Huntington disease: Advances in the understanding of its mechanisms

Abstract

Huntington disease (HD) is a devastating monogenic autosomal dominant disorder. HD is caused by a CAG expansion in exon 1 of the gene coding for huntingtin, placed in the short arm of chromosome 4. Despite its well-defined genetic origin, the molecular and cellular mechanisms underlying the disease are unclear and complex. Here, we review some of the currently known functions of the wild-type huntingtin protein and discuss the deleterious effects that arise from the expansion of the CAG repeats, which are translated into an abnormally long polyglutamine tract. Also, we present a modern view on the molecular biology of HD as a representative of the group of polyglutamine diseases, with an emphasis on conformational changes of mutant huntingtin, disturbances in its cellular processing, and proteolytic stress in degenerating neurons. The main pathogenetic mechanisms of neurodegeneration in HD are discussed in detail, such as autophagy, impaired mitochondrial biogenesis, lysosomal dysfunction, organelle and protein transport, inflammation, oxidative stress, and transcription factor modulation. However, other unraveling mechanisms are still unknown. This practical and brief review summarizes some of the currently known functions of the wild-type huntingtin protein and the recent findings related to the mechanisms involved in HD pathogenesis.

Keywords: Huntington disease; Mechanisms; Pathophysiology.

Fig. 1

Special HD populations.

Fig. 2

HD stages.

Fig. 3

Huntingtin protein schema: HEAT regions and cleavage regions, polyQ expansion at N-terminal -17.

Fig. 4

Scheme of target areas affected by mHTT.

Fig. 5

Colocalization between Huntingtin and Anp32e in SH-SY5Y cell cultures using fluorescence resonance energy transfer (FRET). The image shows PP2A in green co-localized with Anp32e and Htt in the nucleus and cytoplasm of dopaminergic retinoic-acid differentiated SH-SY5Y cells after 10 days of exposure. The three proteins were bound with aptamers whose 5′ ends have FITC for PP2A, Cy3 for ANP32e, and Cy5 for Htt. The figure shows the images acquired with 543 nm excitation and reading above 700 nm in a confocal laser microscope. In this experiment, FRET occurs between Anp32e excited at 543 nm, and Htt receives the emission from Anp32e and emits fluorescence above 630 nm. Control cells were SH-SY5Y cells with Anp32e expression silenced with siRNA 72 h before the test. The third row shows the co-localization of all three proteins. The bar represents 20 nm.