Question

1. What function of intermediate filaments is lacking in people with epidermolysis bullosa complex?

A) what type of intermediate filaments are affected?

2. What type of intermediate filament is affected in Progeria?

3. What is the current hypothesis as to how the loss of intermediate filaments leads to the excessive and vastly premature aging?

Answer 1

1. Intermediate Filaments function as stress sensors in tissue cells and function through various mechanisms of remodeling triggered mechanical stress like cell deformation by stretching, swelling, pressure, friction and heat. IFs have a role in maintaining mechanical resilience in epithelia and act as a scaffold for maintaining cell and tissue integrity due to unique configuration of keratin filament bundles and desmosome cell-cell junctions. It is the loss of this function of IFs in people with epidermolysis bullosa complex which results in cell fragility as the cell's internal reinforcement becomes inadequate and is easily torn apart by mechanical forces acting on skin that would normally cause no detectable response in the tissue.

A. The affected types of Intermediate Filaments in epidermolysis bullosa complex are Keratin 5 (belonging to type II keratin family) and Keratin 14 ( belonging to type I keratin family).

2. Progeria or more specifically called Hutchinson-Gilford progeria syndrome is a condition that causes dramatic and rapid appearance of ageing beginning in childhood. The type of Intermediate Filament that is affected in this condition is lamin A which is a class V intermediate Filament protein which resides in the cell nucleus.

3. Progeria, a premature aging syndrome, is a rare genetic disorder that results in greatly accelerated ageing approximately 8 times faster than normal ageing. The individuals suffering from this condition usually die during their second decade of life. The underlying genetic causes of this disease affect the post translational processing of the intermediate filament protein lamin A which resides in the cell nucleus and forms a cage-like network structure against mechanical strain and is involved in transcriptional regulation, protecting the cell's genome from damage.

Progeria is caused by a mutation in LMNA , the gene encoding lamin A, which results in a truncated/ deformed mutant protein called progeria. These defective/mutated forms of lamin A may lead to the production of reactive oxygen species (ROS) in cells which can cause various types of damages in cells including DNA damage. This type of damage ultimately leads to cellular senescence whereby cells enter more readily into a state of premature aging process when exposed to oxidizing condition.

This is the current hypothesis that explains how the loss or absence of normal IFs leads to the excessive and vastly premature aging.