Parkinson’s Disease Mechanisms
HGNC Approved Symbol Mutation Gene Locus Inheritance Disease onset
SNCA Park 1/Park 4 α-synuclein 4q21.3-q22 Dominant Early
PARK2 Park 2 Parkin 6q25.2-q27 Recessive Juvenile; Early
PARK3 Park 3 ? 2p13 Dominant Late
UCHL1 Park 5 UCHL1 4p13 Dominant Late
PINK1 Park 6 PINK1 1p36.12 Recessive Early
PARK7 Park 7 DJ-1 1p36.23 Recessive Early
LRRK2 Park 8 LRRK2 12q12 Dominant Late
ATP13A2 Park 9 ATP13A2 1p36 Recessive Juvenile KRS, Early PD
PARK10 Park 10 AAOPD 1p32 Unclear Late
PARK11PARK12
Park 11 GIGYF2 2q36-q37 Recessive Early
HTRA2
Park 12 ? Xq21-q25 Unclear Late
PLA2G6
Park 13 Omi/HTRA2 2p13.1 Unclear Late
FBXO7
Park 14 PLA2G6 22q13.1 Recessive Juvenile LDOPA-responsive dystonia Parkinsonism
PARK16
Park 15 FBX07 22q11.2-qter
Recessive Early parkinsonian- pyramidal syn.
VPS35
Park 16 ? 1q32 Unclear Unclear
EIF4G1
Park 17 VSP35 16q12 Unclear Unclear
Park 18 EIF4G1 3q27-qter Unclear Unclear
PD-related gene mutations
α-Synuclein
Protofibrils
Fibrils
Neurodegeneration
Decreased Neurotoxicity
ProteinDegradation
PinkDegraded
ES ProteosomalDegradation Protective
Cell Death
Autophagy
Clinical Onset20 year disease stage20 year prodrome
HyposmiaConstipation
Bladder DisorderSYMPTOMS
HOEN / YAHR STAGE
PATHOLOGY
Braak Stage 1 2 3 4 5 6
Enteric Plexus;Olfactory Bulb;
CNX; Dorsal IX/X MN
Sleep Disorder,Obesity
Depression
Coerulus,Caudal Raphe
and Magnocellular RF
Unilateral Tremor,Rigidity, Bradykinesia
Substantia Nigra;Amygdala
(CN); Meynert’s Nucleus; PPN
BilateralDisease
Temporal Lobe: TEC;CA-2 Plexus; Intralaminar
Thalamic Nuclei; Signicant loss of melano-neurons
Poor Balance
Prefrontal Cortex: Tertiary Sensory Association Areas
Falls,Dependency,
Cognitive Decline
Chair/Bed Bound,Dementia
Secondary, then Primary Motor and Sensory Areas
Autophagy
Parkinson’s Disease Timeline
Dopamine Production Pathway
α-Synuclein Structure
Inflammation
Toxicity
Excreted
Toxicity
Excessive ROS Oxidative Stress
Excessive destruction or Accumulation of defective
mitochondria
Interaction with microtubule network
Synaptic vesicle formation
Amphipathic Region
Helix 1
Point mutations A30P E46K A53T
Helix 2
NAC Region Acidic Tail
Calcium homeostasis regulation
Catecholamine metabolismin DAergic neurons
Increased Mitophagy
Parkin
α-Methyl-paratyrosine
CarbidopaBenserazide
Pargyline
Tyrosine hydroxylase (TH)(tetrahydrobiopterin)
L-aromatic amino aciddecarboxylase (AADC)(Pyridoxal phosphate)
Monoamine oxidase (MAO)
Aldehyde dehydrogenase (ALDH)
Catechol-o-methyltransferase (COMT)
Tyrosine
MPTPMAO-B
DAT
D2 Autoreceptor
Rotenone
BLOO
D VE
SSEL
ASTROCYTE
POSTSYNAPTIC CELL
MPP+
Dihydroxy-phenylalanine(L-DOPA)
Dihydroxyphenyl-acetaldehyde
(DOPAL)
Dihydroxyphenyl-acetic acid(DOPAG)
Homovanillicacid (HVA)
OxidativeStress
O2-
Tetrabenazine
UCHL1
Caspases 1,8
Clioquinol
α-Sp22
Synphillin-1
SIAH
HSP70
CHIP
Ubc6/7
CDCRel-1/Septin5
EPRS
Cyclin E
Ataxin
Proteasome
Tubulins
Synaptotagmin XIUbCH7/8
UBA1 AMP + PPiATP
cullin1
Ligase
Hydr
olas
e
FBXw7
PAELRPAELR
PINK1p64
DA Oxidation
O-glycosylation
Glycation
Accumulation ofunfolded PAELR
Increased inhibitionof DA release
Mutant decreases hydrolase activity
Cx Ie-
MAO
NF-κB
NADH
NAD+
DA
DOPAL + H2O2
α-KG
Succiny-CoA
ADP+PI ATPCx IICoQ
Cx IIICyto C
Cx IVCx V
LRRK2
Tau
PINK1p64
PINK1p60
CCCP
MG132
LRRK2-IN-1
Caspase-9, Inhibitor I
Caspase-3 Inhibitor V
PINK1MTS
TOM
TOM
ParkinParkin
Accumulation of misfolded pPINK1
DepolarizedMitochondrion
Release ofIMS Proteins
PINK1p64
Abnormal Phosphorylation
Ca2+ Disfunction
DJ1
Apaf1ATP
Cyto C
DOPAMINE
ex2 ex3 ex4 ex5 ex6
NNN +
-20y -10y 0 10y 20y
UbUb
Ub
UbUb
Ub
UbUb
UbUb
UbUb
UbUb
UbUb
UbUb
UbUb
UbUb
UbUb
UbUb
Ub
Ub
UbUb
UbUbUb
HO
NH2
COOH
HO
HO NH2
COOH
L-Dopa
HO
HO NH2
Dopamine
Dopamine o-quinone
Oxidation (H+ + 2e-)
O
O NH2
HO
OH
O
HO
OH
O
OH
HO
O
O
OH
CH3
SuccinateFumerate
VMAT
D2R
DAT
DA
3-MT
HVA
DMHPA
MAO
COMT
ALDH
VSSC CaV 1.2/1.3/2.1/2.2
GIRK
VGCC
Ca2+
Na+ Ca2+
K+
MFNVDACFIS1Ub
UbUb
Ub
TOM
TOM
TIM
TIM
TIMMPP PARL
PINK1p53
MG132SensitiveProtease
TIM
Cyto C
BaxBcl2
p53
Caspases 3,6,7
Caspase 9 p50 p65
IκB
p50 p65
ASC NLRP3
Pro-IL-18
Pro-Caspase-1
JNK/c-Jun kinase
AIF
TRX
TXNIP
Caspase-1
Pro-IL-1β
IL-18IL-1β
?
PINK1p64
DNA Strand Breaks
ATP Depletion
Astrocyte µglia IL-1
Pro-Inflammatory signals
Quinacrine HCl
Mitophagy
I. II. III. IV. V.
Lewy Bodies
Lewy Neurites
PINK1
MTS TM
A68P A168P H271Q
I II III IV V VI VII VIII IX X XISubstrate Recognition
CN
G309D
L347P
E417G
W437X
LRRK2
ANK LRR
R1441CR1441GR1441H R1628P
ROC COR Kinase WD40
CN
12012T 12020T
Y1699C G2019S G2385R
Parkin
Ubiquitin
V15MR33Q
P37LR42P
A46PAB2E
A92V
KN61N
S167N
M192LM192V
K211RK211N
C212Y
T240RT240N
C253YR256CR271S
R275W
A339ST351P
R366WV380L
D394N
T415N
G430D
C431FP437L
D280NG284R
C289G
Q100H
RING1 IBR RING2
CN
D1R D2R D3R D4R D5R
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