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INTRODUCTION TO NEURODEGENERATIVE DISORDERS

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Neurodegenerative disorders are characterized by progressive and irreversible loss of neurons from specific regions of the brain. Prototypical neurodegenerative disorders include PD and HD, where loss of neurons from structures of the basal ganglia results in abnormalities in the control of movement; AD, where the loss of hippocampal and cortical neurons leads to impairment of memory and cognitive ability; and ALS, where muscular weakness results from the degeneration of spinal, bulbar, and cortical motor neurons. Currently available therapies for neurodegenerative disorders alleviate the disease symptoms but do not alter the underlying neurodegenerative process.

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ABBREVIATIONS

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Abbreviations

AADC: aromatic L-amino acid decarboxylase

Aβ: amyloid β

ACh: acetylcholine

AChE: acetylcholinesterase

AD: Alzheimer disease

ALDH: aldehyde dehydrogenase

ALS: amyotrophic lateral sclerosis

apoE: apolipoprotein E

APP: amyloid precursor protein

BuChE: butyrylcholinesterase

CNS: central nervous system

COMT: catechol-O-methyltransferase

DA: dopamine

DAT: DA transporter

DβH: dopamine-β-hydroxylase

DOPAC: 3,4-dihydroxyphenylacetic acid

GABA: γ-aminobutyric acid

Glu: glutamatergic

GPe: globus pallidus extern

GPi: globus pallidus interna

HD: Huntington disease

5HT: serotonin

HVA: homovanillic acid

MAO: monamine oxidase

MCI: mild cognitive impairment

MPTP: N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

3MT: 3-methoxyltyramine

NE: norepinephrine

NET: NE transporter

NMDA: N-methyl-D-aspartate

3-OMD: 3-O-methyl dopa

PD: Parkinson disease

PDD: Parkinson disease dementia

PET: positron emission tomography

PH: phenylalanine hydroxylase

REM: rapid eye movement

SNpc: substantia nigra pars compacta

SNpr: substantia nigra pars reticulate

SOD: superoxide dismutase

SSRI: selective serotonin reuptake inhibitor

STN: subthalamic nucleus

TAR: transactivation response element

TDP-43: TAR DNA-binding protein 43

TH: tyrosine hydrolase

VA/VL: ventroanterior and ventrolateral

VMAT2: vesicular monoamine transporter 2

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COMMON FEATURES OF NEURODEGENERATIVE DISORDERS

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Proteinopathies

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Each of the major neurodegenerative disorders is characterized by accumulation of particular proteins in cellular aggregates: α-synuclein in PD; Aβ and the microtubule-associated protein tau in AD; TDP-43 in most cases of ALS; and huntingtin in HD (Prusiner, 2013). The reason for accumulation of these proteins is unknown, and it is also unclear in most cases whether it is the large cellular aggregates or smaller soluble species of the proteins that most strongly drive pathogenesis.

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Selective Vulnerability

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A striking feature of neurodegenerative disorders is the exquisite specificity of the disease processes for particular types of neurons. For example, in PD there is extensive destruction of the dopaminergic neurons of the substantia nigra, whereas neurons in the cortex and many other areas of the brain are unaffected. In contrast, neural injury in AD is most severe in the hippocampus and neocortex, and even within the cortex, the loss of neurons is not uniform but varies dramatically in different brain networks. In HD, the mutant gene responsible for the disorder is expressed throughout the brain and in many other organs, yet the pathological changes are most prominent in the neostriatum. In ALS, there is loss of spinal motor neurons and the cortical neurons that provide ...

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