Transgene Triggers Parkinsonian Neurodegeneration

SELECTIVE DISAPPEARANCE: Compared to nontransgenic controls, transgenic (tg) mice that express human a-synuclein (SYN) show a loss of dopa-minergic terminals in the brain's basal ganglia, which include the striatum. In the half-decade after human a- synuclein (ha-syn) was discovered in amyloid plaques purified from brains of patients with Alzheimer,1 neuroscientists logically suspected that this synaptic protein played a role in Alzheimer disease. Codiscoverer Eliezer Masliah began to develop an ha-syn transgenic mouse in 1996 that he hoped would serve as an Alzheimer model. Over the next two years, however, views about ha-syn underwent a radical makeover. Studies linked mutations in its gene to Parkinson disease and identified the protein in aggregates, known as Lewy bodies, which form inside neurons in Parkinson and other neurodegenerative disorders; ha-syn's role in Alzheimer disease appeared, in comparison, less compelling. Researchers began to envision an ha-syn mouse as the first transgenic Parkinson model. Masliah, a professor of neurosciences and pathology at the University of California, San Diego, published what he claims was the first report of an ha-syn mouse in this Hot Paper.2 The achievement was hard-won, he recalls, because a transgene can have unpredictable effects, depending on which promoter and which stretches of the gene are used. "We had to try a lot of different combinations until we came up with something that worked," he says. Several features of Masliah's mice conformed to expectations. For example, ha-syn aggregates developed in neurons of the cortex, hippocampus, and substantia nigra, a brain region devastated by Parkinson disease. Moreover, the mice that expressed high transgene levels also exhibited motor deficits, as do patients with Parkinson disease. Data derived from the Science Watch/Hot Papers database and the Web of Science (ISI, Philadelphia) show that Hot Papers are cited 50 to 100 times more often than the average paper of the same type and age. E. Masliah et al., "Dopaminergic loss and inclusion body formation in a-synuclein mice: implications for neurodegenerative disorders," Science, 287:1265-9, Feb. 18, 2000. (Cited in 87 papers) One observation, however, raised doubts: None of the animals manifested the neuronal loss seen in patients with the disease. Masliah touts this feature of his model as an asset, noting that "the first thing that happens in neurodegenerative diseases isn't that neurons die." Early-stage Parkinson disease, he observes, is instead characterized by synaptic loss in the brain's striatum, which is the endpoint for the axons of the dopamine-releasing neurons of the substantia nigra. These neuronal terminals deteriorate. Masliah's highest transgene-expressing mice similarly showed a significant reduction in dopaminergic nerve terminals in the striatum. Another apparent deficit in Masliah's mice is actually an asset, contends Peter T. Lansbury Jr., an associate neurology professor at Harvard Medical School. Unlike Lewy bodies, which are fibrillar, the h a-syn aggregates in the mouse neurons lacked fibrils, possibly, he surmises, because of interactions between transgenic and endogenous a-syn. Masliah's model "shows that you can induce disease-like phenotypes without progressing to this end-stage fibril," says Lansbury. "Our work, which is all in vitro biochemistry, has really focused on the idea that it is these early aggregates, which we call protofibrils, that are toxic." Lansbury hypothesizes that tiny toxic protofibrils have a high affinity for cellular membranes. Upon incorporation into a membrane, the protofibrils form pores that cause depolarization and other cellular disasters. By sequestering ha-syn, the fibrillar Lewy bodies, in contrast, might protect cells. In the past two years, Masliah has moved on to creating double-transgenic mice. One model expressed both ha-syn and the B-amyloid precursor protein whose AB fragment is implicated in Alzheimer disease.3 The mice showed a significant loss of cholinergic neurons. Another model churned out ha-syn and a close homologue, hB-synuclein, which lacks an amyloidogenic domain.4 The double transgenics exhibited fewer motor deficits and intraneuronal aggregates and less neurodegeneration than did ha-syn mice. These findings suggest that hB-syn can counteract ha-syn's toxicity. Lansbury consequently is seeking drug-like molecules that will boost the expression of endogenous B-syn as a possible treatment for Parkinson disease. Masliah asserts that a unified Parkinson theory is emerging. It holds that Parkinson disease strikes when ha-syn is impacted by mutations of its gene or by environmental elements, such as certain pesticides, oxidative stress, or too much ambient AB. According to the theory, disease can also result from mutations of proteins, such as parkin, that interact, even indirectly, with ha-syn. Douglas Steinberg (dougste@attglobal.net) is a freelance writer in New York City. References 1. K. Uéda et al., "Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease," Proceedings of the National Academy of Sciences (PNAS), 90:11282-6, 1993. 2. E. Masliah et al., "Dopaminergic loss and inclusion body formation in a-synuclein mice: implications for neurodegenerative disorders," Science, 287:1265-9, Feb. 18, 2000. (Cited in 182 papers) 3. E. Masliah et al., "B-amyloid peptides enhance a- synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease," PNAS, 98:12245-50, 2001. 4. M. Hashimoto et al., "B-synuclein inhibits a-synuclein aggregation: a possible role as an anti-parkinsonian factor," Neuron, 32:213-23, 2001.

Transgene Triggers Parkinsonian Neurodegeneration

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