FAST TRANSPORT AND RETROGRADE MOVEMENT OF HUNTINGTIN AND HAP-1 IN AXONS

HUNTINGTIN, the protein product of the Huntington's disease gene, asso ciates with vesicle membranes and microtubules in neurons. Analysis of axonal transport with a stop-flow, double crush ligation approach in rat sciatic nerve showed that full length huntingtin (350 kDa) and an N-terminal cleavage product (50 kD) were increased within 6-12 h on bo th the proximal and distal sides of the crush site when compared with normal unligated nerve. The huntingtin associated protein HAP 1 and th e retrograde motor protein dynein also accumulated on both sides of th e crush, whereas the vesicle docking protein SNAP-25 was elevated only proximally. The cytoskeletal protein alpha-tubulin was unaffected. Th e rapid anterograde accumulation of huntingtin and HAP 1 is compatible with their axonal transport on vesicular membranes. Retrograde moveme nt of both proteins, as seen by accumulation distal to the nerve crush , may be necessary for their degradation at the soma or for a function in retrograde membrane trafficking.