The nuclear lamina is a meshwork of intermediate filaments adjacent to the inner nuclear membrane, integral to all metazoan cells. It performs a critical structural role in the maintenance of nuclear architecture and integration of cytoskeletal structure in addition to aiding in regulation of gene expression, chromatin positioning, cell proliferation, migration and senescence. Exciting, recent work in Drosophila models and from Alzheimer?s diseases (AD) brain tissue has implicated a down regulation, specifically of B type lamins, and nucleoskeletal dysfunction as a critical step mediating the neurodegeneration associated with tauopathies such as AD. Lamin B1 (LB1) is the major B type lamin expressed in the mammalian CNS and loss of this protein during development results in significant defects in neuronal migration and cortical organization. We propose to test the hypothesis that overexpression of LB1 in neurons can provide a neuroprotective effect and ameliorate the phenotype in a mouse model of tau mediated neurodegeneration. The experiments we have proposed will allow us to test the intriguing possibility that modulating the levels of the nuclear lamina protein, LB1 can impact pathology in a clinically relevant mouse model of tau mediated Alzheimer?s disease
A decrease in the amount of a specific type of nucleosteketal proteins known as B type lamins have been implicated in Alzheimer?s disease (AD). We propose to use a mouse model we have generated to increase lamin B1 specifically in neurons in a mouse model of AD to determine if it can reduce disease pathology.
| Lo Martire, Viviana; Alvente, Sara; Bastianini, Stefano et al. (2018) Mice overexpressing lamin B1 in oligodendrocytes recapitulate the age-dependent motor signs, but not the early autonomic cardiovascular dysfunction of autosomal-dominant leukodystrophy (ADLD). Exp Neurol 301:1-12 |
| Padiath, Quasar S (2016) Lamin B1 mediated demyelination: Linking Lamins, Lipids and Leukodystrophies. Nucleus 7:547-553 |
