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Source: University of Bonn Summary: Hypotrichosis simplex leads to progressive hair loss starting in childhood. Geneticists have now deciphered a new gene that is responsible for this rare form of hair loss. Changes in the LSS gene lead to impairment of an important enzyme that has a crucial function in cholesterol metabolism.  Hypotrichosis simplex leads to progressive hair loss starting in childhood. A team of researchers led by human geneticists at the University Hospital of Bonn has now deciphered a new gene that is responsible for this rare form of hair loss. Changes in the LSS gene lead to impairment of an important enzyme that has a crucial function in cholesterol metabolism. The scientists now present their findings in the journal the American Journal of Human Genetics.
In infancy, fine hair tends to sprout sparsely. With increasing age, hair loss progresses. Ultimately, only a few hairs are left on the head and body. Hypotrichosis simplex is a rare form of hair loss (alopecia). The condition is limited to a few hundred families worldwide. So far, only a few genes are known that are causally related to the disease. Under the leadership of the Institute of Human Genetics at the University Hospital of Bonn, a team of researchers from Germany and Switzerland has now deciphered mutations in another gene that are responsible for hair loss. The scientists examined the coding genes of three families that are not related to each other and are of different ancestry. A total of eight relatives showed the typical symptoms of hair loss. All those affected had mutations in the LSS gene. "This gene encodes lanosterol synthase -- LSS for short," said Prof. Dr. Regina C. Betz from the Institute of Human Genetics at the University Hospital of Bonn. "The enzyme plays a key role in cholesterol metabolism." However, the cholesterol blood values of those affected are not changed. Betz: "There is an alternative metabolic pathway for cholesterol, which plays an important role in the hair follicle and is not related to blood cholesterol levels." Mutation leads to displacement of lanosterol synthase Using tissue samples, the scientists tried to find out exactly where the lanosterol synthase is located in the hair follicle cells. The hair roots are formed in the follicle. If the LSS gene is not mutated, the associated enzyme is located in a system of very fine channels in the follicle cells, the endoplasmic reticulum. If a mutation is present, the lanosterol synthase also spreads outside these channels into the adjacent substance, the cytosol. "We are not yet able to say why the hair is falling out," says lead author Maria-Teresa Romano, a doctoral student in Prof. Betz's team. "It is likely that the displacement of LSS from the endoplasmic reticulum results in a malfunction." Prof. Dr. Matthias Geyer from the Department of Structural Immunology at the University of Bonn investigated the consequences of mutations for the structure of the enzyme lanosterol synthase. With him and Prof. Betz, there are now two principal investigators from the Cluster of Excellence ImmunoSensation of the University of Bonn, which was impressively endorsed in the latest round of the Excellence Competition and will receive further funding. Improved diagnosis For the scientists, the current study result is an important finding: Each further gene decoded is yet another part of the jigsaw and helps to complete the picture of the biological basis of the disease. "A better understanding of the causes of the disease may in future enable new approaches to the treatment of hair loss," said the human geneticist. But there is still a long way to go. However, the discovery of the gene already contributes to an improved diagnosis of the rare disease. Betz: "Those affected by hypotrichosis simplex only have to deal with hair loss. This is upsetting, but other organs are not affected." Source: University of Alabama at Birmingham Summary: Researchers have reversed wrinkled skin and hair loss, hallmarks of aging, in a mouse model. When a mutation leading to mitochondrial dysfunction is induced, the mouse develops wrinkled skin and extensive, visible hair loss in a matter of weeks. When the mitochondrial function is restored by turning off the gene responsible for mitochondrial dysfunction, the mouse returns to smooth skin and thick fur, indistinguishable from a healthy mouse of the same age.  Wrinkled skin and hair loss are hallmarks of aging. What if they could be reversed?
Keshav Singh, Ph.D., and colleagues have done just that, in a mouse model developed at the University of Alabama at Birmingham. When a mutation leading to mitochondrial dysfunction is induced, the mouse develops wrinkled skin and extensive, visible hair loss in a matter of weeks. When the mitochondrial function is restored by turning off the gene responsible for mitochondrial dysfunction, the mouse returns to smooth skin and thick fur, indistinguishable from a healthy mouse of the same age. "To our knowledge, this observation is unprecedented," said Singh, a professor of genetics in the UAB School of Medicine. Importantly, the mutation that does this is in a nuclear gene affecting mitochondrial function, the tiny organelles known as the powerhouses of the cells. Numerous mitochondria in cells produce 90 percent of the chemical energy cells need to survive. In humans, a decline in mitochondrial function is seen during aging, and mitochondrial dysfunction can drive age-related diseases. A depletion of the DNA in mitochondria is also implicated in human mitochondrial diseases, cardiovascular disease, diabetes, age-associated neurological disorders and cancer. "This mouse model," Singh said, "should provide an unprecedented opportunity for the development of preventive and therapeutic drug development strategies to augment the mitochondrial functions for the treatment of aging-associated skin and hair pathology and other human diseases in which mitochondrial dysfunction plays a significant role." The mutation in the mouse model is induced when the antibiotic doxycycline is added to the food or drinking water. This causes depletion of mitochondrial DNA because the enzyme to replicate the DNA becomes inactive. In four weeks, the mice showed gray hair, reduced hair density, hair loss, slowed movements and lethargy, changes that are reminiscent of natural aging. Wrinkled skin was seen four to eight weeks after induction of the mutation, and females had more severe skin wrinkles than males. Dramatically, this hair loss and wrinkled skin could be reversed by turning off the mutation. The photos below show the hair loss and wrinkled skin after two months of doxycycline induction, and the same mouse a month later after doxycycline was stopped, allowing restoration of the depleted mitochondrial DNA. Little change was seen in other organs when the mutation was induced, suggesting an important role for mitochondria in skin compared to other tissues. The wrinkled skin showed changes similar to those seen in both intrinsic and extrinsic aging -- intrinsic aging is the natural process of aging, and extrinsic aging is the effect of external factors that influence aging, such as skin wrinkles that develop from excess sun or long-term smoking. Among the details, the skin of induced-mutation mice showed increased numbers of skin cells, abnormal thickening of the outer layer, dysfunctional hair follicles and increased inflammation that appeared to contribute to skin pathology. These are similar to extrinsic aging of the skin in humans. The mice with depleted mitochondrial DNA also showed changed expression of four aging-associated markers in cells, similar to intrinsic aging. The skin also showed disruption in the balance between matrix metalloproteinase enzymes and their tissue-specific inhibitor -- a balance of these two is necessary to maintain the collagen fibers in the skin that prevent wrinkling. The mitochondria of induced-mutation mice had reduced mitochondrial DNA content, altered mitochondrial gene expression, and instability of the large complexes in mitochondria that are involved in oxidative phosphorylation. Reversal of the mutation restored mitochondrial function, as well as the skin and hair pathology. This showed that mitochondria are reversible regulators of skin aging and loss of hair, an observation that Singh calls "surprising." "It suggests that epigenetic mechanisms underlying mitochondria-to-nucleus cross-talk must play an important role in the restoration of normal skin and hair phenotype," Singh said, who has a secondary UAB appointment as professor of pathology. "Further experiments are required to determine whether phenotypic changes in other organs can also be reversed to wildtype level by restoration of mitrochondrial DNA." Source: University of Manchester Summary: A new drug could ease the distress of men and women who suffer from baldness.  A new drug could ease the distress of men and women who suffer from baldness, according to researchers from The University of Manchester's Centre for Dermatology Research.
The study from the laboratory of Prof Ralf Paus, is published today (8 May) in the open access journal PLOS Biology It shows that a drug originally designed as a treatment for osteoporosis has a dramatic stimulatory effect on human hair follicles donated by patients undergoing hair transplantation surgery. Currently only two drugs -- minoxidil and finasteride -- are available for treatment of male-pattern balding (androgenetic alopecia). However, both agents have moderate side effects and often produce disappointing hair regrowth results. The only other option available to patients is hair transplantation surgery. The PhD project, led by Dr Nathan Hawkshaw and colleagues, sought to develop new ways to promote human hair growth with the hope of finding novel, well-tolerated agents for treating androgenetic alopecia. The approach was to first identify the molecular mechanisms of an old immunosuppressive drug, Cyclosporine A (CsA). Cyclosporine A has been commonly used since the 1980s as a crucial drug that suppresses transplant rejection and autoimmune diseases. However, it often has severe side-effects, the least serious -- but most interesting -- of which is that it enhances cosmetically unwanted hair growth. The team carried out a full gene expression analysis of isolated human scalp hair follicles treated with CsA. This revealed that CsA reduces the expression of SFRP1, a protein that inhibits the development and growth of many tissues, including hair follicles. This identifies a completely novel mechanism of action of this old and widely used immunosuppressant. The research also explanains why CsA so often induces undesired hair growth in patients as it removes an inbuilt and potent molecular brake on human hair growth. The inhibitory mechanism is completely unrelated to CsA's immunosuppressive activities, making SFRP1 a new and highly promising therapeutic target for anti-hair loss strategies. After some detective work, Dr Hawkshaw found that a compound originally developed to treat osteoporosis, called WAY-316606, targets the same mechanism as CsA by specifically antagonising SFRP1. When he then treated hair follicles with WAY-316606, the unrelated agent also effectively enhanced human hair growth like CsA. The external application of WAY-316606 or similar compounds to balding human scalp, he argued, may promote hair growth to the same magnitude as CsA or even better, but without its side effects. Dr Hawkshaw said: "Thanks to our collaboration with a local hair transplant surgeon, Dr Asim Shahmalak, we were able to conduct our experiments with scalp hair follicles that had generously been donated by over 40 patients and were then tested in organ cultures. "This makes our research clinically very relevant, as many hair research studies only use cell culture." He added: "When the hair growth-promoting effects of CsA were previously studied in mice, a very different molecular mechanism of action was suggested; had we relied on these mouse research concepts, we would have been barking up the wrong tree. "The fact this new agent, which had never even been considered in a hair loss context, promotes human hair growth is exciting because of its translational potential: it could one day make a real difference to people who suffer from hair loss. "Clearly though, a clinical trial is required next to tell us whether this drug or similar compounds are both effective and safe in hair loss patients." |
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May 2024
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