Background
Global scenario and risk factors for PD
Symptoms of PD
Early symptoms
Primary motor symptoms
Secondary motor symptoms
Primary non-motor symptoms
Secondary non-motor symptoms
Causes of motor impairment in PD
Molecular mechanisms of PD
The role of aggregation of misfolded proteins in PD
Role of gene mutations in PD
Gene | PARK loci | Chromosome | Form of PD | Mutations and their origin | Refs. |
---|---|---|---|---|---|
SNCA | PARK 1 | 4q21 | Autosomal dominant | A30P (Germany), E46K (Spain), A53T (Greece, Italia, Sweden, Australia, Korea), A18T (Poland), A29S (Poland), E46K (Spain) H50Q (UK), G51D (France) | |
Parkin | PARK 2 | 6q25.2–q27 | Autosomal recessive, juvenile | Various mutations, exonic deletions, dupli/triplications (Japan) | |
Unknown | PARK 3 | 2p13 | Autosomal dominant | Europe | [241] |
SNCA | PARK 4 | 4q21 | Autosomal dominant | Duplication and triplication USA | [242] |
UCHL1 | PARK 5 | 4p14 | Autosomal dominant, idiopathic | I93M and S18Y (Germany) | |
PINK1 | PARK 6 | 1p35–p36 | Autosomal recessive | G309D, exonic deletions (Italy) | [244] |
DJ-1 | PARK 7 | 1p36 | Autosomal recessive, early onset | Homozygous exon, deletion L166P (Europe) | |
LRRK2 | PARK 8 | 12q12 | Autosomal dominant, idiopathic | R1441C ⁄ G ⁄ H, Y1699C G2019S, I2020T, G2385R (Japan) | |
ATP13A2 | PARK 9 | 1p36 | Kufor–Rakeb syndrome, early onset | Loss-of-function mutations (Jordan, Italy, Brazil) | |
Unknown | PARK 10 | 1p32 | Idiopathic | (Iceland) | [255] |
Unknown | PARK 11 | 2q36–q37 | Autosomal dominant, idiopathic | (USA) | [256] |
Unknown | PARK 12 | X | Familial | (USA) | [257] |
HTRA2 | PARK 13 | 2p13 | Idiopathic | A141S, G399S (Germany) | |
MAPT | MAPT | 17q21.31 | Familial | 79 of Ser/Thr of tau (tauopathies) (Asian, USA) | |
Glucocerebrosidase-1 | GBA-1 | 1q21 | Recessive | Lysosomal storage disorders (USA) | |
Other genes | TMEM, IF4G1E, GRIN2A, GSTP1, TNF-alfa, COX-2, SLC6A3, ADH1C rs356219, SREBF1 and SREBF2, COMT HLA-DRB5, BST1, GAK, ACMSD, STK39, MCCC1, SYT1, CCDC62/HIP1R [262] |
PD caused by impairment of protein degradation pathways
HSPs | MW (kDa) | Location in cell | Co-localization | Functions | Refs. |
---|---|---|---|---|---|
HSP27 | 20–30 | Cytosol, ER, nucleus | SNCA, Tau | Protein degradation | |
HSP40 | 40 | Cytosol, | SNCA | Protein folding | |
HSP60 | 60 | Mitochondria | SNCA | Prevent protein aggregation | |
HSP70 | 70 | Mitochondria, Cytosol, ER, nucleus | SNCA | Protein folding and unfolding | |
HSP90 | 90 | Cytosol, ER, | SNCA | Protein degradation and transcription factor | |
HSP100/104 | 100–110 | Cytosol, ER, | SNCA | Thermal tolerance |
Role of environmental toxins on PD
Toxins | Use | Mode of action | Effects on nervous system | Refs. |
---|---|---|---|---|
MPTP | Herbicide | Inhibit electron transport | Parkinsonism | |
Rotenone | Pesticide, insecticide | Interfere with Mitochondrial electron transport system | Parkinson’s like symptoms | |
Paraquat | Herbicide | Interfere electron transport, photo synthesis | Oxidative stress | |
Maneb | Fungicide | Interferes glucocorticoid metabolism | Parkinson’s like symptoms | |
Zineb | Pesticide | Metabolized to carbon disulfide-a neurotoxin | Convulsions, tiredness, dizziness weakness, headache, fatigue, slurred speech, unconsciousness | |
Ziram | Pesticide | Unknown | Prolonged inhalation causes neural and visual disturbances | |
Thiram | Pesticide | Unknown | Convulsions, headaches, dizziness, fatigue drowsiness, confusion | |
Nabam | Fungicide | Unknown | Convulsion, dizziness, confusion |
Category | Models | Mechanism | NS loss | Inclusions | Motor deficit | Non-motor deficit | Applications | Demerits | Refs. | ||
Environ mental toxins | 6-OHDA | Complex I inhibition | +++ | _ | +++ | Cognitive, psychiatric, and GI disorders | Screen therapies for PD, study mechanisms of cell death | Degeneration non-progressive | [283] | ||
MPTP | Complex I inhibition | ++ | -, presence of SNCA at SNpc | +++ | Numerous | Screen therapies for PD, study mechanisms of cell death | Non-progressive rare inclusions | ||||
Rotenone | Complex I inhibition, ↑ROS | ++ | Presence of SNCA at SNpc | +++ | Decrease GI motility | Test neuroprotective compounds | morbidity, mortality, time consuming & laborious | [286] | |||
Paraquat | Complex I inhibition, ↑ROS | +++ | No inclusions at SNpc | _ | Not detected | Test neuroprotective compounds | Substantial morbidity, mortality, time consuming & laborious | ||||
Maneb | Impairment of glutamate and DA uptake | + | _ | + | Not detected | Study glutamate uptake in DA neurons | No inclusion, less DA neuronal damage | ||||
Others | SHH, Nurr1, Pitx3, EN1 | Impaired protein synthesis in DA-neurons | ++ | _ | +/− | Not known | Study the mechanism of Translation in DA neurons | No SNCA | |||
MitoPark | Mitochondrial deficit | ++ | +/− | + | Not known | Study the role of mitochondria in PD | Less motor deficit | ||||
PDC | EAATs blockade, excitotoxicity, ↑ROS | ++ | _ | + | Not known | To study excitotoxicity and Oxidative pathway in PD | No SNCA | ||||
Genetic | Parkin (PARK2) | Loss of ubiquitin E3- ligase activity | +/− | +/− | +/− | _ | Study the role of E3 ligase in PD | No inclusion, less DA neuronal damage | |||
LRRK2 (PARK 8) | Loss of enzymatic activity | _ | _ | Drosophila + | Not detected | Study the role of LRRK2 mutations related to PD | No SNCA nor no DA degeneration | ||||
PINK (PARK6) | Mitochondrial damage | +/− | +/− | +/− | Not detected | Study the role of mitochondria in PD | No SNCA or no DA degeneration | ||||
DJ-1(PARK 7) | Increase ROS, Mito. dysfunction | +/− | +/− | +/− | Not detected | Study oxidative stress & mitochondrial dysfunction in PD | Less inclusion & DA neuronal damage | ||||
SNAC mutation and animal models of PD | |||||||||||
Models | Promoter | Background | SNCA | Motor signs | Nonmotor signs | TH neurons loss | Disease progression | Ref | |||
WT, A53T | PDGF-b | C57BL/6 9 DBA2 | + | + | – | + | – | ||||
A53T | Mouse Thy-1 | C57BL/6 | LB | + | – | – | – | [305] | |||
WT, A30P, A53T | Mouse Thy-1 | C57BL/6 | + | + | + | – | + | ||||
WT, (A30P) | Mouse Thy-1 | C57BL/6 x DBA2 | + | + | IFC | + | + | ||||
Y39C | Mouse Thy-1 | FVB/N | + | + | CD | – | + | [309] | |||
A30P + A53T | Human Thy-1 | C57BL/6 x DBA2 | + | + | – | + | + | [310] | |||
(WT), (A30P), A53T | Mouse prion | C3H/HeJ 9 C57BL/6 J backcrossed into C57BL/6 J PARKIN KO | + | + | MD | – | + | ||||
WT, A53T | Mouse prion | C57BL/6 x C3H | + | + | RA | – | + | ||||
(WT), A53T | Mouse prion | FVB/N, FVB 9129, SNCA-KO | – | + | – | – | + | [315] | |||
(WT), A30P | Mouse prion | C57BL/6 J 9 DBA2 backcrossed into C57BL/6 J | – | + | ASP | – | – | [316] | |||
WT, A30P, A53T | Hamster prion | C57BL/6 J x SJL | – | + | – | – | + | ||||
WT, A30P, A53T | Rat THP | Swiss Webster x C57BL/DBA | – | – | – | – | – | [287] | |||
WT, A30P ± A53T | Rat THP | C57BL/6 | – | + | – | – | + | [319] | |||
WT, A30P, A53T | CaM-tTA (tet-off) | C57BL/6 (WT and A30P), C57BL/CH3 (WT and A53T) | – | + | CD | – | + | ||||
A30P | KI in endogenous SNCA | C57BL/6 | – | + | – | RD | + | [322] | |||
WT, A30P, A53T | Endogenous SNCA (BAC) | FVB/N 9129S6 / SvEvTac | – | + | + | – | + | [323] |
Role of mitochondrial damage and oxidative stress in PD
Role of excitotoxicity in PD
Neuroinflammation involved in PD
Prion hypothesis
Diagnosis of PD
Stages | Characteristics |
---|---|
Stage-I | Signs and symptoms on one side only; tremor of the limb; minute changes in posture, locomotion, and facial expression. |
Stage-II | Symptoms are both sides; minimal disability; posture and gait affected |
Stage-III | Slowing of body movements; early impairment of equilibrium on walking or sliding; generalized dysfunctions. |
Stage-IV | Severe symptoms; can still walk to a limited extent; rigidity and bradykinesia; unable to live alone; tremor may be less than in earlier stage. |
Stage-V | Cachectic stage; invalidism complete; cannot stand or walk; requires constant nursing care. |
Treatment of PD
Drug treatments in PD
Dopaminergic drugs
Drugs | Mode of action | Effects | Adverse side effects | Refs. |
---|---|---|---|---|
L-DOPA | Dopamine agonist | Increases dopamine concentrations | Nausea, vomiting, low blood pressure, restlessness, drowsiness. | |
Selegiline | MAO-B inhibitor | Maintains L-DOPA levels | Dizziness, dry mouth, insomnia, muscle pain, rash, nausea, constipation, severe headache, tachycardia, arrhythmia, hallucinations, chorea, or difficulty in breathing. | [326] |
Creatine | Boosts mitochondrial function | Antioxidant, prevents MPTP-induced neuronal damage | Nausea, stomach pain, diarrhea, muscle cramps; difficult breathing; swelling of face, lips, tongue, or throat, and weight gain. | [327] |
Bromocriptine, Apomorphine, Pramipexole, Rropinirole | Dopamine agonist | Increases dopamine levels | Drowsiness, nausea, vomiting, dry mouth, dizziness, leg swelling, and feeling faint upon standing, drop in blood pressure, confusion, hallucinations, or psychosis. | [328] |
Entacapone and tolcapone | preventing the breakdown of dopamine | prolongs the effects of L-DOPA | Hepatotoxic, nausea, diarrhea, orthostatic hypotension, urine discoloration and dizziness, mitochondrial dysfunction, | [329] |
Amantidine | Activate dopamine synthesis | Increases dopamine levels | Blurred vision, confusion, difficult urination, dizziness, fainting seeing, and hearing, swelling of the hands, feet, or lower legs. | [330] |
Rofecoxib | Inhibit COX-2 | Prevents inflammation | Back pain, diarrhea, dizziness, headache, heartburn, and loss of energy or weakness, nausea, stuffy or runny nose, swelling of legs and feet, blurred vision, constipation. | [331] |
ACP-103 (Pimavanserin) | Blocks serotonin receptors | Decrease levodopa-associated complications | Hyperprolactinemia, menstrual and sexual dysfunction, akathisia, distressful motor disturbance, restlessness | [332] |
GM1 gangliosides | Dimerization of tyrosine kinase A and increases neurotropic factors | Increases dopamine | Not known | [333] |
Quetiapine | Blocking of the dopamine type 2 (D2) and serotonin type 2 (5-HT2) receptors | Reduce psychosis and/or agitation | Agitation, dizziness, tremor, anxiety, hypertonia, abnormal dreams, dyskinesia, involuntary movements, confusion, amnesia, hyperkinesia, increased libido, abnormal gait, myoclonus, apathy, ataxia, hemiplegia, aphasia, buccoglossal syndrome | [334] |
Ubiquinone or coenzyme Q10 | Improves mitochondrial function | Antioxidant, slows disease progression in early-stages | Lower blood pressure, hemorrhage, skin itching, nausea, vomiting, headache or migraines, abnormal breathing, back pain, bronchitis, changes in attention, chest pain, constipation, coughing, diarrhea, dizziness, fainting, falling, fatigue, hearing loss, heart attack, indigestion, insomnia, irritability, loss of appetite, low energy, muscle pain, night sweats, respiratory tract infection, sore throat, urinary infection etc. | |
S-Adenosyl-methionine (SAM) | Methylates phospholipid and increase nerve-cell communication | Improves dopamine transmission, decreases depression | Gastrointestinal disorders, dyspepsia, and anxiety. | [337] |
Entacapone, tolcapone | COMT inhibitors | Inhibit DA breakdown | Diarrhea, nausea, sleeps disturbances, dizziness, urine discoloration, abdominal pain, low blood pressure, hallucinations. | [338] |
Non-dopaminergic drugs
Other drugs
Immunotherapies
Active immunization | Refs. | ||
---|---|---|---|
Animal models | Ag/Ab | Outcomes | |
Tg-mice expressing hSNCA under the PDGF-β promoter, D-line | rh-SNCA | Reduction of accumulated SNCA in neurons and higher number of synaptophysin-positive nerve terminals ameliorating neuronal damage, mild microglia activation | |
Sprague-Dawley rats injected with rAAV-SNCA into SN | rh-SNCA | Reduction of SNCA inclusions in SN, induction of regulated T cells and activated microglia | |
Two models: PDGF-SNCA mice expressing hSNCA under the PDGF-β promoter and mThy1-SNCA mice expressing hSNCA under the murine Thy1 promoter | C-terminus of SNCA (aa 110–130), also able to bind to full-length and N-terminal-truncated forms of α- syn, such as SNCA 96–140 | Reduced SNCA oligomers in axons and synapses, reduced degeneration of striatal TH-immunoreactive fibers, clearance of SNCA involved microglia, improved motor and cognitive deficits in both models | |
Mice expressing hSNCA under the control of the myelin basic protein promoter | Ag mimicking the C-terminus of SNCA or the original C-terminus peptide (aa 110–130) | Decreased accumulation of SNCA, reduced demyelination in neocortex, striatum and corpus callosum, reduced neurodegeneration, activation and clearance of SNCA by microglia, reduced spreading of SNCA to astrocytes | [341] |
Passive immunization | |||
Tg-mice expressing hSNCA under the PDGF-β promoter, D-line | SNCA C-terminus Ab-9E4 (IgG1), epitope 118–126 | Reduction of calpain-cleaved SNCA in neurons, no difference in microglia activation between control and Ab-treated mice, less motor and cognitive impairment | [342] |
Tg-mice expressing hSNCA under the PDGF-β promoter, M-line | SNCA C-terminus Ab274 (IgG2a), epitope 120–140 | Reduced accumulation of SNCA in neurons and astroglia, increased presence of SNCA in microglia, improved function in open field and pole tests | [180] |
Tg-mice expressing hSNCA under the Thy-1 promoter, line 61 | C-Terminus SNCA Ab: 1H7, 9E4, 5C1, and 5D12 | Attenuated synaptic and axonal pathology in cortex, hippocampus and striatum, reduced accumulation of C-terminus-truncated SNCA in striatal axons and mitigated loss of TH fibers, reduced astrogliosis and microgliosis, improved motor and cognitive deficits | [343] |
Tg-mice expressing hA30P SNCA under the Thy-1 promoter | SNCA protofibril-selective monoclonal Ab (mAb47) | Reductions of soluble and membrane-associated SNCA protofibrils in spinal cord, no change of astrocytic or microglial activity | |
Mice overexpressing hSNCA under the PDGF-β promoter (line D) | Single-chain fragment variables against oligomeric SNCA fused to the low-density lipoprotein receptor-binding domain of APOE-B | Decreased oligomeric and phosphorylated SNCA accumulation in neocortex and hippocampus, reduced levels of astrocytes, improved memory function | [344] |
Intrastriatal stereotaxic injections of SNCA preformed fibrils in wild type C57Bl6/C3H-mice | Monoclonal Ab: Syn303 (binds pathological conformations of human and mouse SNCA) targeting N-terminus) | Reduction of LB, amelioration of nigral DA-neuron loss, no differences in astrogliosis and microgliosis, improved motor behavior | [345] |
Fisher 344 male rats injected into SN with rAAV expressing hSNCA | Ab against the N-terminal or central region of SNCA | Lowered levels of SNCA, reduced SNCA-induced DA-neuron loss, decreased number of activated microglia, partial improvement of behavioral deficits | [346] |
Surgical treatments
Cell transplantation therapy
Gene therapy for PD
Supplementation of neurotrophic factors
Complementary and supportive therapies
Diet | Chemical compound (s) | Usefulness in Parkinson’s disease | Refs. |
---|---|---|---|
Fava beans | Levodopa | Increases dopamine levels. | |
Olive oil | Hydroxytyrosol | Antioxidants. | |
Turmeric powder | Curcuminoid | Antioxidants, decrease SNCA aggregation, anti-inflammatory | |
Cinnamon | Sodium benzoate | Stops the loss of Parkin and DJ-1 in Parkinson’s mice model. | |
Soy (genistein) | Isoflavone | Increases dopamine, dopamine transporters, and Bcl2 levels | |
Coffee | Caffeine | Antioxidants, adenosine A2A receptor antagonists. | |
Tea | Epigallocatechin-3-gallate (EGCG), theaflavins | Antioxidants, antiamyloid, decreases activity of COMT, increases dopamine uptake | |
Red wine | Resveratrol | Anti-amyloid, prevent blood clots and decreases inflammation. | |
Fish | Omega-3 fatty acids (DHA) | Antidepressant effect, lowers blood pressure, and decreases the risk of strokes and inflammation. |