Cover: The cover figure shows Hypothetical Model of Huntingtin Function in Relation to Sub-cellular Localization Signals. Huntingtin is an ER-localized protein, tethered to membranes by the amphipathic alpha helix in 1-18, allowing huntingtin to bind ER, late endosomes and autophagic vesicles. Early/late endosomal association allows huntingtin to travel from long axonal processes towards and away from the nuclear envelope, continuous with the ER. Early endosome localization is via Hap40 interaction at the carboxyl-terminus (see ref. 9). ER stress and/or other events trigger huntingtin release from membranes, allowing huntingtin to enter the nucleus via sequences between 81-588. Effects of huntingtin in the nucleus have been described by others, and the off switch of this activity is huntingtin nuclear export via its nuclear export signal (NES) near the carboxyl terminus. Inactivation of huntingtin 1-18 targeting by M8P mutation results in increased nuclear huntingtin, inhibition of aggregation and greatly increased toxicity, but only when expanded polyglutamine is present. See Atwal et al., pp. 2600-2615, this issue, for more information.
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