Cell immortalization facilitates prelamin A clearance by increasing both cell proliferation and autophagic flux.

Carlos González-Blanco, Patricia Marqués, Jesús Burillo, Beatriz Jiménez, Gema García, Manuel Benito, Carlos Guillén

Aging 2022 Mar 08

filter terms:

Hutchinson-Gilford Progeria Syndrome is an ultrarare disease which is characterized by an accelerated senescence phenotype with deleterious consequences to people suffering this pathology. The production of an abnormal protein derived from lamin A, called progerin, presents a farnesylated domain, which is not eliminated by the causal mutation of the disease, and accumulates in the interior of the nucleus, provoking a disruption of nuclear membrane, chromatin organization and an altered gene expression. The mutation in these patients occurs in a single nucleotide change, which creates a de novo splicing site, producing a shorter version of the protein. Apart from this mutation, an alteration in the metalloproteinase Zmpste24, involved in the maturation of lamin A, causing a similar alteration than in progeria. However, in this case, patients accumulate a protein, called prelamin A, which generates similar alterations in the nucleus than progerin. The reduction of prelamin A protein levels facilitates the recovery of the phenotype in different mice models of the disease, reducing the aging process. Different strategies have been studied for eliminating this toxic protein. Here, we report that immortalization of primary cells derived from the Zmpste24 KO mice, facilitates prelamin A degradation by different mechanisms, being essential, the enhancing proliferative capacity that the immortalized cells present. Then, these data suggest that using different treatments for increasing proliferative capacity of these cells, potentially could have a beneficial effect, facilitating prelamin A toxicity.

Citation

Carlos González-Blanco, Patricia Marqués, Jesús Burillo, Beatriz Jiménez, Gema García, Manuel Benito, Carlos Guillén. Cell immortalization facilitates prelamin A clearance by increasing both cell proliferation and autophagic flux. Aging. 2022 Mar 08;14(5):2047-2061