Huntington's disease: a synaptopathy?

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Abstract

Huntington's disease (HD) is caused by a polyglutamine expansion in the protein huntingtin. In its terminal stage, HD is characterized by widespread neuronal death in the neocortex and the striatum. Classically, this neuronal death has been thought to underlie most of the symptoms of the disease. Accumulating evidence suggests, however, that cellular dysfunction is important in the pathogenesis of HD. We propose that specific impairment of the exocytosis and endocytosis machinery contributes to the development of HD. We also suggest that abnormal synaptic transmission underlies the early symptoms of HD and can contribute to the triggering of cell death in later stages of the disease.

Section snippets

Biochemical properties and functions of huntingtin

Huntingtin is highly conserved from Drosophila to mammals including humans, suggesting that it has a central role in cell functioning. Its broad subcellular distribution implies that it functions at several intracellular sites. Wild-type huntingtin is located mainly in the cytoplasm [6], is partly affiliated with membranous profiles [7] and binds to β-tubulin and microtubules 8, 9. Among the membrane compartments with which huntingtin is associated, synaptic vesicles 6, 7, recycling endosomes,

Huntingtin-binding proteins

Wild-type huntingtin is a very large protein of 350 kDa that might be involved in several functions through its numerous binding partners (Table 1). Among these partners are proteins with important roles in transcriptional regulation, intracellular trafficking and cytoskeletal organization.

Many of the known huntingtin-binding proteins have roles in endocytosis, whereas comparatively few are involved in exocytosis. It is reasonable to propose that mutant huntingtin shows aberrant binding to

Mutant huntingtin and synaptic dysfunction

Distinct morphological abnormalities in neuronal dendrites are apparent as early degenerative changes both in transgenic mouse models of HD and in individuals affected with HD [16]. A marked decrease in the number of dendritic spines and a thickening of proximal dendrites has been observed before cell death is detectable [17]. Clinically, some individuals with genetically confirmed HD have been reported to develop severe motor and cognitive deficits and mental deterioration, even in the absence

Presynaptic versus postsynaptic involvement

In the above sections, we focused on the role of presynaptic mechanisms in the pathogenesis of HD symptoms. But are postsynaptic mechanisms also important in this process?

Mutant huntingtin can downregulate several Sp1-dependent neuronal genes, including those encoding the dopamine D1, D2 and D3 receptors that are localized in both pre- and postsynaptic components [51]. In HD, mutant huntingtin selectively decreases the expression of N-methyl-D-aspartic acid (NMDA) receptors at presymptomatic

Concluding remarks and future directions

Little is known about the normal cellular function of huntingtin or how its function is altered by an expansion of polyglutamine. Recent studies suggest that the polyglutamine expansion might enable mutant huntingtin to corrupt normal gene transcription [51] and to disrupt normal intracellular trafficking and transmitter release 25, 54. But several issues remain with regard to how cellular dysfunction, including synaptic disturbances, can lead to neurodegeneration.

Molecular genetic approaches

Note added in proof

Very recently, it was demonstrated that nerve terminals in different HD animal models have far fewer synaptic vesicles [79]. Mutant huntingtin binds more tightly to synaptic vesicles compared with wild-type huntingtin; glutamate release is substantially reduced in the HD brain slice. These observations indicate impairment of synaptic function in HD.

Acknowledgements

We thank Åsa Petersén and Ruben Smith for critically reading the manuscript. Work cited from our laboratories is supported by grants from the Swedish Research Council, the Hereditary Disease Foundation, the Swedish Society for Medicine, Crafoord Foundation and Hedlund Foundation, the Center for Molecular Medicine (CMMC; TP78) and Köln Fortune from the Medical Faculty of the University of Cologne. Some of the ideas presented in this article were stimulated by discussions in European Research

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