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I never wanted chaperones — until now

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By Warren R. Heymann, MD
Sept. 25, 2019
Vol. 1, No. 29

heymann-warren-95px.jpgMy oldest brother George had just gotten his driver’s license — under no circumstances would my mother allow him to drive his date Ruth to the movies. George protested vehemently, but ultimately relented, with my mother sitting in the backseat. This was my first exposure to the concept of a chaperone. More than half a century later, I still do not know if my mother was trying to protect my brother, Ruth, the car, or some combination thereof. (Being the youngest of three sons had its advantages — my mother never pulled that trick on me!)

Proteins perform and/or mediate virtually all biological processes in all living organisms. In humans, there are approximately 50,000 different proteins that are synthesized on ribosomes as linear polypeptides. To realize their biological functions, newly synthesized polypeptides must fold into their correct three-dimensional configurations. Misfolded proteins may be pathogenic. Molecular chaperones are a class of proteins (such as heat-shock proteins) that facilitate the proper folding of proteins by binding to and stabilizing unfolded or partially folded proteins. (1) This results in the proper trafficking, sequestration, and turnover of proteins ensuring protein homeostasis (proteostasis). There are approximately 150 genes for molecular chaperones in the human genome. (2)

Oculocutaneous albinism (OCA) is a group of phenotypically similar genetic disorders of melanin synthesis. To date, seven types of nonsyndromic OCA have been described. Syndromic forms of albinism include the Hermansky-Pudlak syndrome(s) and Chediak-Higashi syndrome. Ocular albinism (OA1) is limited to the eyes. OCA Type 1A (OCA1A) has a complete absence of melanin. Patients display white skin, white hair, pink-red irides, nystagmus, foveal hypoplasia, iris transilumination, and photophobia. (3) Patients with OCA1B show residual pigmentation of the skin, hair and eyes. (4)

Lifelong vigilance especially for nonmelanoma skin cancers and even melanoma (amelanotic) is essential. In 1988 my wife (a geneticist) and I were on a Panamanian cruise that was diverted to the San Blas Islands, because of political unrest of the Noriega regime. That excursion allowed us to witness the cutaneous ravages of the “Cuna Moon” children, with one of the highest incidences of albinism worldwide. According to Keeler, “among albinistic Moon-Children, if they live to grow up, the chief cause of death is probably metastatic skin cancer.” (5)

Oculocutaneous albinism type 1 (OCA1) is caused by pathogenic variations in the tyrosinase gene (TYR). Limited experimental evidence suggests retention of tyrosinase (TYR) in the endoplasmic reticulum (ER) causes OCA1 pathogenesis, thereby inhibiting its enzymatic activity. (4)

Teramae et al investigated the intracellular localization of Japanese OCA type 1A missense mutant tyrosinases usingchaperones Western blotting and immunohistochemical staining. R77Q, R239W, D383N, and P431L mutant tyrosinases were retained in the endoplasmic reticulum, and H211Y mutant tyrosinase was partially transported to the Golgi apparatus. 

Chemical chaperones, usually at low concentrations of competitive inhibitors, have been shown to bind and stabilize misfolded proteins. Properly folded proteins are transported from the ER to the Golgi apparatus at neutral pH, and protein-chaperone complexes are safely transported to lysosomes, where they dissociate under the acidic condition and enzymatic activity is then rescued. The authors studied the concept of chemical chaperone therapy (using deoxyarbutin) for their patients with OCA type 1A missense mutations and found that HeLa cells expressing P431L mutant tyrosinase have restored tyrosinase activity after treatment with the chemical chaperone, in a dose-dependent manner. These results provide support for the possibility of chemical chaperone therapy to recover tyrosinase activity in patients with OCA type 1A patients. The authors suggest that the antihypertensive agent captopril, and the antifungal drug miconazole, both of which demonstrate in vitro tyrosinase inhibition, are potential chemical chaperone candidates for patients with OCA1A. (6)

Chemical chaperone therapy has been utilized in other disorders, including Gaucher disease, Fabry disease, epidermolysis bullosa simplex (7), and Kindler syndrome. (8) Future research on developing chemical chaperone therapy may prevent biologic mischief resulting in disease. Dorothy Shaw, a showgirl played by Jane Russell in “Gentleman Prefer Blondes,” upon being introduced to the all-male athletic U.S. Olympic Team observed: “The chaperone’s job is to see that no one else is having any fun, but nobody chaperones the chaperone. That’s why I’m so right for this job.” That is the key — getting the right chemical chaperone to do its job on the right protein abnormality.

Point to remember: Chemical chaperone therapy offers promise for genodermatoses such as oculocutaneous albinism by facilitating proper protein folding, and ultimately, restoring protein function.

Our expert’s viewpoint

Hensin Tsao, MD, PhD
Professor of Dermatology
Harvard Medical School

In the larger scheme, there is a tremendous need in medicine, including dermatology, for drugs that can correct pathophysiology due to mutations. For instance, selective BRAF inhibitors that can target mutated forms of BRAF (i.e. the V600E mutation) have brought about a sea change in the treatment of melanoma. Embedded between the lines of this OCA study is the hope that, one day, we can treat OCA with a pill. The actual studies, no matter how promising, remain highly preliminary.

First, for “chaperone” therapy to work, we must know if the tyrosinase mutation induces misfolding and mistrafficking of the protein (i.e. responsive to the therapy) or if it causes a deleterious change in the enzymatic function (probably will not respond to chaperone therapy). Second, not all misfolding mutations of tyrosinase will predictably respond to chaperone therapy. Using deoxyarbutin as a tool compound, even super-physiological doses of the drug did not restore tyrosinase activity in several mutations. Lastly, experiments in cell culture with non-melanocytes (HeLa cells in the article) represent notoriously treacherous grounds for translational speculation. That said, new pharmacological strategies are always exciting, especially for diseases with very limited treatment options.

1. Ma FH, Li C, Liu Y, Shi L. Mimicking molecular chaperones to regulate protein folding. Adv Mater 2019; May 2 [Epub ahead of print].
2. Gestwicki JE, Shao H. Inhibitors and chemical probes for molecular chaperone networks. J Biol Chem 2019; 294: 2151-2161. 
3. Federica JR, Krishnamurthy K. Albinism. StatPearls [Internet]. StatPearls, Treasure Island (FL), January 2019.
4. Mondal M, Sengupta M, Ray K. Functional assessment of tyrosinase variants identified in individuals with albinism is essential for unequivocal determination of genotype-to-phenotype correlation. Br J Dermatol 2016; 175: 1232-1242.
5. Keeler C. The Cuna Moon-child syndrome. Int J Dermatol 1964; 3: 1-11.
6. Teramae A, Kobayashi Y, Kunimoto H, Nakajima K, et al. The molecular basis of chemical chaperone therapy for oculocutaneous albinism type 1A. J Invest Dermatol 2019; 139: 1143-1149.
7. Chamcheu JC, Siddiqui IA, Mukhtar H. Chemical chaperone therapy, a new strategy for genetic skin fragility disorders. Exp Dermatol 2016; 25: 183-184.
8. Maier K, He Y, Esser PR, Thriene K, et al. Single amino acid deletion in Kindlin-1 results in partial protein degradation which can be rescued by chaperone treatment. J Invest Dermatol 2016; 136: 920-929.

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