Abstract
Nucleoskeleton dysfunction has been implicated in Alzheimer disease (AD). Tubular invaginations of the nuclear envelope observed in AD brains are consistent with the accumulation of farnesylated prelamin A (encoded by the LMNA gene) that occurs in Hutchinson-Gilford Progeria Syndrome, a premature aging disorder caused by LMNA mutations. Proper function of the nuclear membrane is required for neuronal survival and for maintenance of genetic architecture. To determine whether dysregulated LMNA expression and prelamin A processing are responsible for nucleoskeleton dysfunction in AD, we performed differential gene expression and network analyses in human AD and age-matched control brains. Lamin A protein levels were evaluated in AD and control brains using mass spectrometry. Gene network analyses were carried out using induced pluripotent stem cell-derived neurons transduced with progerin or GFP controls in order to identify molecular pathways influenced by altered LMNA processing. In AD brains, we observed a significant increase in LMNA and a significant decrease in ZMPSTE24, resulting in a significant increase Lamin A protein levels, which we observe through mass spectrometry. We replicated these findings in laser capture microdissected neurons from AD brains, suggesting that the effect is neuronally driven. Thus, high levels of LMNA paired with low levels of ZMPSTE24 could result in the accumulation of farnesylated prelamin A and tubular invaginations in the nuclear membrane. LMNA-associated networks were also differentially expressed in AD brains. Genes within the dysregulated LMNA network were enriched in lysosomal and chromatin remodeling pathways. Our findings suggest that β-amyloid and tau accumulation disrupts prelamin A processing and downstream changes in the nuclear membrane. Alterations in the nucleoskeleton induce genomic instability, loss of proteostasis, and cellular senescence, which may accelerate AD pathogenesis.
Published Version
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