Roles of lactate and protein lactylation in neurogenesis and neurodegenerative disease

Neurodegenerative diseases are characterized by the gradual deterioration and impaired functionality of neuronal cells, which in turn results in the progressive decline of both cognitive capabilities and motor performance. Over the past few years, accumulating evidence has demonstrated that neurogenesis participates in pathogenesis of various neurodegenerative conditions. In the adult brain, neurogenesis involves the proliferation and differentiation of neural stem cells into functional neurons, a process that serves a critical function in sustaining neuroplasticity and repairing neural damage. Additionally, studies conducted recently show that lactate and the protein lactylation modification it induces can regulate neurogenesis and influence the progression of neurodegenerative diseases.

We elaborate on how lactate, as an energy substrate and signaling molecule, supports neuronal survival and synaptic plasticity, and discuss the mechanisms by which histone lactylation regulates neural stem cell proliferation and differentiation via epigenetic pathways, as well as the regulation of specific protein functions by non‑histone lactylation. We further integrate the dual effects of lactate and lactylation in diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). They can be neuroprotective by improving energy metabolism, promoting neurotrophic signals, and reducing inflammation, but they can also be neurotoxic via inflammation, oxidative damage, and protein aggregation under certain conditions. Key factors that determine this switch include concentration, cell type, pathological context, and lactylation site. We also evaluate therapeutic strategies targeting lactate metabolism and lactylation, and the challenges for clinical translation.

Lactate and protein lactylation exhibit a regulatory duality in neurogenesis and neurodegenerative diseases, encompassing both neuroprotective and neurotoxic effects. This finding provides a new perspective for understanding disease mechanisms and reveals potential intervention targets.