- Email: [email protected]
New mechanism for inclusion formation in neurodegeneration
Newsdesk
Researchers reasoned that the presence of -amyloid fragments prompted inflammatory cells to attack the brain, so future vaccines would need to circumvent this problem. Masliah hopes to identify and produce a recombinant antibody against synuclein that could be injected directly into patients, reducing the risk of side effects. Hopes are high that vaccines will prove a viable therapy. A follow-up study on the vaccinated Alzheimer’s patients suggested that, side-effects apart, the treatment might slow cognitive decline (Neuron 2003; 38: 1–20). Masliah has yet to assess his vaccine’s effect on parkinsonian symptoms in mice, but hopes that it will improve motor skills. And whereas the Alzheimer’s vaccine targeted extracellular protein plaques, the Parkinson’s vaccine targets protein found within the cell.
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
©Lysia Forno/Science Photo Library
Masliah thinks that the vaccine targets abnormal -synuclein oligomers rather than Lewy bodies, and that these smaller, membrane-bound fragments are the toxic element behind PD. But the theory is controversial and the role of synuclein aggregates in PD remains uncertain. Strategies that aim to remove the abnormal protein might have unpredictable results in humans, cautions Manuel Graeber (Imperial College, London). The study, which was partially funded by Elan Pharmaceuticals, comes after the company’s aborted 2002 Alzheimer’s vaccine clinical trial. Patients were injected with -amyloid protein to encourage their bodies to make antibodies against the -amyloid plaques characteristic of Alzheimer’s disease. But the trial was halted when a handful of patients developed brain inflammation.
synuclein forms the Lewy bodies characteristic of Parkinson’s disease
“It’s a completely new dimension”, says Masliah. The study shows that vaccines can affect intracellular proteins and that a vaccine-based treatment for PD is a possibility.
Helen Pilcher
New mechanism for inclusion formation in neurodegeneration Failure to clear aggregation-prone proteins from neurons efficiently may contribute to some forms of motor neuron disease (MND) that are caused by mutations affecting dynein activity, report David Rubinsztein from the Cambridge Institute for Medical Research (UK) and his colleagues. The researchers show that defects in the dynein machinery impair the autophagic clearance of aggregationprone proteins from neurons. “Our results”, says Rubinsztein, “suggest that speeding up this clearance process in diseases where aggregation-prone proteins are mutated, such as Huntington’s or familial Parkinson’s disease, might provide a therapeutic strategy”. The molecular basis for most MNDs is unknown but mutations in genes that regulate dynein-mediated transport cause MND-like pathology in mice and human beings. Within cells, explains Rubinsztein, “dyneins act as engines to move cargos along http://neurology.thelancet.com Vol 4 August 2005
microtubule ‘railway lines’ from the cell’s periphery towards its centre”. Rubinsztein’s starting place for his current study was the observation that mice with dynein mutations develop intraneuronal aggregates resembling those seen in Huntington’s and Parkinson’s disease, even though huntingtin and synuclein, respectively, are normal in these mice. “We wanted to know why aggregates formed in this mouse model and exactly how cells normally remove aggregation-prone proteins”, says Rubinsztein. “We knew that aggregation-prone proteins are cleared from cells by autophagy, a process where the cell enwraps part of its cytosol in a double-layered membrane and transports it to lysosomes for degradation, so could defects in dynein function slow down autophagy?” The researchers used genetic and chemical inhibition of dynein function in tissue culture and in mouse and fly models of Huntington’s disease to
show that dynein defects do indeed slow down the autophagic clearance of aggregation-prone proteins (Nat Genet; published online June 26, DOI: 10.1038/ng1591). “In cells with dynein mutations autophagosomes formed”, says Rubinsztein, “but failed to fuse efficiently with lysosomes. It was like the cell could load garbage on to rubbish trucks but these got stuck in a traffic jam on the way to the dump.” “Aggregates and inclusions are hallmarks of many neurodegenerative diseases”, comments Erika Holzbaur (University of Pennsylvania, Philadelphia, PA, USA), “and this paper describes an interesting new pathway that may contribute to the pathogenic process. A better understanding of aggregate formation”, she adds, “and of the processes that may inhibit the cell’s ability to clear aggregates, is crucial to the improved design of neuroprotective drugs”.
Jane Bradbury 459
Researchers reasoned that the presence of -amyloid fragments prompted inflammatory cells to attack the brain, so future vaccines would need to circumvent this problem. Masliah hopes to identify and produce a recombinant antibody against synuclein that could be injected directly into patients, reducing the risk of side effects. Hopes are high that vaccines will prove a viable therapy. A follow-up study on the vaccinated Alzheimer’s patients suggested that, side-effects apart, the treatment might slow cognitive decline (Neuron 2003; 38: 1–20). Masliah has yet to assess his vaccine’s effect on parkinsonian symptoms in mice, but hopes that it will improve motor skills. And whereas the Alzheimer’s vaccine targeted extracellular protein plaques, the Parkinson’s vaccine targets protein found within the cell.
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
©Lysia Forno/Science Photo Library
Masliah thinks that the vaccine targets abnormal -synuclein oligomers rather than Lewy bodies, and that these smaller, membrane-bound fragments are the toxic element behind PD. But the theory is controversial and the role of synuclein aggregates in PD remains uncertain. Strategies that aim to remove the abnormal protein might have unpredictable results in humans, cautions Manuel Graeber (Imperial College, London). The study, which was partially funded by Elan Pharmaceuticals, comes after the company’s aborted 2002 Alzheimer’s vaccine clinical trial. Patients were injected with -amyloid protein to encourage their bodies to make antibodies against the -amyloid plaques characteristic of Alzheimer’s disease. But the trial was halted when a handful of patients developed brain inflammation.
synuclein forms the Lewy bodies characteristic of Parkinson’s disease
“It’s a completely new dimension”, says Masliah. The study shows that vaccines can affect intracellular proteins and that a vaccine-based treatment for PD is a possibility.
Helen Pilcher
New mechanism for inclusion formation in neurodegeneration Failure to clear aggregation-prone proteins from neurons efficiently may contribute to some forms of motor neuron disease (MND) that are caused by mutations affecting dynein activity, report David Rubinsztein from the Cambridge Institute for Medical Research (UK) and his colleagues. The researchers show that defects in the dynein machinery impair the autophagic clearance of aggregationprone proteins from neurons. “Our results”, says Rubinsztein, “suggest that speeding up this clearance process in diseases where aggregation-prone proteins are mutated, such as Huntington’s or familial Parkinson’s disease, might provide a therapeutic strategy”. The molecular basis for most MNDs is unknown but mutations in genes that regulate dynein-mediated transport cause MND-like pathology in mice and human beings. Within cells, explains Rubinsztein, “dyneins act as engines to move cargos along http://neurology.thelancet.com Vol 4 August 2005
microtubule ‘railway lines’ from the cell’s periphery towards its centre”. Rubinsztein’s starting place for his current study was the observation that mice with dynein mutations develop intraneuronal aggregates resembling those seen in Huntington’s and Parkinson’s disease, even though huntingtin and synuclein, respectively, are normal in these mice. “We wanted to know why aggregates formed in this mouse model and exactly how cells normally remove aggregation-prone proteins”, says Rubinsztein. “We knew that aggregation-prone proteins are cleared from cells by autophagy, a process where the cell enwraps part of its cytosol in a double-layered membrane and transports it to lysosomes for degradation, so could defects in dynein function slow down autophagy?” The researchers used genetic and chemical inhibition of dynein function in tissue culture and in mouse and fly models of Huntington’s disease to
show that dynein defects do indeed slow down the autophagic clearance of aggregation-prone proteins (Nat Genet; published online June 26, DOI: 10.1038/ng1591). “In cells with dynein mutations autophagosomes formed”, says Rubinsztein, “but failed to fuse efficiently with lysosomes. It was like the cell could load garbage on to rubbish trucks but these got stuck in a traffic jam on the way to the dump.” “Aggregates and inclusions are hallmarks of many neurodegenerative diseases”, comments Erika Holzbaur (University of Pennsylvania, Philadelphia, PA, USA), “and this paper describes an interesting new pathway that may contribute to the pathogenic process. A better understanding of aggregate formation”, she adds, “and of the processes that may inhibit the cell’s ability to clear aggregates, is crucial to the improved design of neuroprotective drugs”.
Jane Bradbury 459