Intranuclear Neuronal Inclusions: A Common Pathogenic Mechanism for Glutamine-Repeat Neurodegenerative Diseases?

The unexpected discovery of inclusion bodies in the polyglutamine disorders, and the clear demonstration that polyglutamine-containing proteins can aggregate, indicate that these polyglutamine disorders are more similar to each other than was previously anticipated and may be related to other neurodegenerative disorders. As is described in the accompanying review (Lansbury, 1997 [this issue of Neuron]), protein aggregation is a common mechanism in other late-onset neurodegenerative diseases, including Alzheimer's disease, prion disease, and Parkinson's disease. Shared mechanisms or shared biological modifiers may underlie several of these diseases. Cross-fertilization among investigators working on these various disorders is bound to lead to rapid advances in our understanding of the pathogenesis of these diseases.Figure 1Tentative Model for Generation of Intranuclear Inclusions in Polyglutamine Diseases, Focusing on HD(1) The normal protein, with its normal-length glutamine repeat.(2) The expanded glutamine repeat undergoes a conformational change, presumably due to hairpin formation via a polar zipper. Interactions with other proteins such as HAP1 and HIP1 are altered, possibly resulting in pathological events within the cytoplasm.(3) The protein with the expanded glutamine repeat undergoes proteolytic cleavage, via caspase 3 or other enzymes. Dystrophic neurites form in the cytoplasm (data not shown).(4) The N-terminal fragment is translocated to the nucleus, where it may bind to the nuclear matrix (for ataxin-1, binding to LANP takes place in the nuclear matrix), forming a nidus for additional molecules to associate via a β-pleated sheet.(5) As additional huntingtin fragments aggregate, the proteins are modified by ubiquitinization.(6) Proteins cannot be removed and form the intranuclear neuronal inclusions. Cytoplasmic aggregates can also form (data not shown), yielding dystrophic neurites.View Large Image | View Hi-Res Image | Download PowerPoint Slide

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