolution, particularly the loss of cytidine monophospho-N-acetylneuraminic acid hydroxylase (CMAH), significantly altered hominin metabolism, brain development, and neuromuscular junctions (NMJs).
- The sialome, influenced by CMAH, plays a role in viral infections and NMJ stability, with GM1 neurotrophin being a key component.
Purpose of the Study:
- To explore the hypothesis that recent human genetic variants, specifically CMAH pseudogenization, are pivotal in the pathogenesis of ALS.
- To investigate the link between altered lipid/lactate metabolism, human evolution, and the incidence of ALS.
- To evaluate the potential of targeting metabolic pathways, such as those involving lactate and GBA2, for ALS therapy.
Main Methods:
- Comparative analysis of human genetic evolution and metabolic changes.
- Review of existing research on CMAH function, sialome composition, and NMJ integrity.
- Examination of the role of lactate metabolism and GBA2 in neurodegenerative diseases and human performance.
Main Results:
- The loss of CMAH in hominins correlated with accelerated brain growth and enhanced running capacity, suggesting significant metabolic shifts.
- GM1, a crucial sialylated molecule, is lost from NMJs during denervation, potentially linked to increased GBA2 activity.
- Lactate, a key metabolic fuel, is compromised in ALS patients, indicating its relevance to disease progression.
Conclusions:
- Human-specific genetic changes in CMAH and subsequent alterations in the sialome and metabolism are proposed as critical factors in ALS.
- Targeting metabolic pathways, including lactate utilization and GBA2 inhibition (e.g., with ambroxol), presents a promising therapeutic direction for ALS.
- Understanding the interplay between human evolution, metabolism, and neuromuscular function may unlock new strategies for combating ALS.
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