Axonal transport of N-terminal huntingtin suggests early pathology of corticostriatal projections in Huntington disease

Aggregation of N-terminal mutant huntingtin within nuclear inclusions and d ystrophic neurites occurs in the cortex and striatum of Huntington disease (HD) patients and may be involved in neurodegeneration. We examined the pre valence of inclusions and dystrophic neurites in the cortex and striatum of 15 adult onset HD patients who had mild to severe striatal cell loss (grad es 1, 2 or 3) using an antibody that detects the N-terminal region of hunti ngtin. Nuclear inclusions were more frequent in the cortex than the striatu m and were sparse or absent in the striatum of patients with low-grade stri atal pathology. Dystrophic neurites occurred in both regions. Patients with low-grade striatal pathology had numerous fibers with immunoreactive punct a and large swellings within the striatal neuropil, the subcortical white m atter, and the internal and external capsules. In the globus pallidus of 3 grade 1 cases, N-terminal huntingtin markedly accumulated in the perinuclea r cytoplasm and in some axons but not in the nucleus. Findings suggest that in the earlier stages of HD, accumulation of N-terminal mutant huntingtin occurs in the cytoplasm and is associated with degeneration of the corticos triatal pathway.