Chapter 7 Huntington Disease From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved.

Reproduced with permission from Ref. 3. Figure 1 Samples of coronal and sagittal magnetic resonance images from a patient with Huntington disease (top row) and a normal control (bottom row) showing the outlines of the caudate and putamen that are part of the striatum (left), cerebral (center), and cerebellar volumes (right). Reproduced with permission from Ref. 3. From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 2

Figure 2 (A) Voxel-based MRI based morphometry in 2 human subjects during the prodromal phase of disease (PreA and PreB) indicates early changes in striatum and other brain regions including subcortical white matter compared with controls. As disease progresses (HD1 and HD2), striatal atrophy remains severe, but widespread brain atrophy arises, especially in other subcortical nuclei and subcortical white matter and in cortical grey matter. Red indicates substantial atrophy and yellow the greatest degree of atrophy. (B) Striatal volume derived from magnetic resonance images obtained from asymptomatic individuals who carry the mutated htt gene and therefore will develop disease. Striatal volume gradually declined over a 20-year time period preceding disease onset. The three groups of patients (far from onset, mid, and near to predicted onset) were each divided into two subgroups (n=40–50). For all groups, the first point is striatal volume at the time of the first MRI scan, and the second point is volume at the second scan (about 2 years later). Error bars indicate SE Reproduced with permission from Ref. 4. From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 3

Reproduced with permission from Ref. 7. Figure 3 CAG repeat length is a predictor of the age at which disease manifests. The red line shows the age at onset as a function of the length of the CAG repeat, indicating that longer repeats cause much earlier disease onset. The blue line shows the duration of disease, from onset to death, as a function of the number of repeats. This line shows that repeat length does not affect disease duration. HD, Huntington disease. Reproduced with permission from Ref. 7. From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 4

Reproduced with permission from Ref. 6. Figure 4 Intranuclear inclusion bodies in neurons in a sample from the autopsy from a patient with Huntington disease (A, arrow) and in a tissue section from a mouse model of Huntington disease (B, arrows). Reproduced with permission from Ref. 6. From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 5

Reproduced with permission from Ref. 9. Figure 5 Hind limb clasping is an abnormal motor response in a mouse carrying the mutated huntingtin gene (right) as opposed to the splaying of the hind limbs observed in wild-type (wt) mice (left). Reproduced with permission from Ref. 9. From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 6

Reproduced with permission from Ref. 11. Figure 6 Schematic diagram of the huntingtin amino acid sequence. The polyglutamine tract (Q)n is followed by the polyproline sequence (P)n, and the red squares indicate the three main clusters of HEAT repeats. The green arrows indicate the caspase cleavage sites and their amino acid positions, and the blue arrowheads indicate the calpain cleavage sites and their amino acid position. B identifies the regions cleaved preferentially in the cerebral cortex, C indicates those cleaved mainly in the striatum, and A indicates regions cleaved in both. Green and orange arrowheads point to the approximate amino acid regions for protease cleavage. The red and blue circles indicate post-translational modifications: ubiquitination (UBI) and/or sumoylation (SUMO) (red) and phosphorylation at serine 421 and serine 434 (blue). The glutamic acid (Glu)-, serine (Ser)-, and proline (Pro)-rich regions are indicated (Ser-rich regions are encircled in green). NES, nuclear export signal. Reproduced with permission from Ref. 11. From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 7

Reproduced with permission from Ref. 11. Figure 7 Brain-derived neurotrophic factor (BDNF) is produced by cortical neurons and transported to striatal neurons. Wild-type huntingtin contributes to Bdnf transcription in the cortical neurons that project to the striatum by inhibiting the repressor element 1/neuron-restrictive silencer element (RE1/NRSE) that is located in the BDNF promoter exon II. I–IV indicate BDNF promoter exons in rodent Bdnf; V indicates the coding region. The RE1/NRSE consensus sequence is shown. Inactivation of the RE1/NRSE in Bdnf leads to increased messenger RNA transcription and protein production in the cortex. BDNF, which is also produced through translation from exons III and IV, then is made available to the striatal targets via the corticostriatal afferents. Wild-type huntingtin might also facilitate vesicular BDNF transport from the cortex to the striatum. Reproduced with permission from Ref. 11. From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 8

Reproduced with permission from Ref. 2. Figure 8 Cellular pathogenesis in Huntington disease. Mutated HTT oligomers and polymeric inclusion have been shown to affect a wide variety of cell biological process in the motor neuron, as well as in surrounding astrocytes and microglial cells. Among these, the most important pathways affected are proteostasis, mitochondrial energy production, regulation of gene transcription and translation, axonal transport, and vesicular transmitter and peptide release. ATP, adenosine triphosphate; BDNF, brain-derived neurotrophic factor; CSF, cerebrospinal fluid; IL, interleukin; NMDA, N-methyl-d-aspartate; ROS, reactive oxygen species; TNF, tumor necrosis factor. Reproduced with permission from Ref. 2. From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 9

Reproduced with permission from Ref. 16. Figure 9 The proteostasis network. Molecular chaperones bind nonnative proteins and prevent their aggregation. Folding or degradation of the client protein is initiated in conjunction with regulatory co-chaperones. Association with an ubiquitin ligase leads to the formation of a ubiquitin chain on the chaperone-bound client. This induces client sorting to the proteasome or triggers the autophagic engulfment of the client during chaperone-assisted selective autophagy (CASA). On the latter pathway, the client is eventually degraded in lysosomes. During chaperone-mediated autophagy (CMA), the client is directly translocated across the lysosome membrane. Reproduced with permission from Ref. 16. From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 10

Reproduced with permission from Ref. 17. Figure 10 Contribution of extrasynaptic N-methyl-d-aspartate (NMDA) receptors to neuronal cell death in Huntington disease. Spillover of glutamate from synapses activates extrasynaptic NMDA receptors that couple via p38MAPK and m-Calpain to promote cell death. By contrast, synaptic NMDA receptors act via a variety of signaling cascades to enhance survival. Reproduced with permission from Ref. 17. From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 11