Long-term Caloric restriction reestablishes TDP-43 mutation-driven cognitive alterations through modifications in RNA metabolism at synapses

Bulk RNA sequencing of mouse and FTLD-TDP patient frontal cortex and spinal cord revealed a consistent disease-associated upregulation of ribosomal and translational machinery. CR effectively normalized this global transcriptional signature in the frontal cortex of the TDP-43-M323K mice, and this reduction in general translation was associated with a marked improvement in synaptic assembly genes and synaptic protein levels in the cortex, but not at the neuromuscular junction.

To resolve the paradox of how reducing global translation improves synaptic function, we performed long-read RNA sequencing of isolated hippocampal synaptosomes. This compartment-specific analysis yielded a striking contrast: contrary to the global upregulation, ribosomal mRNAs were specifically depleted within the synaptic compartment of mutant mice. CR robustly rescued this local deficit, restoring the synaptic translatome, suggesting a coherent mechanism that could directly improve synaptic integrity.

We identified a novel mechanism wherein CR counteracts synaptic failure by selectively restoring local ribosomal content, explaining the region- specific rescue of learning and cognitive circuits, and offering a new strategy for mimicking its benefits therapeutically even in other regions where the CR is not beneficial.