Aging is the leading risk factor for cardiovascular, oncological and neurodegenerative diseases. Hutchinson-Gilford progeria syndrome (HGPS) serves as a model of accelerated aging: a mutation in the LMNA gene leads to the synthesis of a shortened lamin A, progerin, which accumulates at the nuclear membrane and disrupts the cell's workings. In physiological aging, low levels of progerin also turn up in various tissues, which links this rare disease to ordinary aging. Understanding the mechanisms of progerin-induced aging may open the way to fighting age-related pathologies.
The researchers screened 704 kinases using RNA interference in an inducible cell model of progeria (fibroblasts with GFP-progerin). The kinase they singled out, LRRK2, was further suppressed with shRNA in primary fibroblasts from HGPS patients and from elderly donors (82-84 years old). Effects were assessed by markers of cellular senescence: levels of lamin B1, heterochromatin (HP1α, H3K27me3, H3K9me3) and DNA damage (γH2AX). The impact on protein transport was studied with a RUSH assay (tracking a reporter's movement from the ER to the Golgi apparatus), and endocytosis was measured by Dil-LDL uptake. At the organism level, knockdown of the homolog lrk-1 was tested in C. elegans nematodes.
LRRK2 knockdown lowered progerin levels and partially restored lamin B1, LAP2α, HP1α and H3K27me3, while reducing γH2AX foci in cells with progerin. In primary fibroblasts from HGPS patients, the same changes appeared in all three lines. Overexpression of the LRRK2 activator Rab29 accelerated aging, whereas overexpression of the phosphatase PPM1H, which counteracts LRRK2, rescued the phenotype. Progerin delayed transport from the ER to the Golgi (RUSH assay) and disrupted endocytosis. In worms, lrk-1 knockdown extended lifespan and improved mobility in old age, despite nuclear deformation.
LRRK2 links disrupted membrane transport to cellular aging. Its hyperactivity, known from Parkinson's disease, turns out to be harmful in both progeria and physiological aging. This points to a shared mechanism of age-related decline, in which a breakdown of intracellular logistics leads to an accumulation of damage. Since LRRK2 inhibitors are already in clinical trials for Parkinson's disease, their potential for geroprotection could be tested relatively quickly.
Further studies need to work out which Rab GTPases, the substrates of LRRK2, mediate its pro-aging effect. It is important to check how far pharmacological inhibition of LRRK2 (not just genetic knockdown) will slow aging in animal models. The question of a safe degree of LRRK2 suppression remains open, given its role in normal transport and possible side effects.
The results could influence the development of therapies for progeria and age-related diseases, especially neurodegenerative ones. They also broaden our understanding of the role of intracellular transport in aging.
Test the effect of LRRK2 kinase inhibitors (for example, MLi-2) on cell and animal models of progeria. Determine which Rab proteins are critical for the pro-aging action of LRRK2.
For gerontology, the question of a single mechanism linking different hallmarks of aging remains unresolved. This work shows that dysfunction of intracellular transport may be a common hub uniting nuclear, metabolic and proteostatic defects. This fits with the concept of 'transport collapse' as one of the pillars of aging.
Progerin differs from normal lamin A by the absence of just 50 amino acids, yet that is enough for the protein to get permanently 'stuck' to the nuclear membrane and set off a cascade of aging.
Not published on arXiv. Here are its page, the PDF and the formalization: you can check it yourself, not only read our account.