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

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.

Publication

Differential vulnerability of neurons in Huntington's disease: The role of cell type-specific features. () Ina Han, et al. J Neurochem. ;113(5):1073-1091. Figure: F2. All organisms Homo sapiens Rattus norvegicus Mus musculus Drosophila melanogaster

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