Alopecia Areata Hair Breakage Linked to Cysteine Deficiency

Alopecia areata has symptoms like hair breakage that show links to the dysregulation of cysteine metabolism. | Image Credit: shidlovski - stock.adobe.com

Patients diagnosed with alopecia areata (AA) have different levels of severity when compared with the entire patient population. While the etiology of AA is not completely understood, the pathogenesis typically involves the disruption of hair follicle immune privilege and oxidative stress.¹

In a review published in Amino Acids, data reassessed the associations between the hair characteristics of AA and cysteine metabolism. Researchers hypothesized cysteine metabolism could play a pivotal role in keratin function abnormalities, including damage to the keratin layer of the follicle, and they proposed new therapeutic strategies for AA, mainly focused on cysteine metabolism modification.

The Role of Cysteine Metabolism in AA

Cysteine, an abundant amino acid in hair, contributes to the stability of the hair shaft by participating in the formation of disulfide bonds, which are essential for its structural integrity.

When this process is disrupted, it often leads to hair fragility and breakage or loss. The 2 primary pathways cysteine is derived from are the endogenous synthesis within the body and exogenous sources like diet and N-acetylcysteine pharmaceutical agents or those similar to it.

Cells absorb essential amino acids like cysteine, glutamate, alanine, and serine through 3 specific transporters known as the cysteine-glutamate transporter exchange system (System XC-), the excitatory amino acid transporter 3, and the alanine-serine-cysteine transporter (ASCT), with ASCT1 and ASCT2 subtypes.

When System XC-expression is inhibited in tumor cells, they may present a potential antitumor strategy.

The relationship between cysteine and hair follicles displays predominant engagement in processes that include the antioxidative stress response, energy transmission, keratin stabilization, protein cysteinylation, and hair pigmentation.

Existing research found that patients with AA have lower levels of serum zinc compared with healthy individuals. This finding highlights the importance of zinc for hair health and suggests a potential link between zinc and cysteine in maintaining strong, healthy hair.

Examination of the potential role of cysteine metabolism in the pathogenesis of AA was the main concern for investigators. It is possible cysteine affects hair growth through keratin because it is rich in cysteine and the protein synthesis could be impacted.

Early AA symptoms included exclamation point hair and hair breakage, which could be factors of dysregulation in the cysteine metabolism.

Exclamation mark hair typically appears as very small hairs around 3 mm to 4 mm, oftentimes wider at the top and then tapering to thinner progression of hair as it meets the scalp.² The hairs usually appear pale toward the ends and darker near the top of the head.

Since there are various signs and symptoms of AA, the review aimed to dissect the etiology of AA in relation to cysteine metabolism.

Cysteine Metabolism, Autophagy, and AA

Autophagy, the cellular mechanism responsible for the degradation and recycling of macromolecules and damaged organelles, is associated with the cellular functions of cysteine. When nutrient deprived, cysteine metabolism supports autophagy.

More specifically, autophagy is experienced when cells are invaded by microbes, stress from nutrient deprivation, presence of dysfunctional organelles, and pathogenic proteins.³ Dysregulated levels of autophagy have been associated with several inflammatory disorders. By considering the regulation of autophagy, this could potentially lead to new emerging therapeutic options.

A previous study showed evidence that under conditions of oxidative stress, elevated concentration of cysteine can facilitate the biogenesis and maturation of autophagosomes.¹ These findings suggest cysteine might play a regulatory role in autophagy, potentially protecting cells from damage caused by oxidative stress.

An uptake in oxidative stress may show links to adversely affected hair follicles, possibly triggering the onset of AA.

Cysteine Metabolism, Immunity in AA

Lately, cysteine and its metabolic products have increasingly showed signs in inflammation reduction properties and modulating immune responses, vital to the pathogenesis of various autoimmune disorders.

Conditions like mucositis are alleviated when supplemented with cysteine and could decrease oxidative stress and inflammation in older patients, providing evidence of therapeutic benefits in AA.

The anti-inflammatory properties of cysteine have extended to the overall modulation of immune cells, specifically relevant in AA where immune dysregulation is crucial.

New strategies are continuously being discovered for the impact cysteine has on oxidative and inflammatory pathways to fight autoimmune disorders similar to AA, which emphasizes cysteine as a beneficial therapeutic target.

Cysteine Metabolism, Ferroptosis, AA Pathogenesis

A specific form of cell death known as ferroptosis is instigated by lipid peroxidation and relies on iron ions.

When cysteine is denied cellular entry to System XC-, it initiates an alternative cysteine-dependent mechanism to resist ferroptosis. Patients with early AA symptoms have observed CD8+ T cells infiltrate hair follicles substantially. This research indicates that T cells have the ability to release interferon-γ, and ultimately inhibits the System XC-, resulting in a decline in intracellular cysteine levels and triggers ferroptosis.

Patients with AA that have increased blood levels of the lipid peroxidation product malondialdehyde could experience enhanced risk of cysteine metabolism and ferroptosis.

The pathway production of GPX4, a counteracting lipid peroxidation that deters ferroptosis, involves interferon-γ from CD8+ T cells that impact hair follicle uptake.

The research data prompted the authors to propose the hypothesis regarding both ferroptosis and disturbances in cysteine metabolism as constituting mechanisms in the pathogenesis of AA.

Hypothetical Links

Homocysteine is the predecessor to cysteine based on its involvement in the metabolic pathway of methionine. Factors like lifestyle habits, nutritional status, and chronic disease states can lead to hyperhomocysteinemia.

Homocysteine acts as a metabolic crossroads, playing a key role in both methionine metabolism and the production of cysteine, a vital amino acid with various functions in the human body.⁴ It can be recycled back into methionine through a process called remethylation, preventing a methionine deficiency, especially when dietary methionine intake is low.

Data revealed an increased incidence of psychiatric disorders like depression in patients with AA compared with health counterparts.¹ The homocysteine levels examined found an independent association with psychiatric conditions such as depression and obsessive-compulsive disorder, often linked to AA.

Some data found N-acetylcysteine, known for efficient plasma level reduction for homocysteine, to display favorable clinical responses in AA conditions.

N-acetylcysteine has been approved to offer therapeutic benefits for psychiatric disorders, appearing to be beneficial in treating trichotillomania, a disorder classified as hair-pulling and usually associated with psychological factors. Certain types of autoimmune and inflammatory responses have been influenced by N-acetylcysteine, but the effectiveness may vary across different conditions and symptoms.

Psychiatric disorders, often correlated with AA, show a secondary role in its pathogenesis. Depression was of the most common psychiatric conditions linked with AA due to the excessive release of corticotropin-releasing hormones.

The connection between cysteine metabolism and psychiatric symptoms shows signs of indirectly affecting hair structure while adding complexity to the understanding of the pathogenesis of AA.

Conclusion

Cysteine metabolism appears to play a role in the pathogenesis of AA and impacts diverse biological pathways that range from oxidative stress and disruptions in keratin functionality to autophagy, immunity, and ferroptosis.

Recent reviews of research acknowledge more important roles in stress-related hormones like corticotropin-releasing hormones that could operate as primary instigators for the development of AA.

The authors conclude it is necessary for future experimental studies to confirm these hypotheses and fully elucidate the complex methods that link cysteine metabolism to the pathogenesis of AA.

References:

1. Xu W, Xie B, Wei D. et al. Dissecting hair breakage in alopecia areata: the central role of dysregulated cysteine homeostasis. Amino Acids. 2024; 56(36): 1-11. doi:10.1007/s00726-024-03395-5

2. Donovan J. Exclamation mark hairs. Donovan Hair Clinic. August 17, 2011. Accessed June 25, 2024. https://donovanmedical.com/hair-blog/2011/8/17/exclamation-mark-hairs.html

3. Liu C, Ji L, Hu J, et al. Functional amino acids and autophagy: diverse signal transduction and application. Int J Mol Sci. 2021;22(21):11427. doi:10.3390/ijms222111427

4. Rehman T, Shabbir MA, Inam‐Ur‐Raheem M, et al. Cysteine and homocysteine as biomarker of various diseases. Food Sci Nutr. 2020;8(9):4696-4707. doi:10.1002/fsn3.1818