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GeNeViSTA
Loci | Gene | Mode of inheritance | Clinical phenotype |
PARK1 (4q21-22) | SNCA | AD | EOPD |
PARK2 (6q25.2–q27) | PRKN | AR | Juvenile onset Parkinson disease |
PARK3 (2p13) | Unknown | AD | Classical PD |
PARK4 (4q21-22) | SNCA | AD | EOPD due to heterozygous triplication in SNCA gene. |
PARK5 (4p13) | UCHL1 | AD | Single family with late onset PD |
PARK6 (1p36.12) | PINK1 | AR | EOPD |
PARK7 (1p36.23) | DJ1 | AR | EOPD |
PARK8 (12q12) | LRRK2 | AD | Classical PD |
PARK9 (1p36) | ATP13A2 | AR | Juvenile onset atypical Parkinson disease (Kufor-Rakeb syndrome) |
PARK10 (1p32) | Unknown | AD | Classical PD |
PARK11 (2q37.1) | ?GIGYF2 | AD | Late onset PD; unconfirmed |
PARK12 (Xq21-25) | Unknown | X linked | Classical PD |
PARK13 (2q13.1) | HTRA2 | AD | Classical PD; unconfirmed |
PARK14 (22q13.1) | PLA2G6 | AR | Adult onset dystonia-Parkinsonism |
PARK15 (22q12.3) | FBX07 | AR | Early onset Parkinsonian pyramidal syndrome |
PARK16 (1q32) | Unknown | Not known | Susceptibility to Classical PD |
PARK17 (16q11.2) | VPS35 | AD | Classical PD |
PARK18 (3q27.1) | EIF4G1 | AD | Classical PD |
PARK19 (1p31.3) | DNAJC6 | AR | Early onset and juvenile PD |
PARK20 (21q22.11) | SYNJ1 | AR | EOPD |
PARK21 (3q22) | Unclear | AD | Classical PD |
PARK22 (7p11.2) | CHCHD2 | AD | Classical PD |
PARK23 (15q22.2) | VPS13C | AR | EOPD |
AD: Autosomal dominant
AR: Autosomal Recessive
PD: Parkinson disease
EOPD: Early onset Parkinson Disease
Autosomal dominant PD: Heterozygous variants in the SNCA, LRRK2, VPS35, CHCHD2 and EIF4G1 genes cause autosomal dominant forms of Parkinson disease. Generally autosomal dominant forms tend to manifest at a later age compared to autosomal recessive forms. SNCA is the first gene in which a mutation was identified in Parkinson disease and this gene codes for alpha- synuclein, which is the primary protein found in Lewy bodies. Disease causing variants in SNCA could be single nucleotide variants or gene duplications and triplications. The p.Gly2019Ser variant in LRRK2 accounts for 5-7% of autosomal dominant forms (Nichols et al.,2005).
Autosomal recessive PD: Autosomal recessive forms have an earlier onset of disease, mild non-motor symptoms and a slow progression. They are caused due to biallelic variations in PRKN which codes for Parkin, PINK1, ATP13A2, DNAJC6, SYNJ1 etc.
X-linked PD: PARK 12 is the only locus that has been shown to demonstrate X-linked transmission. ATP6AP2 is the gene that has been implicated in X-linked Parkinsonism (Korvatska et al., 2013).
The genes identified as causing idiopathic Parkinsonism are shown to affect four different processes: synaptic transmission, endosomal trafficking, lysosomal autophagy and energy metabolism.
Alpha- synuclein, which is found in presynaptic terminals in the central and autonomous nervous system, is involved in exocytosis and synaptic release of neurotransmitters and it is the main component of Lewy bodies. Triplications of the SCNA gene which codes for alpha synuclein lead to earlier onset of symptoms compared to duplications, implicating a dosage effect in the pathogenesis. The exact mechanism by which alpha synuclein leads to neuronal death and spreads throughout the CNS still remains unexplained. There are various theories regarding the spread of alpha synuclein pathology in the brain, like ‘selective vulnerability hypothesis’ and ‘pathogenic spread hypothesis’ (Lill, 2016).
LRRK2 codes for a protein kinase, which regulates glutamate transmission and striatal signal transduction (Lin et al., 2014). DNAJ6, a biallelic mutation of which causes autosomal recessive forms of Parkinsonism, encodes a protein auxilin, which aids in clathrin mediated synaptic vesicle recycling. Synaptojamin, a protein coded by SYNJ1, forms complexes with auxilin and has been implicated in autosomal recessive Parkinsonism.
This is a complex process by which the receptors or vesicles are internalized and then recycled in the Golgi complex or degraded in the lysosomes. VPS35 and DNAJC13 are implicated in endosomal trafficking causing Parkinsonism.
Alpha synuclein, which gets accumulated in cells in Parkinsonism, is not degraded by lysosomes and it is not clear whether this is the cause or effect of dysfunction in that pathway. Accumulation of intracellular alpha synuclein is found in many disorders like neuronal ceroid lipofuscinosis, Gaucher disease and Neimann-Pick type C. Heterozygous carriers of mutations in GBA, which in the homozygous state cause Gaucher disease, have an increased prevalence of Parkinsonism and Lewy body-associated dementia. It is postulated that accumulation of glucosylceramide due to decreased GBA enzyme activity, results in decreased lysosomal degradation of alpha synuclein (Mazzulli et al.,2011). ATP6AP2 which is implicated in X-linked Parkinsonism and ATP13A2 code for lysosomal proteins and when mutated cause impairment in lysosomal autophagy.
Mitochondrial dysfunction has been implicated in the pathogenesis of Parkinsonism and several mutations in genes in the common pathway in mitophagy in mitochondria cause Parkinsonism. The most important among them are PARK2, PINK1, FBXO7 and DJ1.
Three-generation pedigree, detailed family history and evaluation need to be done in every family to determine whether the cases are simplex or familial. Age of presentation of affected individuals and their relevant medical records should be collected and noted in detail. No formal guidelines have been formulated to regulate genetic testing in Parkinson disease (Klein et al., 2012).
Testing strategy can be stepwise single gene testing or multigene panel testing. In families with autosomal dominant inheritance, the European Federation of Neurological Sciences recommends screening for mutations in LRRK2. In specific populations with familial and sporadic PD, the same federation recommends screening for the LRRK2 mutation - p.G2019S. Testing for Parkin, PINK1 and DJ1 is indicated in families with autosomal recessive PD.
Without appropriate pretest counseling by a trained Medical Geneticist and/ or genetic counselor, molecular testing for Parkinson disease should not be attempted. Direct- to- consumer testing is available and is being used by patients and healthy at-risk individuals. With many susceptible loci being identified without ample evidence to prove causality, genetic counseling is crucial before molecular testing is ordered. Susceptibility testing should be strongly discouraged, especially in healthy individuals. Providing prenatal diagnostic testing for an adult onset disease is still debatable.
A family with an affected individual should be counseled regarding the environmental, epigenetic and genetic factors, which can cause Parkinson disease. Since Parkinson disease is a common neurodegenerative condition, the lifetime risk of developing this condition is 1-2% (Elbaz et al., 2002). The empiric risk of recurrence in a family with a sporadic case of late onset classical PD is 3-7%. (Elbaz et al., 2002). In monogenic forms, depending on the pattern of inheritance, the risk of recurrence will vary.
The treatment strategies being tried for Parkinson disease include pharmacologic therapy, therapies based on molecular mechanisms of disease, cell-based therapy and gene therapy.
a. Pharmacological therapy: The main intention of pharmacological methods is to achieve symptom control by normalizing dopamine levels. This includes monotherapy with dopaminergic drugs like levodopa, combination of levodopa-carbidopa, monoamine oxidase B inhibitors (MAO B inhibitors) and Catechol-o-methyl transferase inhibitors, which increase the levels of dopamine. Dopamine agonists like pramipexole and ropinirole can also be tried in early stages of disease. Non-dopaminergic drugs, which are useful, include anticholinergic compounds, antiviral drugs like amantadine, norepinephrine and serotonergic receptor and muscarinic related compounds. The main drawbacks of these pharmacological agents are that they cannot alleviate non-motor symptoms like dementia and mood disorders and they do not correct the abnormalities in cholinergic and serotonergic pathways.
b. Therapeutic strategies based on molecular mechanism of disease:
c. Surgical therapy: The two surgical approaches that are used for Parkinsonism include deep brain stimulation and pallidotomy or thalamotomy.
Small molecule | Targeted protein | Model | Effect | Reference |
BIOD303 | SCNA (Synuclein) | Neuronal cell culture | Synuclein accumulation decreased | Moore et al., 2015 |
ELN484228 and ELN484217 | SCNA (Synuclein) | Cortical neuron from embryonic rat | Rescue of synuclein-induced disruption of vesicle trafficking and dopaminergic neuronal loss and neurite retraction | Toth et al., 2014 |
Flavonoid epigallocatechin gallate (EGCG) | SCNA (Synuclein) | OLN-93 oligodendrocyte cell line | Neuroprotective effect by decreasing cytotoxicity | Lorenzen et al., 2014 |
Oligomer modulator anle138b | SCNA (Synuclein) | PD mouse model | Improved survival 50 weeks after onset of symptoms | Levin et al., 2014 |
PREP inhibitor, KYP-2047. | SCNA (Synuclein) | Homozygous A03P mice | Increases clearance of protein by increasing autophagy | Savolainen et al., 2014 |
NOS inhibitor, NG -nitro-L-arginine methyl ester (L-NAME) | Parkin | Mice model | Protection against dopamine neurotoxicity | Singh et al., 2013 |
STI 571 | Parkin | Cell model (SH-SY5Y) | Neuroprotective | Ko et al., 2010 |
K 560 | LRRK2 | Cellular and mice models | Prevented neuronal death by inhibiting HDAC1 and HDAC2 (Histone deacetylase) | Choong et al., 2016 |
Nurr1 agonists (Amodiaquine and chloroquine) | Nurr1 | Mice | Neuroprotective | Kim et al., 2015 |
Parkinson disease is a common neurodegenerative condition, which occurs due to interplay between environmental, epigenetic and genetic factors. Only 5-10% of Parkinson disease is due to monogenic causes. Genetic testing for Parkinson disease should be attempted with utmost care only after appropriate pretest counseling. Newer modalities of treatment for Parkinsonism like cell-based therapy are on the horizon with clinical trials being conducted now.
1. Barker RA, et al. Cell-based therapies for Parkinson disease – past insights and future potential. Nat Rev Neurol 2015;11: 492-503.
2. Barker RA, et al. Human Trials of Stem Cell-Derived Dopamine Neurons for Parkinson’s Disease: Dawn of a New Era. Cell Stem Cell 2017; 21: 569-573.
3. Choong CJ, et al. A novel histone deacetylase 1 and 2 isoform-specific inhibitor alleviates experimental Parkinson’s disease. Neurobiol Aging 2016; 37:103-116.
4. de Lau LM, et al. Epidemiology of Parkinson’s disease. Lancet Neurol 2006; 5: 525-535.
5. Elbaz A, et al. Risk tables for parkinsonism and Parkinson’s disease. J Clin Epidemiol 2002; 55: 25-31.
6. Klein C, Westenberger A. Genetics of Parkinson’s Disease. Cold Spring Harb Perspect Med 2012; 2: a008888.
7. Kim CH, et al. Nuclear receptor Nurr1 agonists enhance its dual functions and improve behavioral deficits in an animal model of Parkinson’s disease. Proc Natl Acad Sci USA 2015; 112: 8756-8761.
8. Ko HS, et al. Phosphorylation by the c-Abl protein tyrosine kinase inhibits parkin’s ubiquitination and protective function. Proc Natl Acad Sci USA 2010; 107: 16691-16696.
9. Korvatska O, et al. Altered splicing of ATP6AP2 causes X-linked parkinsonism with spasticity (XPDS). Hum Mol Genet 2013; 22: 3259-3268.
10. Levin J, et al. The oligomer modulator anle138b inhibits disease progression in a Parkinson mouse model even with treatment started after disease onset. Acta Neuropathol 2014; 127: 779-780.
11. Lill CM. Genetics of Parkinson’s disease. Mol Cell Probes 2016; 6: 386-396.
12. Lin MK, Farrer MJ. Genetics and genomics of Parkinson’s disease. Genome Med 2014; 6: 48.
13. Lorenzen N, et al. How Epigallocatechin Gallate Can Inhibit alpha-Synuclein Oligomer Toxicity in Vitro. J Biol Chem 2014; 289: 21299-21310.
14. Maiti P, et al. Current understanding of the molecular mechanisms in Parkinson’s disease: Targets for potential treatments. Transl Neurodegener 2017; 6: 28.
15. Mazzulli JR, et al. Gaucher disease glucocerebrosidase and alphasynuclein form a bidirectional pathogenic loop in synucleinopathies. Cell 2011; 146: 37-52.
16. Moree B, et al. Small molecules detected by second-harmonic generation modulate the conformation of monomeric alpha-synuclein and reduce its aggregation in cells. J Biol Chem 2015; 290: 27582-27593.
17. Nichols WC, et al. Genetic screening for a single common LRRK2 mutation in familial Parkinson’s disease. Lancet 2005; 365: 410-412.
18. Pankratz N, Foroud T. Genetics of Parkinson disease. NeuroRx 2004; 1: 235-242.
19. Parmar M. Towards stem cell based therapies for Parkinson’s disease. Development 2018; 145(1). pii: dev156117. doi: 10.1242/dev.156117.
20. Toth G, et al. Targeting the Intrinsically Disordered Structural Ensemble of alpha-Synuclein by Small Molecules as a Potential Therapeutic Strategy for Parkinson’s Disease. PLoS One 2014; 9: .
21. Trinh J, et al. Advances in the genetics of Parkinson disease. Nat Rev Neurol 2013; 9: 445-454.
22. Savolainen MH, et al. The beneficial effect of a prolyl oligopeptidase inhibitor, KYP-2047, alpha-synuclein clearance and autophagy in A30P transgenic mouse. Neurobiol Dis 2014; 68:1-15.
23. Singh S, et al. Involvement of nitric oxide in neurodegeneration: a study on the experimental models of Parkinson’s disease. Redox Rep 2005; 10:103-109.
24. Wagner J, et al. Anle138b: a novel oligomer modulator for disease-modifying therapy of neurodegenerative diseases such as prion and Parkinson’s disease. Acta Neuropathol 2013; 125:795-813.
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