1. Chapter 5 Chapter 5 Parkinson Disease From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved.

2. Figure 1 James Parkinson (1755–1824) published an article on the “shaking palsy,” a condition that was later named Parkinson disease in his honor (public domain). 2 From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved.

3. Figure 2 Front and side views of a man with a festinating or forward-leaning gait characteristic of Parkinson disease. Drawing after St. Leger, first published in Wm. Richard Gowers’ Diseases of the Nervous System, in London, 1886 (public domain). 3 From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved.

4. Figure 3 Loss of pigmented dopamine neurons in the substantia nigra from a patient with PD (left) compared to a normal sustantia nigra (right). The distinct loss of the black-appearing dopaminergic cells that contain the black pigment neuromelanin, serving as a marker for dopaminergic neurons is prominently seen in the substantia nigra from the patient with PD. Image was kindly provided by Dr Dimitri Agamanolis, Director, Anatomical Pathology and Neuropathology, Akron Children’s Hospital. 4 From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved.

5. Figure 4 Lewy body pathology. A high-resolution histological image of the substantia nigra shows neurons containing brown melatonin granules along with characteristic Lewy bodies (arrow). Image was kindly provided by Dr Thomas Caceci. 5 From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved.

6. Figure 5 Presence of dopamine neurons assessed by 18-fluorodopa positron emission tomography (PET). (A) PET scan from a control subjects showing high striatal uptake of the precursor used to synthesize dopamine, indicative of the presence of dopaminergic neurons (highest value in red). (B) Example of a patient with Parkinson disease with motor signs mainly confined to the left limbs. Uptake of the dopamine precursor is markedly reduced in the right posterior putamen (area indicated by arrow is 70% below normal) and to a lesser extent in the anterior putamen and caudate of the left hemisphere. Reproduced with permission in a modified form from Ref. 7. 6 From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved.

7. Figure 6 “Archimedian” spiral drawn by an individual with tremor (B) and an unaffected individual without tremor (A). The jittery appearance of the spiral indicates the presence of tremor. Reproduced with permission from Ref. 4. 7 From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved.

8. Figure 7 The motor homunculus based on Wilder Penfield’s original drawings from 1940 shows the cortical representation of our body with regard to control of voluntary movement (public domain). 8 From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved.

9. Figure 8 Cortical control of movement involves primary motor cortex and premotor and supplementary motor areas. Their activity is modulated by the midbrain, particularly the basal ganglia. Reproduced with permission from Ref. 8. 9 From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved.

10. Figure 9 The basal ganglia include the caudate nucleus (CN), putamen (Put), nucleus accumbens (Acb), and globus pallidus internal (GPi) and external (GPe). All four are part of the telencephalon. The subthalamic nucleus (STN) and substantia nigra (SN), with its two parts, pars compacta (SNc) and pars reticulata (SNr), modulate the output of the globus pallidus to the thalamus to control the associated motor cortex. The labeled histological sections are parasagittal section through the monkey brain (stained with the acetylcholinesterase method) showing the localization and boundaries of all major components of the basal ganglia system. Reproduced with permission from Ref. 9. 10 From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved.

11. Figure 10 Direct and indirect pathway of movement control by the basal ganglia illustrated as a schematic. Abbreviations are as follows: glutamate—Glu; acetylcholine—ACh; enkephaline—Enk; dopamine—DA; substantia nigra pars compacta—SNc; substantia nigra pars reticularis—SNr; globus pallidus external—GP3; glubus pallidus internal—GPi; subthalamic nucleus—STN. Reproduced with permission from Ref. 10. 11 From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved.

12. Figure 11 A medium spiny neuron in the mouse striatum densely covered with synaptic spines. These are the sites receiving glutamatergic input. The cell was filled with biocytin and labeled with a streptavidin-conjugated fluorophore (green). Image was kindly provided by Dr Rita Cowell, University of Alabama Birmingham. 12 From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved.

13. Figure 12 Stimulation of the D1 receptor (left) couples via the stimulatory G protein G s to increase cAMP, causing the striatal neuron to be excited, whereas activation of the D2 receptor (right) couples via the inhibitory G protein G i to reduce cAMP levels and inhibits striatal neurons. National Institutes on Drug Abuse. 13 From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved.

14. Figure 13 Ion flux via numerous ion channels and transporters across the neuronal membrane is essential for neuronal activity. Fluxes are particularly pronounced in pacemaking neurons, which persistently fire action potentials at a high frequency. Ionic movement is directly or indirectly fueled by ATP, putting cells at a high risk for failure should energy supplies deplete. Reproduced with permission from Ref. 11. 14 From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved.

15. Figure 14 Mitochondrial production of energy by oxidative phosphorylation produces reactive oxygen (ROS) and nitrogen species (NOS), particularly O 2 −, OH−, and H 2 O 2. These radicals with unpaired electrons are highly reactive and are destructive to DNA, RNA, proteins, and lipids. In PD, the high energy consumption of pacemaking neurons generates an overabundance of ROS and NOS. 15 From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved.

16. Figure 15 Role of synuclein in synaptic function. Synuclein acts as a molecular chaperone, directly interacting with the vesicle associated membrane protein (VAMP) that stimulates the assembly of vesicles containing neurotransmitter. Reproduced with permission from Ref. 22. 16 From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved.

17. Figure 16 Parkin and PINK synergistically act as surveyors of mitochondrial health. (A) In healthy mitochondria, PINK1 is maintained at low levels because it is cleaved by an unidentified protease. (B) When a mitochondrion malfunctions, with associated depolarization of the membrane electrical-potential gradient, PINK1 is stabilized at the outer mitochondrial membrane with its kinase domain facing the cytoplasm. Directly or indirectly through an unknown protein, X, PINK1 then recruits Parkin to the mitochondrial surface. A loss of membrane potential in damaged mitochondria causes PINK1 to stay associated with the outer membrane, where it is then recognized by Parkin. Parkin is an E3 ligase that marks damaged mitochondria for degradation. Reproduced with permission from Ref. 24. 17 From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved.

18. Figure 17 Putting the various disease-causing events into relationship reveals multiple ways in which single events or combinations of events or abnormalities can readily contribute to neuronal cell death in PD. 18 From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved.

19. Figure 18 The chemical MPTP induces Parkinson-like symptoms by killing dopaminergic neurons. It is converted to the toxic MPP + molecule that is the substrate for uptake via the dopamine transporter. MPP + inhibits complex 1 of the mitochondrial oxidative chain, causing a failure to produce ATP. Reproduced with permission from Ref. 29. 19 From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved.

20. Figure 19 Deep brain stimulation (DBS) electrodes and electric leads visualized after implantation through X- rays. Images courtesy of Dr Helen Mayberg, Emory University. 20 From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved.

21. Figure 20 Deep brain stimulation set-up schematized. The battery containing pulse generators are implanted subcutaneously near the clavicle. All lead wires are run under the scalp and skin. National Institute for Mental Health (www.nimh.nih.gov).www.nimh.nih.gov 21 From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved.

22. Box 1-Figure 1 The ubiquitin-proteasome pathway. Target proteins of the proteasome are tagged with polyubiquitin molecules in an ATP-dependent process through E1, E2, and E3 ligases. Polyubiquitinated proteins are then recognized by the 19S regulatory complex of the 26S proteasome and fed into the 20S catalytic core for degradation and the ubiquitin molecules recycled. Reproduced with permission from Ref. 17. 22 From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved.