Genetics and neuropathology of Huntington's disease

Abstract

Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disorder that prominently affects the basal ganglia, leading to affective, cognitive, behavioral and motor decline. The basis of HD is a CAG repeat expansion to >35 CAG in a gene that codes for a ubiquitous protein known as huntingtin, resulting in an expanded N-terminal polyglutamine tract. The size of the expansion is correlated with disease severity, with increasing CAG accelerating the age of onset. A variety of possibilities have been proposed as to the mechanism by which the mutation causes preferential injury to the basal ganglia. The present chapter provides a basic overview of the genetics and pathology of HD.

Fig. 1

Image A shows the location of the Huntington’s disease gene in band 4p16.3 of chromosome 4 (Adapted from Figure 1 of Gusella et al., 1994). Image B illustrates the huntingtin protein, showing that it contains a polyglutamine region (polyQ) and a proline-rich domain (PRD) at its N-terminus, and 10 HEAT repeats clustered in three domains in the N-terminal half of the protein (Adapted from Figs. 1 and 2 of Harjes and Wanker, 2003). Numbers indicate amino acids. Image C shows a graph depicting the relationship between CAG repeat and Huntington’s disease age of onset. Note the overall significant negative correlation between HD onset and the expanded repeat length (n = 609, r² = 0.65, p = 0.0001). Nonetheless, the relationship is more complex than this. For example, while there is a strong correlation between CAG repeat and age of onset for adult-onset cases (>20 years) over the 35-55 repeat range, in the case of juvenile (<20 years) onset increasing CAG does not notably advance age of onset highlighted (by dark and pale shading). Moreover, this is also true for the few HD cases found with repeats >200 CAG (not shown in graph). The textured box highlights anomalous adult onset cases with expansion beyond the 60 CAG typically associated with juvenile onset (Adapted from Fig. 4 of Squitieri et al., 2006). (For color version of this figure, the reader is referred to the web version of this book.)

Fig. 2

Immunofluorescence labeling for huntingtin (Ht) in the rat striatum viewed with CLSM. Two low-magnification fields (A, B) and two high-magnification fields (C, D) show that scattered large neurons intensely labeled for huntingtin and numerous medium-sized neurons moderately labeled for huntingtin are present in striatum. Magnification in A is as in B; magnification in C is as in D. Images E and F show immunofluorescence labeling for huntingtin in the lower layers of rat cerebral cortex, at increasingly higher magnification. Both fields show intense labeling of pyramidal neurons in Layer 5 of cortex. All images are from Fusco et al. (1999).

Fig. 3

Images showing immunolabeling for huntingtin in HD brain, revealing aggregates of mutant huntingtin in neuronal nuclei, termed intranuclear inclusions (NIIs). Image A shows the presence of numerous NIIs in cerebral cortex of juvenile HD victim at low magnification. Images B and C show immunolabeled NIIs in individual cortical pyramidal neurons in the same juvenile HD victim, using Nomarski optics to highlight the NIIs. The nucleolus in each cell is unlabeled. These images are adapted from A-C of Fig. 1 from DiFiglia et al. (1997).

Fig. 4

Coronal slices though human telencephalon, showing a normal brain on the right and an advanced HD brain (Grade 4) on the left. Note the profound shrinkage of cortex and caudate and the resulting ventricular expansion in the HD brain. Image courtesy of the Harvard Brain Tissue Resource Center. (For color version of this figure, the reader is referred to the web version of this book.)

Fig. 5

Schematic illustrations of caudate at HD Grades 0 through 4 according to the Vonsattel et al grading scale. Note that the ventricular profile of the caudate is diagnostic for classification, and the extent of caudate neuron loss distinguishes normal from HD, and Grade 0 versus Grade 1 HD. This illustration is adapted from Fig. 2 of Vonsattel et al. (1985).

Fig. 6

Images of immunohistochemically labeled sections showing GPi, GPe, and substantia nigra in control, Grade 1 HD, and Grade 3 HD cases, immunostained for SP in the case of GPi and the nigra and for ENK in the case of GPe. In the control, SP+ fibers abound in GPi, ENK+ fibers abound in GPe, and SP+ fibers abound in the nigra. In Grade 1 HD, ENK+ fibers in GPe and SP+ fibers in the nigra are depleted, while SP+ fibers in GPi remain abundant. The contrast is even more evident in the Grade 3 specimen, where ENK+ fibers are markedly depleted in the atrophied GPe and SP+ fibers in the nigra are sparse and patchy, but SP+ fibers in GPi are still quite prominent. This illustration is Fig. 5 from Deng et al. (2004).

Fig. 7

High-power images showing SP+ fibers in GPi (B, D, F) and ENK+ fibers (A, C, D) in GPe. In the control case, abundant woolly fibers can be seen in both GPi and GPe. In Grade 1, loss of ENK+ fibers in GPe is apparent, while the SP+ fibers in GPi are indistinguishable from that in control. In Grade 3, ENK+ woolly fibers are completely absent, while the SP+ fibers in GPi are relatively preserved, although a decrease in terminal density is apparent. This illustration is Fig. 6 from Deng et al. (2004).

Fig. 8

Low-power images showing GAD+ staining in both GPi and GPe of control, Grade 1 HD, and Grade 3 HD cases. Note the greater loss of GAD+ woolly fibers from GPe than from GPi. This illustration is Fig. 7 from Deng et al. (2004).

Fig. 9

Schematic illustration of the preferential loss of ENK+ striato-GPe neurons compared to SP+ striato-GPi neurons during the progression of HD, and the relation of this differential loss to HD symptoms. In brief, the early loss of striato-GPe neurons, which suppress unwanted movements, explain the early appearance of chorea in HD, while the later loss of the striato-GPi neurons, which promote desired movement, explain the appearance of akinesia as a later symptom. (For color version of this figure, the reader is referred to the web version of this book.)

Fig. 10

Camera lucida reconstructions of the distributions of neuropeptide Y-immunoreactive (NPY +) neurons at comparable levels of the basal ganglia, of a normal individual (A), a choreic Grade 3HD case (B), and a rigid Grade 4 HD case (C). Although the number of NPY+ perikarya in putamen is similar, shrinkage of the putamen greatly elevates the packing density of these neurons in Grades 3 and 4 HD. Note also the progressive shrinkage of GPe and GPi in the HD cases. GPe = external globus pallidus; GPi = internal globus pallidus. This illustration is Fig. 2 from Albin et al. (1990a).