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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.

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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.