Researchers from the University of Cambridge highlight new ways that neurons and many cell types use to sense nutrients — opening potential novel therapeutic avenues for disorders such as Alzheimer's and Parkinson's disease.
Neurons are among the longest-living cells in the human body. Unlike many other cell types, they cannot dilute damaged proteins through cell division and therefore rely heavily on tightly controlled systems that regulate nutrient sensing, protein quality control, and autophagy — the cellular "self-cleaning" process essential for neuronal survival.
In a new review published in EXO – Beyond the Cell , researchers led by Prof. David C. Rubinsztein from the University of Cambridge discuss emerging evidence that neurons may use a previously underappreciated metabolic mechanism to regulate mTORC1, a central signaling hub that coordinates cellular growth, metabolism, and autophagy.
For years, canonical amino acid sensing pathways — such as Sestrin2-mediated leucine sensing — have dominated the field of mTORC1 biology. These studies have been largely conducted in HEK293 cells. However, the researchers highlight growing evidence that in neurons and glial cells, as well as numerous other cell types, leucine-derived acetyl-coenzyme A (AcCoA) may play a more prominent regulatory role. In this pathway, AcCoA activates the acetyltransferase p300, leading to acetylation of the mTORC1 component Raptor and subsequent activation of mTORC1 signaling.
Importantly, chronic overactivation of mTORC1 has been linked to impaired autophagy and toxic protein accumulation across multiple neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and ALS.
Rather than directly suppressing mTORC1, the researchers suggest that targeting upstream metabolic nodes could represent an alternative therapeutic strategy.
In this review, researchers also summarize evidence that metabolic and inflammatory pathways may converge on neuronal mTORC1 regulation. For example, abnormal AcCoA accumulation and inflammatory signaling through CCR5 represent two different mechanisms that have been implicated in pathological mTORC1 activation and autophagy defects in neurodegenerative disease models.
"These findings suggest that neuronal nutrient sensing may have differences to what is seen in HEK293 cells, which have been used extensively in the previous literature," the researchers note. "Understanding these specialized metabolic control mechanisms could help identify new therapeutic opportunities upstream of mTORC1."
The researchers further highlight several emerging therapeutic directions, including modulation of AcCoA production, regulation of p300 acetylation activity, and targeting inflammatory-metabolic crosstalk pathways.
The review, "Nutrient-sensing and mTORC1 regulation in neuronal homeostasis: from metabolic signaling to neurodegeneration," was published in EXO – Beyond the Cell.
