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Huntingtin transports BDNF
Newsdesk Huntingtin transports BDNF The normal physiological role of huntingtin—the protein that is mutated by polyglutamine expansion in Huntington’s disease—in healthy people has been the subject of intense research. Now, Sandrine Humbert (Institut Curie, Orsay, France) and colleagues have shown that huntingtin enhances the transport of brainderived neurotrophic factor (BDNF) along microtubules within neurons. Patients with Huntington’s disease therefore have impaired BDNF vesicular transport, which leads to loss of neurons. “Cytoplasmic defects such as axonal transport, instead of nuclear dysfunction, may be the principle culprit of neuronal dysfunction in Huntington’s disease”, comments Troy Littleton (Massachusetts Institute of Technology, Cambridge, USA). Humbert and colleagues used extra fast 3-D videomicroscopy to study the distribution and dynamics of vesicles containing BDNF (Cell 2004; 118: 127–38). Extra fast 3-D video-
microscopy allows acquisition of many images from live samples. The time for image acquisition was important because these vesicles are fast-moving, averaging 8·62 m/min in control conditions. The researchers compared mouse neurons expressing wild-type huntingtin with those expressing mutant huntingtin and found that the velocity of BDNF-containing vesicles was reduced when huntingtin was mutated. Huntingtin’s role in assisting intracellular transport was confirmed in an experiment in which small interfering RNAs reduced the concentration of huntingtin; this was associated with reduced vesicle velocity, increased numbers of static vesicles, and reduced time spent moving. In the next series of studies, Humbert and colleauges investigated BDNF vesicular transport in Huntington’s disease. The researchers assessed primary cultures of cortical neurons, neurons derived from mice, and cortical and striatal postmortem
samples from human beings; vesicle velocity was greater when huntingtin was normal than when mutant. “Huntingtin stimulates BDNF transport and this function is lost when huntingtin contains the mutation that causes Huntington’s disease”, Humbert told The Lancet Neurology. “The authors have made an important contribution by identifying BDNF as a potential target of huntingtin-mediated axonal transport in mammals”, notes Littleton. “These findings could significantly change the current view that Huntington’s disease is solely a gain-of-function disease and may instead be exasperated by loss of the normal function of huntingtin in axonal transport. But”, he cautions, “it is still uncertain whether BDNF transport defects represent the sole, or even principle defect, in Huntington’s disease”. Humbert and co-workers are continuing their work on the rescue of BDNF when huntingtin is mutated. Gillian Carmichael
Gene mutations in rapid-onset dystonia parkinsonism identified Mutations in the Na+/K+ ATPase cause rapid-onset dystonia parkinsonism (RDP), a rare disorder that was first identified in 1993, says an international team of researchers. “We found six missense mutations in the ATP1A3 gene in seven different families”, says lead investigator Laurie Ozelius from the Albert Einstein College of Medicine (New York, NY, USA). “We hypothesise that the mutations result in haploinsufficiency, but we do not know how this causes the disease.” RDP affects adolescents and young adults suddenly and without warning following a stressful event such as infection, childbirth, or prolonged exercise. The symptoms are irreversible. William Dobyns and Allison Brashear first discovered the condition in 1993 in a large family that had 16 affected members. Six years later researchers at the
514
Massachussetts General Hospital used the family in a genome search and showed that the gene was linked to a large 8 cM region on chromosome 19q. Two other families were also identified. However, it wasn’t until the human genome was sequenced that the research was able to move forward. The researchers looked at the genes in the linked region and identified 260–300 genes that could potentially be affected. “This was a bit discouraging”, recalls Ozelius. “However, we decided to take the candidate gene approach and made some educated guesses based on expression and known function and came up with a list of genes.” The researchers screened eight genes before they found the mutations in ATP1A3 (Neuron 2004; 43: 169–75). Ozelius and her colleagues then used a combination of expression
studies, functional modelling and protein chemistry to investigate the pathophysiology of the ATP1A3 missense mutations in RDP. “While these results indeed suggest the RDP mutations result in loss of function defects, much remains to be established about the molecular details”, writes Stephen Cannon (University of Texas Southwestern Medical Center at Dallas) in an accompanying commentary (Neuron 2004; 43: 153–54). “Is the mutant protein properly folded, processed in the endoplasmic reticulum, and translocated to the plasma membrane? Inheritance of RDP is autosomal dominant. Is this mode of expression due to haploinsufficiency, or do mutant alpha3 subunits exert a dominant negative effect on the oligomeric Na+/K+ATPase complex?”, he asks. James Butcher
Neurology Vol 3 September 2004
http://neurology.thelancet.com
For personal use. Only reproduce with permission from Elsevier Ltd.
microscopy allows acquisition of many images from live samples. The time for image acquisition was important because these vesicles are fast-moving, averaging 8·62 m/min in control conditions. The researchers compared mouse neurons expressing wild-type huntingtin with those expressing mutant huntingtin and found that the velocity of BDNF-containing vesicles was reduced when huntingtin was mutated. Huntingtin’s role in assisting intracellular transport was confirmed in an experiment in which small interfering RNAs reduced the concentration of huntingtin; this was associated with reduced vesicle velocity, increased numbers of static vesicles, and reduced time spent moving. In the next series of studies, Humbert and colleauges investigated BDNF vesicular transport in Huntington’s disease. The researchers assessed primary cultures of cortical neurons, neurons derived from mice, and cortical and striatal postmortem
samples from human beings; vesicle velocity was greater when huntingtin was normal than when mutant. “Huntingtin stimulates BDNF transport and this function is lost when huntingtin contains the mutation that causes Huntington’s disease”, Humbert told The Lancet Neurology. “The authors have made an important contribution by identifying BDNF as a potential target of huntingtin-mediated axonal transport in mammals”, notes Littleton. “These findings could significantly change the current view that Huntington’s disease is solely a gain-of-function disease and may instead be exasperated by loss of the normal function of huntingtin in axonal transport. But”, he cautions, “it is still uncertain whether BDNF transport defects represent the sole, or even principle defect, in Huntington’s disease”. Humbert and co-workers are continuing their work on the rescue of BDNF when huntingtin is mutated. Gillian Carmichael
Gene mutations in rapid-onset dystonia parkinsonism identified Mutations in the Na+/K+ ATPase cause rapid-onset dystonia parkinsonism (RDP), a rare disorder that was first identified in 1993, says an international team of researchers. “We found six missense mutations in the ATP1A3 gene in seven different families”, says lead investigator Laurie Ozelius from the Albert Einstein College of Medicine (New York, NY, USA). “We hypothesise that the mutations result in haploinsufficiency, but we do not know how this causes the disease.” RDP affects adolescents and young adults suddenly and without warning following a stressful event such as infection, childbirth, or prolonged exercise. The symptoms are irreversible. William Dobyns and Allison Brashear first discovered the condition in 1993 in a large family that had 16 affected members. Six years later researchers at the
514
Massachussetts General Hospital used the family in a genome search and showed that the gene was linked to a large 8 cM region on chromosome 19q. Two other families were also identified. However, it wasn’t until the human genome was sequenced that the research was able to move forward. The researchers looked at the genes in the linked region and identified 260–300 genes that could potentially be affected. “This was a bit discouraging”, recalls Ozelius. “However, we decided to take the candidate gene approach and made some educated guesses based on expression and known function and came up with a list of genes.” The researchers screened eight genes before they found the mutations in ATP1A3 (Neuron 2004; 43: 169–75). Ozelius and her colleagues then used a combination of expression
studies, functional modelling and protein chemistry to investigate the pathophysiology of the ATP1A3 missense mutations in RDP. “While these results indeed suggest the RDP mutations result in loss of function defects, much remains to be established about the molecular details”, writes Stephen Cannon (University of Texas Southwestern Medical Center at Dallas) in an accompanying commentary (Neuron 2004; 43: 153–54). “Is the mutant protein properly folded, processed in the endoplasmic reticulum, and translocated to the plasma membrane? Inheritance of RDP is autosomal dominant. Is this mode of expression due to haploinsufficiency, or do mutant alpha3 subunits exert a dominant negative effect on the oligomeric Na+/K+ATPase complex?”, he asks. James Butcher
Neurology Vol 3 September 2004
http://neurology.thelancet.com
For personal use. Only reproduce with permission from Elsevier Ltd.