Adult mice don’t need the gene that, when mutated in humans, causes the inherited neurodegenerative disorder Huntington’s disease.Â The finding suggests that treatment strategies for Huntington’s that aim to shut off the huntingtin gene in adults — now in early clinical stages — could be safe.
The results were publishedÂ Monday, March 7 inÂ PNAS.
How HD gene silencing is supposed to work. The Emory study didn’t test this approach directly, but the Emory studyÂ has implications for what types of side effects HD gene silencingÂ may have in humans. Image from HDBuzz.net via Creative Commons.
Huntington’s disease is caused by a gene encoding a toxic protein (mutant huntingtin) that causes brain cells to die. Symptoms commonly appear in mid-life and include uncontrolled movements, balance problems, mood swings and cognitive decline. A juvenile form of Huntington’s disease also can appear during the teenage years.
Researchers led by Xiao-Jiang Li, MD, PhD and Shihua Li, MD, at Emory University School of Medicine, used genetically engineered mice in which the huntingtin gene can be deleted, triggered only when the mice are given the drug tamoxifen. Note: these mice don’t produce toxic mutant huntingtin protein.
When the huntingtin gene is deleted at an age older than four months, these mice appeared to stay healthy, despite having lost their huntingtin genes in cells all over their bodies. They maintained their body weight and could complete tests of movement and grip strength as well as control mice.Â In contrast with adults, engineered mice younger than four months old whose huntingtin gene was deleted developed lethal pancreatitis.
Those of us who are old enough to remember vinyl records will recall how a scratch can cause the same sounds to repeat many times. A similar type of genetic glitch causes neurodegenerative diseases such as Huntingtonâ€™s and several forms of spinocerebellar ataxia.
Huntingtonâ€™s and the spinocerebellar ataxias are known as â€œpolyglutamineâ€ diseases. In each, the affected gene has a stretch where the same three DNA letters are repeated several times — more than usual. As a result, the protein encoded by the affected gene has a patch, where only the building block glutamine can be found, disrupting that proteinâ€™s usual functions in the body.
Geneticist Xiao-Jiang Li and colleagues recently published a paper in Cell Reports that may explain why more aggressive juvenile-onset forms of polyglutamine diseases have different symptoms and pathology. Read more
The word “chaperone” refers to an adult who keeps teenagers from acting up at a dance or overnight trip. It also describes a type of protein that can guard the brain against its own troublemakers: misfolded proteins that are involved in several neurodegenerative diseases.
Researchers at Emory University School of Medicine led by Shihua Li, MD, and Xiao-Jiang Li, MD, PhDÂ have demonstrated that as animals age, their brains are more vulnerable to misfolded proteins, partly because of a decline in chaperone activity.
The researchers were studying a model of spinocerebellar ataxia, but the findings have implications for understanding other diseases, such as Alzheimer’s, Parkinson’s and Ray Ban outlet Huntington’s. They also identified targets for potential therapies: bolstering levels of either a particular chaperone or a growth factor in brain cells can protect against the toxic effects of misfolded proteins.
The results were published recently in the journalÂ Neuron. Read more