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

ABSTRACT: TDP-43 proteinopathies, encompassing amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are fatal neurodegenerative diseases with no cure. Caloric restriction (CR) is a potent metabolic intervention with proven neuroprotective benefits, but its effects could be domain- specific, improving cognition while potentially exacerbating motor deficits. This dichotomy highlights the urgent need to dissect the compartment-specific molecular effects of CR to harness its therapeutic potential safely. Here, we dissect this paradox in a mouse model of TDP-43 proteinopathy. We first established that lifelong CR rescues cognitive but not motor deficits in TDP-43-M323K mice. Mechanistically, the benefits of CR were mostly independent of TDP-43 dysfunction, operating downstream of the core pathology. 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE311948 | GEO | 2026/09/23

REPOSITORIES: GEO

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Project description:TDP-43 is a nuclear protein encoded by the TARDBP gene, which forms pathological aggregates in various neurodegenerative diseases, collectively known as TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These diseases are characterized by multiple pathological mechanisms, with disruptions in lipid regulatory pathways emerging as a critical factor. However, the role of TDP-43 in the regulation of the brain lipid homeostasis and the potential connection of TDP-43 dysfunction to myelin alterations in TDP-43 proteionopathies remain poorly understood, despite the fact that lipids, particularly cholesterol, comprise nearly 70% of myelin. To investigate the causal relationship between TDP-43 dysfunction and disruptions in brain cholesterol homeostasis, we conducted multi-omics analyses (lipidomics, transcriptomics, and functional splicing) on the frontal cortex from the TardbpM323K/M323K knock-in mouse model. Lipidomic analysis revealed alterations in lipid pathways related to membrane composition and lipid droplet accumulation, particularly affecting cholesterol-related species. We found higher lipid droplets accumulation in primary fibroblast derived from these mice, as well as in the brain of the mutant mice. Similarly, the immunohistochemical detection of a lipid droplet marker was higher in the post-mortem frontal cortex, gray and white matter, of FTLD-TDP patients compared to non-neurological controls. Transcriptomic analyses showed that TDP-43 pathology led to transcriptional dysregulation of genes essential for myelin production and maintenance. We identified impaired cholesterol metabolism, mainly through the downregulation of endogenous cholesterol synthesis, alongside upregulated cholesterol transport pathways, which we further replicated in FTLD-TDP patients transcriptomic datasets. Collectively, our findings suggest that TDP-43 dysfunction disrupts brain cholesterol homeostasis, potentially compromising myelin integrity.

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

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