Repetitive mild traumatic brain injury (rmTBI) produces cumulative cellular stress that can lead to progressive brain dysfunction, yet the mechanisms governing vulnerability to repeated injury remain unclear. Protein kinase RNA-like endoplasmic reticulum kinase (PERK) regulates cellular proteostasis through the unfolded protein response and is implicated in neurodegeneration and acute brain injury. Here, we directly tested the role of PERK deficiency in shaping the brain's response to rmTBI. Using a mouse model of neuronal PERK deficiency, we combined spatial protein profiling and tissue analyses with resting-state functional MRI and diffusion tensor imaging to assess molecular, functional, and structural outcomes after rmTBI. PERK deficiency increased susceptibility to rmTBI-induced disruption of protein homeostasis, altered large-scale functional connectivity, and exacerbated white matter microstructural changes consistent with axonal and myelin damage. Molecular alterations were spatially aligned with imaging-defined network and white matter abnormalities. These findings identify PERK signaling as a key determinant of brain resilience to repetitive mild injury and link ER stress dysregulation to network-level dysfunction following rmTBI.

The unfolded protein response (UPR) sensor PERK exists in two haplotypes termed A and B. PERK-B uniquely confers increased risk for tauopathies like progressive supranuclear palsy (PSP), but the mechanisms distinguishing its function from PERK-A and contributing to its association with tau pathology are not known. Here, we developed a controlled cellular model for a pair-wise comparison of the two PERK haplotypes, finding their UPR functions nearly indistinguishable. However, a careful examination employing puromycin-based proteomics revealed that a subset of mRNA translation events were permissible under PERK-B, but not PERK-A, dependent UPR. Critically, one of the targets that escaped PERK-B suppression was the transcription factor DLX1, which has been genetically linked to PSP risk. Here, we found a shift in the solubility of DLX1 in human PSP brain tissue, and report that silencing of DLX-1 reduced the aggregation of tau in mammalian cells. Furthermore, silencing of the fly homolog of DLX1 was sufficient to decrease tau-induced toxicity, in vivo. Our results detail the haplotype-specific PERK-B/DLX-1 pathway as a novel driver of tau pathology in cells, flies, and likely human brain, revealing new insights into PSP pathogenesis and potential therapeutic targets.

Repetitive mild traumatic brain injury (rmTBI) produces cumulative cellular stress that can lead to progressive brain dysfunction, yet the mechanisms governing vulnerability to repeated injury remain unclear. Protein kinase RNA-like endoplasmic reticulum kinase (PERK) regulates cellular proteostasis through the unfolded protein response and is implicated in neurodegeneration and acute brain injury. Here, we directly tested the role of PERK deficiency in shaping the brain’s response to rmTBI. Using a mouse model of neuronal PERK deficiency, we combined spatial proteomics and tissue analyses with resting-state functional MRI and diffusion tensor imaging to assess molecular, functional, and structural outcomes after rmTBI. PERK deficiency increased susceptibility to rmTBI-induced disruption of protein homeostasis, altered large-scale functional connectivity, and exacerbated white matter microstructural changes consistent with axonal and myelin damage. Molecular alterations were spatially aligned with imaging-defined network and white matter abnormalities. These findings identify PERK signaling as a key determinant of brain resilience to repetitive mild injury and link ER stress dysregulation to network-level dysfunction following rmTBI.

The discovery of RNA in the late 19th century revolutionized the understanding of cell biology. Subsequent discoveries over the next six decades revealed a key role for RNA in protein synthesis. Nevertheless, today, the mechanisms driving RNA metabolism remain enigmatic. Given its fundamental cellular role, RNA alterations are strongly linked to disease, including devastating neurodegenerative disorders pathologically defined by the accumulation of RNA-binding proteins. For example, the mislocalization of TDP-43, an RNA-binding protein, is a pathological feature of amyotrophic lateral sclerosis and frontotemporal dementia TDP-43. Another group of more than 20 neurodegenerative disorders, called tauopathies, is characterized by the aberrant accumulation of the protein tau. Similarly, the emerging concept that tau binds RNA, facilitating the formation of pathological structures, highlights the importance of RNA stability in tauopathies. However, the dynamics and consequences of RNA–tau interactions remain unclear. This review comprehensively catalogs key findings linking tau, RNA, and stress granules. These findings are important because they could offer novel opportunities to design therapeutic strategies.