Lamin Dysfunction Mediates Neurodegeneration in Tauopathies

Curr Biol. 2016 Jan 11;26(1):129-36. doi: 10.1016/j.cub.2015.11.039. Epub 2015 Dec 24.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Animals
  • Animals, Genetically Modified
  • Brain / metabolism
  • Brain / pathology
  • Cytoskeleton / metabolism
  • Drosophila
  • Heterochromatin / metabolism
  • Humans
  • Lamin Type A / genetics
  • Lamin Type A / metabolism*
  • Lamins / metabolism
  • Mutation
  • Nuclear Envelope / metabolism
  • Tauopathies / metabolism*
  • Tauopathies / pathology*
  • tau Proteins / metabolism*

Substances

  • Heterochromatin
  • Lamin Type A
  • Lamins
  • tau Proteins