Hutchinson-Gilford progeria syndrome (HGPS) is a rare childhood disease caused by a mutation in the lamin A gene and the expression of a cytotoxic protein called progerin. Progerin accumulates in the nuclear lamina, causing deformation of the nuclear membrane, loss of heterochromatin and disrupted gene expression. Existing treatments, such as farnesyltransferase inhibitors, only modestly extend life and come with serious side effects. So finding ways to remove progerin from patients' cells is an urgent task.
The researchers performed a meta-analysis of published RNA-seq data from cells of HGPS patients and identified dysregulation of genes linked to the anaphase-promoting complex (APC). They then treated patient fibroblasts with an APC activator, the small molecule M2I-1, and assessed progerin levels using western blotting and immunofluorescence. To study protein interactions, they used proximity ligation assay (PLA) and co-immunoprecipitation. The role of the proteasome and autophagy in progerin degradation was tested using the inhibitors MG132 and chloroquine.
Activating APC with M2I-1 reduced progerin and lamin A/C levels in HGPS cells in a dose-dependent manner. Inhibiting the proteasome with MG132 did not block progerin degradation; in fact, it enhanced it, whereas the autophagy inhibitor chloroquine prevented the drop in progerin levels. This indicates that progerin is destroyed through ubiquitin-dependent autophagy. PLA showed that progerin interacts with the APC subunit CDC20, and APC activation increases the proximity of progerin to ubiquitin. Treatment with M2I-1 also reduced the fraction of cells with nuclear blebs (from 87.5% to 62.5%) and slowed proliferation, consistent with an improvement in the cellular phenotype.
The work demonstrates for the first time that APC can directly participate in progerin degradation through a non-canonical pathway: ubiquitin-dependent autophagy rather than the proteasome. This broadens our understanding of APC's role in maintaining proteostasis and in aging. The findings offer a new target for progeria therapy: pharmacological activation of APC could help clear the toxic protein from cells without genetic intervention.
Future work needs to examine in detail the molecular mechanism by which APC routes substrates to autophagy. It will be important to identify adapter proteins, such as p62 and LC3, that may link ubiquitinated proteins to autophagosomes. The effectiveness of APC activators should also be tested in animal models of progeria, and the long-term consequences of such therapy assessed.
The results could influence the development of drugs for progeria and possibly other diseases linked to the buildup of toxic proteins in the nucleus. Activating APC could become a strategy for tackling age-related pathologies in which proteostasis is disrupted.
The next step will be to test M2I-1 in a mouse model of progeria and to search for more specific APC activators. It will also be necessary to determine which ubiquitin chains and adapters are involved in this pathway.
The work addresses a fundamental problem in cell biology: how a cell selectively destroys abnormal proteins in the nucleus. Understanding this mechanism matters not only for progeria but also for neurodegenerative diseases, where the accumulation of protein aggregates is a key pathological event.
Progerin arises from a mutation that activates a hidden splice site in the LMNA gene. As a result, the protein loses 50 amino acids, including the cleavage site for the enzyme ZMPSTE24, and remains permanently attached to the nuclear membrane.
Not published on arXiv. Here are its page, the PDF and the formalization: you can check it yourself, not only read our account.