Lamin Dysfunction Mediates Neurodegeneration in Tauopathies

The filamentous meshwork formed by the lamin nucleoskeleton provides a scaffold for the anchoring of highly condensed heterochromatic DNA to the nuclear envelope, thereby establishing the three-dimensional architecture of the genome [1]. Insight into the importance of lamins to cellular viability can be gleaned from laminopathies, severe disorders caused by mutations in genes encoding lamins. A cellular consequence of lamin dysfunction in laminopathies is relaxation of heterochromatic DNA [1]. Similarly, we have recently reported the widespread relaxation of heterochromatin in tauopathies [1]: age-related progressive neurodegenerative disorders, including Alzheimer’s disease, that are pathologically characterized by aggregates of phosphorylated tau protein in the brain [2, 3]. Here we demonstrate that acquired lamin misregulation though aberrant cytoskeletal-nucleoskeletal coupling promotes relaxation of heterochromatin and neuronal death in an in vivo model of neurodegenerative tauopathy. Genetic manipulation of lamin function significantly modifies neurodegeneration in vivo, demonstrating that lamin pathology plays a causal role in tau-mediated neurotoxicity. We show that lamin dysfunction is conserved in human tauopathy, as super-resolution microscopy reveals a significantly disrupted nuclear lamina in postmortem tissue from human Alzheimer’s disease brain. Our study provides strong evidence that tauopathies are neurodegenerative laminopathies and identifies a new pathway mediating neuronal death in currently untreatable human neurodegenerative disorders, including Alzheimer’s disease. •Disruption of the lamin nucleoskeleton drives neuronal death in tauopathy•Lamin dysfunction causes heterochromatin relaxation and cell death in neurons•Improper cytoskeletal/nucleoskeletal coupling disrupts lamin in tauopathy•Lamin pathology is conserved in postmortem human Alzheimer’s disease brains In this study, Frost et al. identify the lamin nucleoskeleton and improper cytoskeletal/nucleoskeletal coupling as novel mediators of neurotoxicity in tauopathies, including human Alzheimer’s disease. Their work suggests that tauopathies are neurodegenerative laminopathies.