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AADC: aromatic L-amino acid decarboxylase

Aβ: amyloid β

ACh: acetylcholine

AChE: acetylcholinesterase

AD: Alzheimer’s disease

ALDH: aldehyde dehydrogenase

ALS: amyotrophic lateral sclerosis

apoE: apolipoprotein E

APP: amyloid precursor protein

ARIA: amyloid-related imaging abnormality

ASO: antisense oligonucleotides

BPSD: behavioral and psychiatric symptoms in dementia

BuChE: butyrylcholinesterase

CNS: central nervous system

COMT: catechol-O-methyltransferase

CSF: cerebrospinal fluid

DA: dopamine

DAT: DA transporter

DβH: dopamine-β-hydroxylase

DOPAC: 3,4-dihydroxyphenylacetic acid

FALS: familial ALS

GABA: γ-aminobutyric acid

GBA: β-glucocerebrosidase

GI: gastrointestinal

Glu: glutamatergic

GPCR: G protein-coupled receptor

GPe: globus pallidus extern

GPi: globus pallidus interna

HD: Huntington’s disease

5HT: serotonin

HTT: huntingtin

HVA: homovanillic acid

ICD: impulse control disorder

LRRK2: leucine-rich repeat kinase 2

MAO: monoamine oxidase

MCI: mild cognitive impairment

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

MRI: magnetic resonance imaging

3MT: 3-methoxyltyramine

NIA-AA: National Institute on Aging and Alzheimer’s Association

NE: norepinephrine

NET: NE transporter

NMDA: N-methyl-D-aspartate

3-OMD: 3-O-methyl dopa

PD: Parkinson’s disease

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


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 the 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 degeneration of spinal, bulbar, and cortical motor neurons results in motor weakness. For the most part, currently available therapies for neurodegenerative disorders alleviate the disease symptoms without altering the underlying neurodegenerative process, but a new era of disease-modifying treatments targeting the molecules implicated in pathogenesis is beginning with the approval of the anti-Aβ antibody, aducanumab, for AD.



Each of the major neurodegenerative disorders is characterized by accumulation of particular proteins in cellular aggregates: α-synuclein in PD; amyloid β (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.

Selective Vulnerability

A striking feature of neurodegenerative disorders is the selectivity of the disease processes for particular types of neurons in different brain regions. For example, in PD, there is extensive destruction of the dopaminergic neurons of the substantia nigra, whereas neurons in the cortex and ...

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