Researchers from Oregon Health and Science University (OR, USA) have identified the gene behind the neuroaxonal dystrophies (a category of several rare, genetic disorders) caused by a build up of iron in the brain. As other neurological diseases, including Alzheimer’s and Parkinson’s disease, are also associated with an accumulation of iron in the brain, it is hoped that this finding could have an impact on our understanding of nerve cell degeneration.
Mutations in the PLA2G6 gene have been found responsible for infantile neuroaxonal dystrophy (INAD) and a related disorder, neurodegeneration with brain iron accumulation (NBIA). An international team of geneticists discovered the PLA2G6 gene’s identity from DNA of families of children with INAD or NBIA.
The symptoms of INAD, also known as Seitelberger disease, start by the age of 2 years and worsen progressively with time. These include loss of head control and motor abilities, and deteriorating vision and speech. Diagnosis of INAD is confirmed usually by tissue biopsy to assess the presence of characteristic spheroid bodies in the nerve axons. Eventually, children lose awareness and understanding of their surroundings. The combination of brain disease and physical weakness will lead to the child’s death, usually between the ages of 5 and 10 years.
NBIA, or Hallervorden–Spatz syndrome, usually manifests during teenage years. Symptoms vary among patients, but often include distorting muscle contractions, spasticity, seizures or muscle rigidity. Most patients go through periods of rapid deterioration (lasting 1–2 months) followed by periods of stability. Children with an earlier onset of the disease generally have a worse prognosis than those with later onset.
Both INAD and NBIA are recessive, degenerative diseases, with no known cure or standard therapy. Symptoms are treated as they occur, often with the help of physiotherapists and specialist teachers. Stimulation that does not depend on visual cues can also be beneficial and some parents also turn to complementary or alternative medicines. The disorders are rare, with an incidence as low as one in 500,000 to a million. As a direct outcome of this research, a clinical test could be developed that would help families to determine their chances of passing the disease onto their children.
These disorders are due to a build up of iron in the basal ganglia. This build up, in turn, causes the axons to swell, which interrupts the signal sent to nearby nerve cells. PLA2G6 is a lipid metabolizing gene, thought to encode an enzyme that breaks down lipids involved in reconstruction of cell membranes following damage by light or other toxins. Mutations in the gene alter lipid metabolism, causing the build up of iron that triggers disease.
In collaboration with researchers from the University of Birmingham, UK, DNA from 30–40 affected families was collected. This narrowed the search down to a block of DNA on chromosome 22. A 100-gene block of interest was thoroughly investigated and the field narrowed to just 75 possible genes. Confirmation for the findings came from new patients diagnosed with INAD who also had different, but severe mutations in the same gene.
Researchers claim that this research links PLA2 ‘unequivocally’ with neurodegeneration. Similar metabolic changes are observed in neurodegeneration caused by, for example, such as ischemia from stroke, head injury or Alzheimer’s disease. Thus, this metabolic pathway is a potential drug target for many, more common neurodegenerative disorders.
Dancing the blues away
A research project in Sweden has used dance as a therapeutic strategy for children and adolescents with various mental disorders, including those with attention deficit–hyperactivity disorder, depression or self-harming tendencies.
Six boys, aged between 5 and 7 years, were enrolled in ten sessions of dance therapy, once weekly, over a period of 3 months. The sessions began at ‘full throttle’, followed by components of mimicking, role playing and slower moves. Both parents and teachers reported an improvement in their behavior. The children were calmer and better able to play with classmates without getting into fights.
A group of 11 girls, aged 13–17 years, were also involved in a separate pilot study of dance therapy. Researchers found that dance was a good medium for reaching teenage girls, who may be unwilling to speak about their problems. The therapy is “a good way to crank up the energy and joy of living” according to lead researcher, Erna Grönlund (University College of Dance, Stockholm, Sweden). Grönlund explained that certain dance exercise can be about feelings of self esteem and pride. After the study period, the girls were less depressed and more able to set limits.
While results from both pilot studies were positive, the researchers caution that this was a small sample group and further follow-up studies are necessary. However, as many families requested that the therapy be continued, it is hoped that dance therapy will provide an alternative treatment when traditional treatments are ineffective or insufficient.
A cure for Huntington’s disease?
New research has successfully halted the onset of Huntington’s-like neurodegeneration in a mouse model of the disease.
Researchers from the University of British Colombia (Canada) have prevented the cleavage of the mutant huntingtin protein in a mouse model of Huntington’s disease (HD) to stop the appearance of degenerative symptoms of the disease. This offers hope for the thousands of people carrying the mutated gene responsible for HD.
HD is currently recognized as one of the most common genetic disorders. The gene responsible for HD was identified in 1993. More than 200,000 people in the USA either suffer from HD or are ‘at risk’ through having the faulty gene that causes the disease. The symptoms of HD usually develop in an individual’s mid life (usually between the ages of 30 and 45 years). At present, there is no cure available for HD and treatment is limited to methods of controlling the associated emotional or motor problems caused by the degeneration of neurons.
A hypothesis was put forward 10 years ago, that huntingtin (the protein responsible for HD) cleavage may play a key part in disease development. This latest research provides compelling evidence to support this hypothesis. To investigate the role of huntingtin cleavage in HD, the team from the University of British Colombia used a mouse model of HD. Uniquely, the model used contains the mutant human HD gene in the same manner as in human patients. Disease progression could then be examined and cleavage of the huntingtin protein was duly noted. It was found that this cleavage is caused by an enzyme, caspase-6. When researchers blocked the actions of caspase-6, mice did not exhibit HD symptoms but retained normal brain function.
These results have generated much optimism in the HD community; many see this as a milestone in HD research and hope that we are now approaching an effective treatment and potential cure for this intractable disease. All eyes will now be on the future work of this team as they further test this model of prevention.
Stem cell therapy restores function in paralyzed rats
A team from Johns Hopkins medical institute (MD, USA) has demonstrated the regenerative power of stem cells in an animal model of virus-induced paralysis. The results suggest that this may potentially be a viable therapy for disorders such as spinal cord injury, multiple sclerosis, amyotrophic lateral sclerosis or transverse myelitis.
The study provides proof of principle for the ability of stem cells to successfully engineer fully functioning motor neuron circuits. Aggressive infection with Sindbis virus, a virus that specifically targets and kills motor neurons, caused a loss of motor function in the rodents. Eight groups of paralyzed rats were then treated with cultured embryonic stem cells plus a ‘recipe’ of other chemicals – rolipram, dibutyrl cyclic adenosine monophosphate (dbcAMP) and glial cell-derived neurotrophic factor (GDNF).
The aim of extending new motor neurons in an adult nervous system is, understandably, fraught with many obstacles. Each treatment component was added to overcome a specific hurdle, for example myelin. Myelin insulates nerve fibres, allowing the signals to travel over distances. However, once myelin has been laid down, it also acts as an inhibitor of further nerve growth. Rolipram (a drug developed recently and approved for the treatment of depression) and dbcAMP enabled this inhibitory action to be overcome. A second major problem is that of encouraging the neurons to grow in the right direction. Previous work by this team suggested that application of GDNF may be beneficial as it is a stimulator of neuron growth. By transplanting GDNF into the sciatic nerve (near its former leg contacts), the researchers hoped to draw the axons towards the muscles. Results showed that all four ‘ingredients’ had to be present for recovery.
The rats were examined 3 months after treatment for signs of the survival and integration of stem cell-derived neurons. Rats that had received the full complement of therapy had many more transplant-derived axons extending into the peripheral nervous system than any other group. In this group, functional synapses had been generated and, 4 months post transplantation, an approximately 50% improvement in hind leg function was observed. Follow-up experiments were conducted, where GDNF treatment was administered to only one side of the body. These showed that 6 months post transplantation, 75% of rats receiving the full combination of treatment had regained the ability to bear weight, take steps and push away with the GDNF-treated leg.
These results are certainly promising, but there remains a long way to go before something similar can be tested in human patients. The group is working on a larger animal (pig) model to further test and refine the technique. Further answers regarding tumor formation and the safety of surgery are also needed. If the future work continues as hoped, we are on the way to reaching the goal of regrowing healthy motor circuits, potentially helping those afflicted with different degenerative diseases.