Abbreviations
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.
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 ...