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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
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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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 ...