The Neuropathology of Huntington’s Disease: Classical Findings, Recent Developments and Correlation to Functional Neuroanatomy

Rüb, Udo, Vonsattel, Jean Paul G, Heinsen, Helmut, Korf, Horst-Werner, Udo Rüb, Jean Paul G. Vonsattel, Helmut Heinsen, Horst-Werner Korf

Except for the atrophic neurons in the striatum referred to as neostriatal dark neurons (NDN) (see Sect. 2.2), no consistent pathognomonic alterations of vulnerable brain nerve cells have been reported during more than hundred years of morphological HD research. In particular, despite recent careful and systematical investigations of possibly affected brain regions, no nerve cells have been observed in HD brains which display morphological features associated with the occurrence of classical apoptosis (i.e., chromatin condensation, nuclear fragmentation, apoptotic bodies) (Graeber and Moran 2002; Rüb et al. 2013a). Classical apoptosis is regarded as a specific form of programmed cell death and is defined as a series of stereotypical, biochemical, and morphological alterations leading to nerve cell demise. Classical apoptosis regulates the balance between proliferation and differentiation in the course of brain development and during optimization of adult nerve cell functions. Although it has been implicated in the pathogenesis of neurodegenerative diseases, classical apoptosis cannot account for all cell death phenotypes occurring in these diseases. Therefore, other forms of nerve cell death mechanisms may occur in human diseases affecting the terminally differentiated, postmitotic nerve cells. The absence of apoptotic nerve cells in HD brains supports this point of view and conforms to recent HD studies suggesting that the molecular mechanisms of classical apoptosis do not play a significant role for neurodegeneration occurring in HD patients or in transgenic HD models (Gil and Rego 2008; Graeber and Moran 2002; Pattison et al. 2006; Rüb et al. 2013a).