Huntington disease models and human neuropathology: similarities and differences

Abstract

Huntington disease (HD) occurs only in humans. Thus, its natural pathogenesis takes place exclusively within the human brains expressing the causative, mutated protein huntingtin (mhtt). The techniques applicable to postmortem human HD brains are inadequate for investigating the cellular pathogenesis. The creation of genetically engineered animals represents a critical moment in neuroscience. Monitoring the actions of either normal, or abnormal proteins at subcellular levels, and at different time points is now possible thanks to these models. They are the necessary substitutes to investigate the wild type (whtt), or mhtt. The postmortem neuropathologic phenotype of the human HD is well documented. Its pattern and spectrum are highly predictable. From this point of view, the existent models do not exhibit the phenotypic constellation of changes seen in the human HD brains. On one hand, this deficit reflects the limitations of the methods of evaluation used in a clinical setting. On the other hand, it highlights the limitations of the animals. The validity of the models probably should be measured by their capacity of reproducing the cellular dysfunctions of HD rather than the phenotype of the postmortem human brains. Although not perfect, these models are essential for modeling the human disease in cells, which is not feasible with postmortem human HD brains. Nonetheless, their relevance to the patient population remains to be determined. Ultimately needed are means preventing the disease to occur, the discovery of which probably depends on these models.

Fig. 1

Neurons displaying ubiquitinated nuclear inclusions. a Smear obtained from Brodmann area (BA) 8 of a 54-year-old patient with HD grade 4/4. Three nuclei of neurons harbor an ubiquitinated inclusion. b Microphotograph from the frontal cortex of an R6/2 mouse. R6/2 mice were the first generated that are transgenic for the 5′ end of the human HD gene carrying (CAG)₁₁₅–(CAG)₁₅₀ repeat expansions. The R6/2 mouse was instrumental in the discovery of the occurrence of these aggregates in the human HD brain. a, b Immunohistochemistry, same magnification. Scale bar 6 μm

Fig. 2

Tail of the caudate nucleus. The density of oligodendrocytes is increased and that of the neuron is decreased in the HD neostriatum (a) compared to the control (b). a A 54-year-old man with HD, grade 4/4; b 76-year-old woman without history of neurologic or psychiatric disorder. This change in the density of oligodendrocytes is not observed in the animal models currently available. a, b LHE, same magnification. Scale bar 50 μm

Fig. 3

Rostral neostriatum (a—level CAP) including the head of the caudate nucleus (single asterisk), nucleus accumbens (double asterisks), and putamen. A 46-year-old man with HD, grade 3/4. The medial outline of the head of the caudate nucleus is flattened. b Is the magnified area of the putamen included in the rectangle in “a”, which depicts the transition zone between the severely involved dorsal and the relatively preserved ventral part. The demarcation is below and more or less parallel to the diagonal joining the upper left angle with the lower right angle of the picture. Scale bar 100 μm. c Is a magnified field of the dorsal third of the head of the caudate nucleus (single asterisk in a) showing subtotal neuronal loss, severe astrogliosis, and a loose-textured neuropil. d Is a magnified field of the nucleus accumbens (double asterisks in a), which is relatively preserved. This gradient is a hallmark or human HD, and does not occur in models. c and d same magnification, scale bar 65 μm. LHE