Intermediate Filaments

Introduction – Intermediate Filaments

Intermediate filaments are a type of cytoskeletal protein found in the cells of many eukaryotic organisms. They form a network of fibers that provide structural support and stability to cells and tissues.

Intermediate filaments are composed of several different types of proteins, including keratins, vimentin, desmin, neurofilament proteins, and laminins. These proteins share a common structural motif, consisting of an alpha-helical rod domain flanked by globular head and tail domains.

Overview

•  Structure 
  • stable polymers
    • unlike microtubules and actin → does not undergo dynamic treadmilling
    • must be degraded via the ubiquitin pathway
      • sends to proteasomes
  • intermediate in size between microfilaments (7 nm) and microtubules (25 nm)
• Function
  • give strength to the cytoskeleton
  • 5 types

Type	Filament name	Locations	Stain
I-II	Keratin	Epithelial cells	Cytokeratin
III	Desmin	Muscle (smooth, cardiac, and skeletal)	Desmin
	Peripherin	Peripheral nerve axons	–
	Vimentin	Fibroblasts and endothelium	Vimentin
	Glial fibrillary acidic protein (GFAP)	Astrocytes and Schawnn cells	GFAP
IV	Neurofilaments	Neurons	Neurofilament (NF)
V	Lamins	Nuclear envelope of all cells

• Clinical importance
  • alcoholic liver disease
    • ubiquitinated cytokeratin filaments accumulate in hepatocytes
      • eosinophilic inclusions called Mallory bodies 
  • Parkinson’s disease
    • alpha-synuclein and ubiquitinated neurofilaments accumulate in neurons of substantia nigra
    • eosinophilic inclusions called Lewy bodies

Symptoms – Intermediate Filaments

• Skin disorders: Mutations in keratin intermediate filaments can lead to various skin disorders such as epidermolysis bullosa simplex, a condition characterized by blistering and skin fragility.
• Muscle disorders: Mutations in desmin intermediate filaments are associated with a group of muscle diseases known as desmin-related myopathies, which can lead to muscle weakness and wasting, cardiac abnormalities, and respiratory problems.
• Neurological disorders: Mutations in neurofilament intermediate filaments are associated with Charcot-Marie-Tooth disease, a group of hereditary neuropathies that affect the peripheral nerves and can cause muscle weakness and atrophy, as well as sensory loss.
• Nuclear disorders: Mutations in lamins, the intermediate filaments that form the nuclear lamina, can lead to a group of diseases known as laminopathies. These diseases can affect various tissues and organs and are associated with a range of symptoms, including muscular dystrophy, lipodystrophy, premature aging, and cardiac abnormalities.

Studies – Intermediate Filaments

• “Intermediate Filaments in Cell Migration and Invasion: The Unexplored Role of Keratin 76 in Cancer” (2019). This study, published in the journal Cancers, explores the role of intermediate filaments, specifically keratin 76, in cancer cell migration and invasion. The researchers found that keratin 76 expression is associated with increased cancer cell invasion and metastasis, suggesting that targeting intermediate filaments could be a potential therapeutic strategy for cancer.
• “Vimentin Intermediate Filaments as Potential Target for Cancer Treatment” (2021). This review article, published in the journal Cancers, discusses the potential of targeting vimentin intermediate filaments for cancer treatment. The authors highlight recent findings on the role of vimentin in cancer cell migration, invasion, and drug resistance, and suggest that targeting vimentin could be a promising approach for developing new cancer therapies.
• “Intermediate Filament Proteins in Cardiovascular Development and Disease” (2020). This review article, published in the journal Frontiers in Cardiovascular Medicine, explores the role of intermediate filament proteins in cardiovascular development and disease. The authors discuss the functions of different intermediate filament proteins in heart development, as well as their involvement in various cardiovascular diseases, including cardiomyopathies and atherosclerosis.
• “Intermediate Filaments and Cellular Metabolism: A Complex Relationship” (2020). This review article, published in the journal Trends in Cell Biology, discusses the relationship between intermediate filaments and cellular metabolism. The authors highlight recent findings on the role of intermediate filaments in regulating cellular metabolism, and suggest that targeting these proteins could be a potential therapeutic strategy for metabolic disorders.

Treatment – Intermediate Filaments

• Skin disorders: Treatment for skin disorders associated with intermediate filament mutations typically involves managing symptoms such as blistering and skin fragility, and preventing secondary infections. This may include topical or systemic antibiotics, wound care, and pain management.
• Muscle disorders: Treatment for muscle disorders associated with intermediate filament mutations may include physical therapy, assistive devices, and medications to manage symptoms such as muscle weakness and pain. In some cases, cardiac and respiratory support may also be necessary.
• Neurological disorders: Treatment for neurological disorders associated with intermediate filament mutations may include physical therapy, orthotics, and assistive devices to manage symptoms such as muscle weakness and sensory loss. In some cases, medications may also be used to manage symptoms such as neuropathic pain.
• Nuclear disorders: Treatment for nuclear disorders associated with intermediate filament mutations is typically focused on managing symptoms such as muscular dystrophy, lipodystrophy, and cardiac abnormalities. This may include physical therapy, cardiac monitoring, and medications to manage symptoms such as muscle weakness and pain.

Complications – Intermediate Filaments

Intermediate filament-related disorders can lead to a range of complications depending on the specific disorder and organs involved. Here are some examples of complications that may arise from intermediate filament-related disorders:

• Skin complications: In some cases, intermediate filament-related skin disorders can lead to skin infections, scarring, and permanent skin damage. In severe cases, the fragility of the skin can also lead to life-threatening complications such as sepsis.
• Muscle complications: Intermediate filament-related muscle disorders can lead to muscle weakness, wasting, and atrophy. These complications can affect mobility and quality of life, and in some cases, can lead to respiratory failure and cardiac complications.
• Neurological complications: Intermediate filament-related neurological disorders can lead to a range of complications, including motor and sensory neuropathies, gait disturbances, and cognitive impairment. These complications can affect mobility, independence, and quality of life.
• Nuclear complications: Intermediate filament-related nuclear disorders can lead to a range of complications, including premature aging, cardiac abnormalities, and metabolic disorders such as insulin resistance and type 2 diabetes. In severe cases, these complications can be life-threatening.

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