HD
Pathogenesis
Increasing evidence indicates that the neuronal defect that is observed in Huntington disease is a consequence of defects in microtubule-dependent vesicular transport.
Huntingtin is found in the nucleus and the cytoplasm associated with vesicles and microtubules. Interestingly, huntingtin interacts with huntingtin-associated protein (HAP1), a protein that binds to the DCTN1 subunit of dynactin (DCTNs) and the pericentriolar material 1 protein (PCM1), which is involved in both centrosome and basal-body function.
HAP1 is transported along axons, where it might function in linking transported vesicles with the cytoskeleton and molecular motors such as dynein (DNs).
Huntingtin controls the microtubule-assisted vesicle transport of the brain-derived neurotrophic factor (BDNF).
BDNF is produced in the cortex but is released in the striatum, where it promotes cell survival; therefore, defective vesicle transport might contribute to the pathogenesis of Huntington disease.
The identification of the huntingtin-interacting protein (HIP1) - a peptide that shares similarity to the budding yeast Sla2p, which is involved in cytoskeleton function - provides further supporting evidence for the role of huntingtin in the organization of the cytoskeleton and microtubule-based transport.
HIP1 interacts with huntingtin-interacting protein interactor (HIPPI), which is homologous to the C. reinhardtii intraflagellar transport IFT.
In addition, studies in fibroblast cultures that are derived from mice and patients with Huntington disease exhibit aberrant centrosome numbers, reduced mitotic index, high frequency of aneuploidy and persistence of the MIDBODY103.
Interestingly, the interaction between huntingtin and HIP1 is inversely correlated with the length of the polyglutamine tract, which provides a clue to the mechanism of this devastating disease and indicates once again that the regulatory properties of the centrosome for microtubule-based transport are relevant to disease onset and progression.
References
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