Differential vulnerability of neurons in Huntington's disease: the role of cell type-specific features

Abstract

Abnormal expansion of a polyglutamine tract in huntingtin (Htt) protein results in Huntington's disease (HD), an autosomal dominant neurodegenerative disorder involving progressive loss of motor and cognitive function. Contrasting with the ubiquitous tissue expression of polyglutamine-expanded Htt, HD pathology is characterized by the increased vulnerability of specific neuronal populations within the striatum and the cerebral cortex. Morphological, biochemical, and functional characteristics of neurons affected in HD that might render these cells more vulnerable to the toxic effects of polyglutamine-Htt are covered in this review. The differential vulnerability of neurons observed in HD is discussed in the context of various major pathogenic mechanisms proposed to date, and in line with evidence showing a 'dying-back' pattern of degeneration in affected neuronal populations.

Figure 1. Overview of HD pathology

A subset of projection neurons in the striatum and the cortex (represented by dashed lines) are particularly vulnerable in HD. These include medium spiny neurons (MSNs, pink dashed lines) of the striatum and large pyramidal projection neurons in cortical layers V, VI and III of the cerebral cortex (gray dashed lines). MSNs in the “indirect pathway” of the basal ganglia project to the external segment of the globus pallidus (GPe) and are affected early in the course of the disease. As HD progresses, MSNs projecting to the internal segment of the globus pallidus (GPi) via the “direct pathway” and cortical pyramidal cells projecting to the striatum are also impaired. Remarkably, most interneurons in both the striatum (pink solid lines) and the cerebral cortex (gray solid lines) are largely spared. This morphological and functional difference has been proposed to play a role in the differential vulnerability of neurons observed in HD (Cicchetti et al. 2000), as well as other neurodegenerative diseases (Mattson & Magnus 2006, Morfini et al. 2009a, Morfini et al. 2009b). Abbreviations: STN: subthalamic nucleus; GPe: external globus pallidus; GPi: internal globus pallidus; SN: substantia nigra.

Figure 2. Cell type-specific characteristics of neuronal populations affected in HD

Cumulative pathological and experimental evidence indicates that cell type-specific characteristics modulate the vulnerability of specific neuronal populations to mutant huntingtin expression. Striatal medium spiny neurons (MSN) and cortical neurons affected in HD project axons to anatomically distant target structures outside the striatum and the cortex, respectively. In contrast, striatal and cortical interneurons (IN) that are largely spared in HD bear short axons that remain within the boundaries of these brain structures. Differences in biochemical content may also contribute to the differential vulnerability of these neuronal populations, but the underlying pathogenic mechanisms remain unknown. MSNs are GABA-ergic projection neurons (GABA, blue circles) and receive brain-derived neurotrophic factor (BDNF, yellow circles) from cortical glutamatergic (Glutamate, red circles), as well as dopaminergic afferents (Dopamine, white circles) from the substantia nigra (SN). Interestingly, more vulnerable MSNs in the “indirect pathway” express enkephalin peptides (Enkephalin, green circles) and D2 dopamine receptors (white ovals, bottom), while less vulnerable MSNs in the “direct pathway” express substance P/dynorphin (purple circles) and D1 receptors (white ovals, top). Abbreviations: MSN: medium spiny neuron; IN: interneuron; BDNF: brain-derived neurotrophic factor; D1: dopamine receptor subtype 1; D2: dopamine receptor subtype 2; NMDAR: N-methyl-D-aspartic acid receptor; GABA: γ-aminobutyric acid; GPe: external globus pallidus; GPi: internal globus pallidus; SN: substantia nigra; STN: subthalamic nucleus.

Figure 3. “Dying back” pattern of neuronal degeneration in HD

A) Neurons undergo normal development, retaining normal connectivity and functionality prior to disease state. B) Affected neurons begin to exhibit signs of synaptic and axonal alterations early in the disease process, including abnormalities in the phosphorylation of axonal proteins, abnormal accumulation of membrane-bounded organelles (blue circles) in axons (Davies & Scherzinger 1997, DiFiglia et al. 1997a, Sapp et al. 1999, Davies et al. 1997), and loss of synaptic proteins (DiProspero et al. 2004b). These changes correspond to functional impairments in synaptic function that appear very early on, even in presymptomatic stages (Cepeda et al. 2003, Levine et al. 2004). C) Axonal degeneration steadily advances in a retrograde fashion, and nuclear/neuritic Htt aggregates (red stars) become evident. As HD progresses, dysfunction of striatal and corticostriatal projection neurons manifest in clinical symptoms such as motor deficits and cognitive decline long before evidence of cell death (Mizuno et al. 2000). D) Disruption of functional synaptic connectivity and eventual loss of appropriate trophic support (Zuccato & Cattaneo 2007) ultimately result in cell death, likely by apoptosis-related mechanisms (Vis et al. 2005).