Huntington's Disease

Mutant Huntingtin Blocks BDNF Transport

Science's STKE  13 Jul 2004:
Vol. 2004, Issue 241, pp. tw250
DOI: 10.1126/stke.2412004tw250

The mechanisms by which polyglutamine (polyQ) expansion in the huntingtin protein (htt) cause neuronal pathogenesis are unclear (see Ross). Gauthier et al. report that wild-type huntingtin is required for proper vesicular transport of brain-derived neurotrophic factor (BDNF) through its interactions with huntingtin-associated protein-1 (HAP1), which in turn interacts with the p150Glued subunit of dynactin, a required regulator of the microtubule motor dynein. Vesicle movement was monitored by recording the movement of BDNF-eGFP (enhanced green fluorescent protein)-tagged vesicles by ultrafast 3D videomicroscopy in NG108-15 neuroblastoma cells expressing either wild-type htt or polyQ-htt. Only wild-type htt promoted the movement of vesicles, measured as either the proportion of moving vesicles or the velocity of vesicle movement. To determine the relevance to Huntington's disease, the authors analyzed BDNF vesicular transport rates in wild-type cells, cells with one mutant htt allele (polyQ-htt), and cells with two mutant htt alleles. Cells with polyQ-htt showed decreased vesicle velocity, and overexpression of wild-type htt increased the velocity of vesicle movement. HAP1 was required for the htt stimulation of vesicle movement, because reduction of HAP1 by small interfering RNA blocked htt's stimulation of transport, and htt truncation mutants that did not interact with HAP1 did not stimulate transport. Sucrose gradient sedimentation analysis of wild-type cells or polyQ-htt cells indicated that htt was present in the dynein and dynactin protein complex, whereas polyQ-htt was present in a lower density fraction. In cells from Huntington patients, a disruption in the dynein and dynactin complex was observed. PolyQ-htt inhibited the interaction of HAP1 and various motor proteins (components of both kinesin and dynein) with microtubules. Release of BDNF after an initial stimulation was compromised in cells with polyQ-htt. Thus, the disruption of vesicular transport by polyQ-htt appears to block the refilling of the releasable pool of BDNF, which results in loss of trophic support and cell death.

C. A. Ross, Huntington's disease: New paths to pathogenesis. Cell 118, 4-7 (2004). [Online Journal]

L. R. Gauthier, B. C. Charrin, M. Borrell-Pagès, J. P. Dompierre, H. Rangone, F. P. Cordelières, J. de Mey, M. E. MacDonald, V. Leßmann, S. Humbert, F. Saudou, Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell 118, 127-138 (2004). [Online Journal]