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Researchers uncover a shared mechanism for protein aggregation disorders
SCIENCE AND MEDICINE
Researchers identify genes involved in the inheritance of osteoarthritis new assessment of hand osteoarthritis (OA) in the Framingham Heart Study cohort has identified chromosomal sites harbouring genes for susceptibility to OA. “A lot of hand OA is inherited, and this research is a step on the road to defining which genes increase the susceptibility to the disease in the hand and in other joints”, senior researcher David Felson (Boston University, MA, USA) told The Lancet. “If this research leads to the identification of one or more genes for OA, it could lead to [the development of] a diagnostic test. If it identifies a pathophysiological pathway that produces OA, it could lead to treatment in those whose disease is caused by this pathway.” Felson and colleagues assessed the hand joints of 684 original participants of the Framingham Heart Study (mean age 62 years) and compared them with 793 of their offspring (mean age 54 years), based on features ascertained by
radiographs that included Kellgren/ Lawrence (K/L), osteophyte, and joint space narrowing scores, and proportion of affected joints. DNA
Rights were not granted to include this image in electronic media. Please refer to the printed journal. A handy diagnostic tool
samples extracted from whole blood or buffy coat specimens were used for phenotyping, results of which were adjusted for age. Overall, 50% of the original cohort and 30% of their offspring had at least one joint affected by OA. Heritability ranged from 28%, based on the proportion of joints affected, to 34%, based on the sum of K/L scores. Eight chromosomal regions were identified as being
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likely to have a role in the inheritance of OA (Arthritis Rheum 2002; 46: 946–52). According to Stephen Paget (Hospital for Special Surgery and Weill Medical College of Cornell University, New York, NY, USA), “this is supportive of many years of rheumatologist experience of the genetic association [of OA]. There are many possible regions that may represent a genetic linkage with OA, and certainly larger studies need to be done to confirm them . . . This goes one extra step in defining the genetic linkage.” Paget says that identifying genes linked to OA could lead to the development of screening tests for individuals with a family history of the disorder. The results could also be used to decide whether people in affected families should participate in activities known to increase the risk of developing OA, and whether preventive drugs should be taken if they become available, he adds. Alison Palkhivala
Researchers uncover a shared mechanism for protein aggregation disorders here has been much debate as to whether the pathological effects of protein aggregation disorders, such as Alzheimer’s disease and Creutzfeldt-Jakob disease, are caused by the aggregates themselves, or whether the accumulation of aggregates is a consequence of the disease. Two independent teams of researchers have now provided key evidence that toxicity results from the small aggregates that form initially, before they assemble into fibrils or plaques. Chris Dobson (Cambridge University, UK), Massimo Stefani (University of Florence, Italy), and their colleagues persuaded two normally harmless proteins to form aggregates by incubating them under carefully controlled conditions. They found that small amorphous aggregates or short “protofibrils”, which formed before the well defined fibrillar structures, were toxic to cells but the mature fibrils were not (Nature 2002; 416: 507–11). The researchers suggest that it is not the sequence of the proteins comprising the aggregates that causes pathological effects. “Rather, it is the fact that these small aggregates tend to bind to cells, or cell components, in a non-functional manner—as their structures are not
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folded correctly and so expose ‘sticky’ regions on the surface—that causes disease. In the mature fibrils or plaques, these ‘sticky’ regions are largely buried in the larger assemblies”, explains Dobson. “Our results suggest that different aggregation diseases are caused by the same basic problem—misfolding creates species that can be toxic to cells as well as being non-functional and potentially disruptive to the organs involved.” Jeff Kelly (Scripps Research Institute, La Jolla, CA, USA) comments that these finding imply that aggregates of other polypeptides, not just the 20 or so known to be involved in amyloid disease, could also have deleterious effects. He adds: “Efficient methods need to be conceived that prevent misfolded proteins from forming oligomeric non-fibrillar protein assemblies. While the toxicity of nonfibrillar protein aggregates derived from human amyloid proteins is well established in the literature, this work suggests that there may be more misfolding diseases that are not associated with obvious amyloid deposition.” Meanwhile, Dennis Selkoe (Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, USA) and colleagues
found that cerebral microinjection of oligomers of the amyloid beta (A) protein, which form naturally soon after the generation of the peptide and are then secreted from the cell, inhibit long-term potentiation in vivo—a key element in memory (Nature 2002; 416: 535–39). “Previous research by many scientists had linked A in general to interruption of ‘memory switches’, but precisely which form of the protein was involved, and how this occurred under natural conditions, remained obscure”, Selkoe explains. “We now identify a specific form of A and show directly in living anaesthetised rats how it interrupts memory circuits in the brain.” Kelly comments that Selkoe’s findings could have important therapeutic implications. “Compounds that reduce intravesicular self-assembly by lowering A concentrations, or the distribution of aggregation-prone species, should be useful”, he says. “In contrast, compounds now under evaluation by numerous pharmaceutical companies that prevent the maturation of aggregates into fibrils may in fact exacerbate pathology if these findings hold up.” Helen Frankish
THE LANCET • Vol 359 • April 6, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Researchers identify genes involved in the inheritance of osteoarthritis new assessment of hand osteoarthritis (OA) in the Framingham Heart Study cohort has identified chromosomal sites harbouring genes for susceptibility to OA. “A lot of hand OA is inherited, and this research is a step on the road to defining which genes increase the susceptibility to the disease in the hand and in other joints”, senior researcher David Felson (Boston University, MA, USA) told The Lancet. “If this research leads to the identification of one or more genes for OA, it could lead to [the development of] a diagnostic test. If it identifies a pathophysiological pathway that produces OA, it could lead to treatment in those whose disease is caused by this pathway.” Felson and colleagues assessed the hand joints of 684 original participants of the Framingham Heart Study (mean age 62 years) and compared them with 793 of their offspring (mean age 54 years), based on features ascertained by
radiographs that included Kellgren/ Lawrence (K/L), osteophyte, and joint space narrowing scores, and proportion of affected joints. DNA
Rights were not granted to include this image in electronic media. Please refer to the printed journal. A handy diagnostic tool
samples extracted from whole blood or buffy coat specimens were used for phenotyping, results of which were adjusted for age. Overall, 50% of the original cohort and 30% of their offspring had at least one joint affected by OA. Heritability ranged from 28%, based on the proportion of joints affected, to 34%, based on the sum of K/L scores. Eight chromosomal regions were identified as being
Science Photo Library
A
likely to have a role in the inheritance of OA (Arthritis Rheum 2002; 46: 946–52). According to Stephen Paget (Hospital for Special Surgery and Weill Medical College of Cornell University, New York, NY, USA), “this is supportive of many years of rheumatologist experience of the genetic association [of OA]. There are many possible regions that may represent a genetic linkage with OA, and certainly larger studies need to be done to confirm them . . . This goes one extra step in defining the genetic linkage.” Paget says that identifying genes linked to OA could lead to the development of screening tests for individuals with a family history of the disorder. The results could also be used to decide whether people in affected families should participate in activities known to increase the risk of developing OA, and whether preventive drugs should be taken if they become available, he adds. Alison Palkhivala
Researchers uncover a shared mechanism for protein aggregation disorders here has been much debate as to whether the pathological effects of protein aggregation disorders, such as Alzheimer’s disease and Creutzfeldt-Jakob disease, are caused by the aggregates themselves, or whether the accumulation of aggregates is a consequence of the disease. Two independent teams of researchers have now provided key evidence that toxicity results from the small aggregates that form initially, before they assemble into fibrils or plaques. Chris Dobson (Cambridge University, UK), Massimo Stefani (University of Florence, Italy), and their colleagues persuaded two normally harmless proteins to form aggregates by incubating them under carefully controlled conditions. They found that small amorphous aggregates or short “protofibrils”, which formed before the well defined fibrillar structures, were toxic to cells but the mature fibrils were not (Nature 2002; 416: 507–11). The researchers suggest that it is not the sequence of the proteins comprising the aggregates that causes pathological effects. “Rather, it is the fact that these small aggregates tend to bind to cells, or cell components, in a non-functional manner—as their structures are not
T
1214
folded correctly and so expose ‘sticky’ regions on the surface—that causes disease. In the mature fibrils or plaques, these ‘sticky’ regions are largely buried in the larger assemblies”, explains Dobson. “Our results suggest that different aggregation diseases are caused by the same basic problem—misfolding creates species that can be toxic to cells as well as being non-functional and potentially disruptive to the organs involved.” Jeff Kelly (Scripps Research Institute, La Jolla, CA, USA) comments that these finding imply that aggregates of other polypeptides, not just the 20 or so known to be involved in amyloid disease, could also have deleterious effects. He adds: “Efficient methods need to be conceived that prevent misfolded proteins from forming oligomeric non-fibrillar protein assemblies. While the toxicity of nonfibrillar protein aggregates derived from human amyloid proteins is well established in the literature, this work suggests that there may be more misfolding diseases that are not associated with obvious amyloid deposition.” Meanwhile, Dennis Selkoe (Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, USA) and colleagues
found that cerebral microinjection of oligomers of the amyloid beta (A) protein, which form naturally soon after the generation of the peptide and are then secreted from the cell, inhibit long-term potentiation in vivo—a key element in memory (Nature 2002; 416: 535–39). “Previous research by many scientists had linked A in general to interruption of ‘memory switches’, but precisely which form of the protein was involved, and how this occurred under natural conditions, remained obscure”, Selkoe explains. “We now identify a specific form of A and show directly in living anaesthetised rats how it interrupts memory circuits in the brain.” Kelly comments that Selkoe’s findings could have important therapeutic implications. “Compounds that reduce intravesicular self-assembly by lowering A concentrations, or the distribution of aggregation-prone species, should be useful”, he says. “In contrast, compounds now under evaluation by numerous pharmaceutical companies that prevent the maturation of aggregates into fibrils may in fact exacerbate pathology if these findings hold up.” Helen Frankish
THE LANCET • Vol 359 • April 6, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.