Monogenetic forms of PD and its fly homolog(s).
Abstract
Parkinson’s disease (PD) is the second most common neurodegenerative disorder affecting approximately 1% of the population over age 50. PD is widely accepted as a multifactorial disease with both genetic and environmental contributions. Despite extensive research conducted in the area the precise etiological factors responsible remain elusive. In about 95% Parkinsonism is considered to have a sporadic component. There are currently no established curative, preventative, or disease-modifying interventions, stemming from a poor understanding of the molecular mechanisms of pathogenesis. Here lies the importance of animal models. Pharmacological insults cause Parkinsonian like phenotypes in Drosophila, thereby modelling sporadic PD. The pesticides paraquat and rotenone induced oxidative damage causing cluster specific DA neuron loss together with motor deficits. Studies in fly PD model have deciphered that signaling pathways such as phosphatidylinositol 3-kinase (PI3K/Akt and target of rapamycin (TOR), c-Jun N-terminal kinase (JNK) have been defective. Further, these studies have demonstrated that fruit fly can be a potential model to screen chemical compounds for their neuroprotective efficacy.
Keywords
- Parkinson's disease
- Drosophila
- dopaminergic neurons
- neurotoxicants
- genome‐wide screens
1. Introduction
Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer disease, affecting approximately 1% of the population over the age of 50. Frequency of PD increases with age, but an expected 4% of people with this disease are detected earlier the age of 50. It is assessed that 7–10 million people worldwide are suffering from PD. About one million Americans are surviving with PD, which is more than the collective number of sufferers diagnosed with muscular dystrophy, Lou Gehrig's disease, and multiple sclerosis. Further, about 60,000 Americans are diagnosed with PD each year and this number does not mirror thousands of unnoticed cases [1]. Studies illustrate that prevalence of PD in men is significantly higher (one and half times more) than in women. In poor and developing nations of Asia and Africa no systematic data are available about the number of sufferers. Painful truth is that in these regions, millions of elderly suffer in silence due to poverty and ignorance.
PD is widely accepted as a multifactorial disease with both genetic and environmental contributions. Clinical signs comprise bradykinesia, resting tremble, muscular rigidity, and postural unsteadiness. Supplementary symptoms are characteristic postural anomalies, dystonic spams, and dementia. PD is progressive and usually has a devious onset in mid to late adult life. Pathogenic characters of typical PD comprise loss of dopaminergic neurons in the
Despite intensive research conducted in the field of PD, the etiology of this neurodegenerative disease remains elusive. Although genetic elements and exposure to environmental toxins, such as pesticides, are thought to play a crucial role in disease onset, aging remains the predominant risk factor [3]. In about 95% patients, Parkinsonism is considered to have a sporadic component. Some findings suggest that environmental factors may be more important than genetic factors in familial aggregation of PD. In maximum PD cases the cause is environmental influence, probably toxic, overlaid on a background of slow, sustained neuronal loss due to progressing age [4]. Finding PD in 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) drug consumers rejuvenated curiosity in reassessing environmental influences [5]. Another theory of Parkinsonism suggests that genetic predisposition may be transmitted through mitochondrial inheritance.
Current therapeutic strategies for PD mitigate symptoms by the replacement of dopamine, with variable efficacy and considerable side effects. Levodopa (L‐dopa), a dopamine precursor, the leading treatment of PD for over 40 years, improves motor impairment by increasing dopamine levels [6]. However, continued use of L‐dopa leads to other motor dyskinesias that undermine the benefits of treatment. The development of effective treatment for PD is difficult because pathology is affected by several pathways that may act serially or in parallel. However, there are currently no established curative, preventative, or disease‐modifying interventions, stemming from a poor understanding of the molecular mechanisms of pathogenesis.
This chapter primarily aims to present an overview of the sporadic PD, disease modeling in
2. Animal models of Parkinson's disease
Animal models have been invaluable tools for investigating the underlying mechanisms of the pathogenesis of PD. However, the usefulness of these models is dependent on how precisely they replicate the features of clinical PD. Nonmammalian models are a great cost‐effective alternative to rodent and primate‐based models, allowing rapid high‐throughput screening of novel therapies and investigation of genetic and environmental risk factors. Thus far, the nonmammalian rotenone models have included worm (
Contemporary knowledge on the potential pathogenic and pathophysiological mechanisms of PD derives from innumerable studies conducted, in the past four decades, on experimental models of PD. While animal models, in particular, have provided invaluable information, they also offer the opportunity of trying new therapeutic methods. These model systems have been traditionally grounded on the exposure of neurotoxins able to imitate
Sym bol |
Gene locus |
Gene | homolog |
Inheri tance |
Disorder | Status and remarks |
---|---|---|---|---|---|---|
PARK1 | 4q21‐22 | SNCA [10] | No homolog |
AD | Early‐onset Parkinsonism |
Confirmed |
PARK2 | 6q25.2‐ q27 |
PARK2 encoding Parkin[11] |
Parkin | AR | Early onset Parkinsonism |
Confirmed |
PARK3 | 2p13 | Unknown | – | AD | Classical Parkinsonism |
Unconfirmed |
PARK4 | 4q21‐ q23 |
SNCA | No homolog | AD | Early‐onset Parkinsonism |
Erroneous locus (identical to PARK1) |
PARK5 | 4p13 | UCHL1 | Uch | AD | Classical Parkinsonism |
Unconfirmed |
PARK6 | 1p35‐p36 | PINK1 [12] | Pink1 | AR | Early onset Parkinsonism |
Confirmed |
PARK7 | 1p36 | PARK7 encoding DJ‐1[13] |
Dj‐1α and dj‐1β |
AR | Early onset Parkinsonism |
Confirmed |
PARK8 | 12q12 | LRRK2 [14] | Lrrk | AD | Classical Parkinsonism |
Confirmed |
PARK9 | 1p36 | ATP13A2 [15] |
CG32000 | AR | Kufor–Rakeb syndrome, a formof juvenile‐ onset atypical Parkinsonism with dementia, spasticity and supranuclear gaze palsy |
Confirmed |
PARK10 | 1p32 | Unknown | – | Risk factor |
Classical Parkinsonism |
Confirmed susceptibility locus |
PARK11 | 2q36‐27 | Unknown (maybe GIGYF2) |
– | AD | Late onset Parkinsonism |
Not independently confirmed |
PARK12 | Xq21‐ q25 |
Unknown | – | Risk factor |
Classical Parkinsonism |
Confirmed susceptibility locus |
PARK13 | 2p12 | HTRA2 | HtrA2 | AD or risk factor |
Classical Parkinsonism |
Unconfirmed |
PARK14 | 22q13.1 | PLA2G6 [16] | iPLA2‐VIA | AR | Early‐onset dystonia‐ Parkinsonism |
Confirmed |
PARK15 | 22q12‐ q13 |
FBXO7 [17] | No homolog |
AR | Early‐onset Parkinsonian‐ pyramidal syndrome |
Confirmed |
PARK16 | 1q32 | Unknown (maybe RAB7L1) |
– | Risk factor |
Classical Parkinsonism |
Confirmed susceptibility locus |
PARK17 | 16q11.2 | VPS35 | Vps35 | AD | Classical Parkinsonism |
Unconfirmed |
PARK18 | 6p21.3 | EIF4G1 | eIF4G | AD | Late onset Parkinsonism |
Unconfirmed |
PARK19 | 1p31.3 | DNAJC6 [18] | Auxillin | AR | Juvenile‐ onset Parkinsonism |
Confirmed |
PARK20 | 21q22.11 | SYNJ1 [19, 20] | Synj | AR | Early‐ onset Parkinsonism |
Confirmed |
3. Pathophysiology of Parkinson's disease
3.1. Sporadic Parkinson's disease: an overview
A sporadic disease can be explained as a disease occurring randomly in a population with no known cause. In sporadic PD, the cause is considered to be environmental though the genetic influence is also present and hence the pathogenesis of PD is likely to be multifactorial which may involve gene–environment interactions. The discovery of MPTP (1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine), which reproduces pathological features of idiopathic Parkinsonism by targeting the nigrostriatal system [28] and pesticides (such as rotenone and paraquat), has implicated environmental toxins in the induction of sporadic PD [29, 30]. Both epidemiological and experimental data suggest the potential involvement of specific agents such as neurotoxicants (e.g., pesticides) or neuroprotective compounds (e.g., tobacco products) in the pathogenesis of nigrostriatal degeneration, further supporting a relationship between the environment and PD [28]. Further, the identification of the mutated α‐synuclein (SCNA) gene causing familial PD [10] as a risk factor for sporadic disease [31] provides a genetic context for the disease. The finding of α‐synuclein as a key component of the Lewy body [32] further links this gene to potential molecular mechanisms of PD.
3.2. Environmental basis of sporadic PD
The study of environmental risk factors for PD is difficult because environmental exposures and gene–environment interactions may occur well before the onset of clinical symptoms since it remains undetected for many years. Moreover, the severe neurodegenerative changes that underlie the symptoms of PD may be the result of synergistic effects of multiple exposures and these effects could have been compounded by increased vulnerability of the aging nigrostriatal system to toxic injury over the years. Epidemiological and case–control studies suggest that rural residence, well water consumption, pesticide use, and certain occupations (farming, mining, and welding) are associated with an increased risk of PD [33–36].
Epidemiological studies have suggested an association with environmental toxins, mainly mitochondrial complex I inhibitors like rotenone [37, 38]. The results are consistent with a dose‐dependent effect in agricultural workers and the risk increased with duration of pesticide use [39, 40]. Data also suggest that exposure to specific pesticide such as bipyridyl, organochlorine, and carbamate derivatives could have a causal role in PD [39, 41]. Further, chronic exposure to metals/pesticides is also associated with a younger age at onset of PD among patients with no family history of the disease and that duration of exposure is a factor in the magnitude of this effect [42]. For instance, a study in Taiwan, where the herbicide paraquat (PQ) is commonly spurted on rice fields, a robust relationship was testified between paraquat contact and PD menace and the danger was amplified by more than six times in individuals who had been exposed to PQ chronically [43].
3.3. Environment toxins and their mechanisms of action
The accidental discovery of MPTP leading to Parkinsonian syndrome stimulated the search for environmental factors as potential causes of PD. Several epidemiological studies have suggested that environmental toxins are one of the major causes of sporadic PD [44]. Sporadic PD's main cause is the accumulation of alpha‐synuclein but by an uncertain causative agent and uneven occurrence point in age of patients. The mechanisms by which the neurotoxins induce PD‐like symptoms are briefly described below.
4. Molecular pathways in sporadic PD
Though Mendelian genes are responsible only for a small subset of PD patients, it is speculated that the same pathogenetic mechanisms could also play a relevant role in the development of more frequent sporadic PD [64]. With advancement in molecular biotechnological tools and techniques, a number of genes and proteins linked to PD have been identified, which reveal a complex network of molecular pathways involved in its etiology, suggesting that common mechanisms underlie both familial and sporadic forms of PD (Table 2) [65–79]. Three predominat pathways that can trigger the neurodegenerative process are as follows: (a) accumulation of aggregated and misfolded proteins, (b) impairment of the ubiquitin protein pathway (UPS) and the autophagy pathway, and (c) mitochondrial dysfunction [64]. Functional studies on the proteins encoded by PD‐related genes supports these pathways and it is confirmed by both pathological and biochemical studies performed in patients with sporadic PD with no apparent genetic cause [80–82]. Further, critical cellular protective pathways, such as autophagy, UPS, and mitochondria dynamics, are shown to lose adeptness with increasing age and there is a progressive build‐up of somatic mutations particularly in the mitochondrial DNA during aging process [64]. Recent studies have shown the role for chronic neuroinflammation and microglia activation in PD pathogenesis, suggesting that different molecular/cellular events may contribute to neurodegeneration by activating resident microglial populations in selected brain areas, with potential detrimental effects on vulnerable neuronal populations [83].
Compound treatment |
model |
Modifies phenotype(s) |
Pathway/ process |
References |
---|---|---|---|---|
Sulforaphane and allyl Disulfide |
DA neuron number |
Oxidative stress |
[65] | |
α |
DA neuron number |
[65] | ||
α |
Locomotor activity |
[66] | ||
Polyphenols | α |
Lifespan, Locomotor activity |
[67] | |
Paraquat and Iron |
Locomotor activity |
[68] | ||
α‐Tocopherol | Lifespan | [69] | ||
Ommatidial degeneration |
[70] | |||
SOD | Ommatidial degeneration |
[70] | ||
Melatonin | Lifespan | [69] | ||
Paraquat | Locomotor activity |
[71] | ||
Rotenone | Locomotor activity, Dopamine neuron number |
[71] | ||
leaf extract |
Paraquat; Rotenone |
Oxidative markers; Mitochondrial functions |
[72, 73] | |
Minocycline | DJ‐1α | DA neuron number, dopamine levels |
Oxidative stress/ inflammatory process |
[74] |
Celestrol | DJ‐1α | DA neuron number, dopamine levels, Locomotor activity and survival rate under oxidative stress conditions |
[74] | |
Rapamycin | Parkin/PINK1 | Thoracic indentations, Locomotor activity, DA neuron number, and muscle integrity. |
TOR signaling |
[75] |
Geldanamycin | α‐ synuclein |
DA neuron number |
Removal of excess or toxic protein forms |
[76, 77] |
Zinc Chloride |
Parkin | Life span, Locomotor activity, and percentage of adulthood survivors. |
Zinc homeostasis |
[78] |
4.1. Genetic basis of sporadic PD
The use of genetically tractable organisms to model gene–environment interactions has become an efficient means of identifying genetic risk factors [84, 85]. Functional characterization of the genes involved in familial PD has shown significant comprehensions into the molecular mechanism(s) responsible to the pathogenesis of PD. Abnormal protein and mitochondrial homeostasis are the crucial factors behind the development of PD, with oxidative stress playing a vital connection between the two events. Genome‐wide association studies (GWAS) showed variations in α
The recent application of high throughput whole genome and exome analysis technologies along with bioinformatics has provided valuable inputs in the identification of novel susceptibility loci involved in apparent sporadic PD. It is predicted that many more variants remained to be discovered despite the success of GWAS in discovering novel genetic variants in PD. In this regard, genome‐wide complex trait analysis [91, 92] may prove useful for a more exhaustive screening for PD risk variants [93]. Groundbreaking efforts have begun to establish the relationship between single nucleotide polymorphisms (SNPs) identified by GWAS and gene expression levels to describe their functional meaning. This approach has provided significant insights into various potential novel mechanisms underlying the observed SNP associations with PD etiology.
4.2. Interaction between genetics and environment
The concept that gene–environment interactions affect PD susceptibility was proposed more than a decade ago [94]. Although many studies have described positive associations between genetic polymorphisms and increased risk for PD, only a few human association studies have examined gene–environment interactions. Occupational pesticide exposure as well as high exposure to PQ and MB in carriers of DAT genetic variants was shown to increase the PD risk [36, 95]. Further, SNP in
5. Insights into sporadic PD pathophysiology through Drosophila
The fruit fly
Mutations that induce loss of function or inactivation of the fly homologs of mutations of fly homologs of PINK1, parkin, DJ‐1, or LRKK2 lead to selective DA degeneration leading to mobility defects that can be characterized through behavioral assays.
5.1. Induction of PD in Drosophila
5.2. Toxin models of Drosophila for PD
Several environmental chemicals (neurotoxins) have been employed to recapitulate PD‐like symptoms and pathology in
6. Application of Drosophila model: screening platform for assessment of neuroprotective potential
6.1. Plant‐derived neuroprotective agents in PD
The
7. Notable limitations
Animal models are absolutely necessary for reproducing physiologic and neurosystems aspects of neurodegenerative disorders. However, animal models are complicated by the differing expression levels and patterns of expression of target genes, with different promoters among other issues for genetic models, and complexities of drug administration, drug distribution, and metabolism for toxin models [79]. Rodent models have faced limitations due to lack of strong construct (i.e., genotype or intervention) and face validity (i.e., phenotype), as well as species and strain limitations. In general, toxin‐induced PD models do not recapitulate the process of progressive neuron loss and the protein aggregation in LBs, due to the acute nature of the neurotoxin treatment [137, 138], but they have been useful to support the concept that alterations in mitochondrial biology are essential for the development of PD [139]. However, animal models allow studying a cellular process in the context of a whole organism and are thus more reliable.
Research on PD using cell cultures has many advantages in which they allow rapid screening for disease pathogenesis and drug candidates. Cellular models can be easily used for molecular, biochemical, and pharmacological approaches, but they can lead to misinterpretation and artifacts.
While there are many advantages of the fly PD model, the most common disadvantage is that the important pathogenetic factors which are vertebrate‐specific may be ignored in invertebrate models. The differences between mammals and invertebrates represent potential drawbacks in modeling brain diseases such as PD [141].
8. Potential opportunities
Some of the unique features of the
9. Future perspectives
Identification of PD risk locus SREBF1 through GWAS (genome‐wide association studies) analysis and substantiating its biological function as a regulator of mitophagy [158] remarkably emphasize the importance and potential to decipher the risk loci for idiopathic PD through genome‐wide screens in animal models. However, no systematic genome‐wide functional screens are performed in sporadic PD models. Here lies the importance and necessity to perform genome‐wide screen to identify the risk locus for idiopathic PD. Comprehensive efforts in this direction will provide novel insights into the molecular mechanisms behind the dopaminergic neurodegeneration and also figure out genetic basis for sporadic PD. Here lies the potential relevance and advantage of fly genetics and available technologies such as UAS‐Gal4, fly deletion lines, and RNAi lines, which can be of great help to figure out novel players, pathways, and mechanistic interactions among neurodegenerative disorders. Hence, it is worth placing future endeavors in this direction.
10. Conclusion
In this chapter, we have provided an overview of current knowledge on the pathophysiology of sporadic PD employing
Acknowledgments
This work is partly supported by the Department of Biotechnology (DBT), Ministry of Science and Technology, India (R&D grant nos. BT/249/NE/TBP/2011, 25‐4‐2012, and BT/405/NE/U‐Excel/2013, 11‐12‐2014), to the corresponding author. Dr Muralidhara is a recipient of DBT (Department of Biotechnology, India) Visiting Research Professorship under the North–East scheme.
References
- 1.
http://www.pdf.org/en/parkinson_statistics (Accessed 2016:04:09) - 2.
Polymeropoulos MH, Higgins JJ, Golbe LI, Johnson WG, et al: Mapping of a gene for Parkinson's disease to chromosome 4q21‐q23. Science. 1996;274:1197–1199 - 3.
Reeve A, Simcox E, Turnbull D: Ageing and Parkinson's disease: why is advancing age the biggest risk factor? Ageing Res Rev. 2014; 14:19–30 - 4.
Calne DB, Langston JW: Aetiology of Parkinson's disease. Lancet. 1983;2(8365–8366):1457–1459 - 5.
Langston JW, Ballard P, Tetrud JW, Irwin I: Chronic Parkinsonism in humans due to a product of melperidine‐analog, synthesis. Science. 1983;219:979–980 - 6.
Poewe W, Antonini A, Zijlmans JCM, Burkhard PR: Levodopa in the treatment of Parkinson's disease: an old drug still going strong. Clin Interv Aging. 2010;5:229–238 - 7.
Tieu K: A guide to neurotoxic animal models of Parkinson's disease. Cold Spring Harb Perspect Med. 2011;1(1):a009316 - 8.
Meredith GE, Sonsalla PK, Chesselet M‐F: Animal models of Parkinson's disease progression. Acta Neuropathol. 2008;115(4):385–398 - 9.
Bezard E, Przedborski S: A tale on animal models of Parkinson's disease. Mov Disord. 2011;26(6):993–1002. DOI:10.1002/mds.23696 - 10.
Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, et al: Mutation in the alpha‐synuclein gene identified in families with Parkinson's disease. Science. 1997;276:2045–2047 - 11.
Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, et al: Mutations in the parkin gene cause autosomal recessive juvenile Parkinsonism. Nature. 1998;392:605–608 - 12.
Valente EM, Abou‐Sleiman PM, Caputo V, Muqit MMK, et al: Hereditary early‐onset Parkinson's disease caused by mutations in PINK1. Science. 2004;304:1158–1160 - 13.
Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ et al: Mutations in the DJ‐1 gene associated with autosomal recessive early‐onset Parkinsonism. Science. 2003;299:256–259 - 14.
Paisán‐Ruíz C, Jain S, Evans EW, Gilks WP, et al: Cloning of the gene containing mutations that cause PARK8‐linked Parkinson's disease. Neuron. 2004;44:595–600 - 15.
Ramirez A, Heimbach A, Grundemann J, Stiller B, Hampshire D, et al: Hereditary Parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P‐type ATPase. Nat Genet. 2006;38:1184–1191 - 16.
Paisan‐Ruiz C, Bhatia KP, Li A, Hernandez D, Davis M, et al: Characterization of PLA2G6 as a locus for dystoniaparkinsonism. Ann Neurol. 2009;65:19–23 - 17.
Shojaee S, Sina F, Banihosseini SS, Kazemi MH, Kalhor R, et al: Genome‐wide linkage analysis of a Parkinsonian‐pyramidal syndrome pedigree by 500 K SNP arrays. Am J Hum Genet. 2008;82:1375–1384 - 18.
Edvardson S, Cinnamon Y, Ta‐Shma A, Shaag A, et al: A deleterious mutation in DNAJC6 encoding the neuronal‐specific clathrin‐uncoating co‐chaperone auxilin, is associated with juvenile Parkinsonism. PLoS One. 2012;7:e36458. DOI:10.1371/journal.pone.0036458 - 19.
Krebs CE, Karkheiran S, Powell JC, Cao M, Makarov V, et al: The Sac1 domain of SYNJ1 identified mutated in a family with early‐onset progressive Parkinsonism with generalized seizures. Hum Mutat. 2013;34:1200–1207 - 20.
Quadri M, Fang M, Picillo M, Olgiati S, Breedveld GJ, et al: Mutation in the SYNJ1 gene associated with autosomal recessive, early‐onset Parkinsonism. Hum Mutat. 2013;34:1208–1215 - 21.
Marras C, Lohmann K, Lang A, Klein C: Fixing the broken system of genetic locus symbols: Parkinson disease and dystonia as examples. Neurology. 2012;78:1016–1024 - 22.
Yue Z: LRRK2 in Parkinson's disease: in vivo models and approaches for understanding pathogenic roles. FEBS J. 2009;276(22):6445–6454 - 23.
Liu Z, Hamamichi S, Lee BD, et al: Inhibitors of LRRK2 kinase attenuate neurodegeneration and Parkinson‐like phenotypes in Caenorhabditis elegans and Drosophila Parkinson's disease models. Hum Mol Genet. 2011;20(20):3933–3942 - 24.
Bove J, Prou D, Perier C, Przedborski S: Toxin induced models of Parkinson's disease. NeuroRx. 2005;2:484–494 - 25.
Betarbet R, Sherer TB, DiMonte DA, Greenamyre JT: Mechanistic approaches to Parkinson's disease pathogenesis. Brain Pathol. 2002;12:499–510 - 26.
Gerlach M, Desser H, Youdim MBH, Riederer P: New horizons in molecular mechanisms underlying Parkinson's disease and in our understanding of the neuroprotective effects of selegiline. J Neural Transm. 1996;48:7–21 - 27.
Zigmond MJ, Stricker EM: Animal models of Parkinsonism using selective neurotoxins: clinical and basic implications. Int Rev Neurobiol. 1989;31:1–79 - 28.
Di Monte DA, Mitra Lavasani, Manning‐Bog AB: Environmental factors in Parkinson's disease. NeuroToxicology. 2002;23:487–502 - 29.
McCormack AL, Thiruchelvam M, Manning‐Bog AB, Thiffault C, et al: Environmental risk factors and Parkinson's disease: selective degeneration of nigral dopaminergic neurons caused by the herbicide paraquat. Neurobiol Dis. 2002;10:119 –127 - 30.
Uversky VN: Neurotoxicant‐induced animal models of Parkinson's disease: understanding the role of rotenone, Maneb and paraquat in neurodegeneration. Cell Tissue Res. 2004;318:225–241 - 31.
Simon‐Sanchez J, Schulte C, Bras JM, Sharma M, et al: Genome‐wide association study reveals genetic risk underlying Parkinson's disease. Nat Genet. 2009;41(12):1308–1312 - 32.
Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, et al: Alpha‐synuclein in Lewy bodies. Nature. 1997;388:839–840 - 33.
Dhillon AS, Tarbutton GL, Levin JL, Plotkin GM, et al: Pesticide/environmental exposures and Parkinson's disease in East Texas. J Agromedicine. 2008;13:37–48 - 34.
Elbaz A, Clavel J, Rathouz PJ, Moisan F, et al: Professional exposure to pesticides and Parkinson disease. Ann Neurol. 2009;66:494–504 - 35.
Kamel F, Tanner C, Umbach D, Hoppin J, et al: Pesticide exposure and self‐reported Parkinson's disease in the agricultural health study. Am J Epidemiol. 2007;165:364–374 - 36.
Ritz BR, Manthripragada AD, Costello S, Lincoln SJ, et al: Dopamine transporter genetic variants and pesticides in Parkinson's disease. Environ Health Perspect. 2009;117:964–969 - 37.
Coulom H, Birman S: Chronic exposure to rotenone models sporadic Parkinson's disease in Drosophila melanogaster. J Neurosci. 2004;24(48):10993–10998 - 38.
Ascherio A, Chen H, Weisskopf MG, O’Reilly E, et al: Pesticide exposure and risk for Parkinson's disease. Ann Neurol. 2006;60:197–203 - 39.
Liou HH, Tsai MC, Chen CJ, et al: Environmental risk factors and Parkinson's disease: a case‐control study in Taiwan. Neurology. 1997;48:1583–1588 - 40.
Petrovitch H, Ross GW, Abbott RD, Sanderson WT, et al: Plantation work and risk of Parkinson's disease in a population‐based longitudinal study. Arch Neurol. 2002;59:1787–1792 - 41.
Seidler A, Hellenbrand W, Robra BP, Veiregge P, et al: Possible environmental, occupational, and other etiologic factors for Parkinson's disease: a case‐control study in Germany. Neurology. 1996;46:1275–1284 - 42.
Ratner MH, David HF, Josef O, Robert GF, Raymon D: Younger age at onset of sporadic Parkinson's disease among subjects occupationally exposed to metals and pesticides. Interdiscip Toxicol. 2014;7(3):123–133 - 43.
Di Monte DA: The environment and Parkinson's disease: is the nigrostriatal system preferentially targeted by neurotoxins? Lancet Neurol. 2003;2(9):531–538 - 44.
Uversky VN, Li J, Bower K, Fink AL: Synergistic effects of pesticides and metals on the fibrillation of alpha‐synuclein: implications for Parkinson's disease. Neurotoxicology. 2002;23(4–5):527–536 - 45.
Chiba K, Trevor AJ, Castagnoli Jr. N :Active uptake of MPP+, a metabolite of MPTP, by brain synaptosomes. Biochem Biophys. Res Commun. 1985;128:1228–1232 - 46.
Javitch JA, D’Amato RJ, Strittmatter SM, Snyder SH: Parkinsonism inducing neurotoxin, N‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine: uptake of the metabolite N‐methyl‐4‐phenylpyridine by dopamine neurons explains selective toxicity. Proc Natl Acad Sci USA. 1985;82:2173–2177 - 47.
Daniels AJ, Reinhard Jr. JF: Energy‐driven uptake of the neurotoxin 1‐methyl‐4‐phenylpyridinium into chromaffin granules via the catecholamine transporter. J Biol Chem. 1988;263:5034–5036 - 48.
Miller GW, Gainetdinov RR, Levey AI, Caron MG: dopamine transporters and neuronal injury. Trends Pharmacol Sci. 1999;20:424–429 - 49.
Javoy F, Sotelo C, Herbet A, Agid Y: Specificity of dopaminergic neuronal degeneration induced by intracerebral injection of 6‐hydroxydopamine in the nigrostriatal dopamine system. Brain Res. 1976;102:201–215 - 50.
Jeon BS, Jackson‐Lewis V, Burke RE: 6‐Hydroxydopamine lesion of the rat substantia nigra: time course and morphology of cell death. Neurodegeneration. 1995;4:131–137 - 51.
Dauer W, Przedborski S: Parkinson's disease: mechanisms and models. Neuron. 2003;39:889–909 - 52.
Cicchetti F, Drouin‐Ouellet L, Gross RE: Environmental toxins and Parkinson's disease: what we have learned from pesticides‐induced animal models? Trends Pharmacol Sci. 2009;30(9):475–483 - 53.
Wang XF, Li S, Chou AP, Bronstein JM: Inhibitory effects of pesticides on proteasome activity: implication in Parkinson's disease. Neurobiol Dis. 2006;23:198–205 - 54.
Olanow CW: The pathogenesis of cell death in Parkinson's disease. Mov Disord. 2007;22 (17):335–342 - 55.
Shimizu K, Ohtaki K, Matsubara K, Aoyama K, et al: Carrier‐mediated processes in blood–brain barrier penetration and neural uptake of paraquat. Brain Res. 2001;906:135–142 - 56.
Miller GW: Paraquat: the red herring of Parkinson's disease research. Toxicol Sci. 2007;100:1–2 - 57.
Fei Q, McCormack AL, Di Monte DA, Ethell DW: Paraquat neurotoxicity is mediated by a Bak dependent mechanism. J Biol Chem. 2008;283:3357–3364 - 58.
Zhang J, Fitsanakis VA, Gu G, Jing D, et al: Manganese ethylene‐bis‐dithiocarbamate and selective dopaminergic neurodegeneration in rat: a link through mitochondrial dysfunction. J Neurochem. 2003;84:336–346 - 59.
Fei Q, Ethell DW: Maneb potentiates paraquat neurotoxicity by inducing key Bcl‐2 family members. J Neurochem. 2008;105:2091–2097 - 60.
Gorell JM, Johnson CC, Rybicki BA, Peterson EL, et al: Occupational exposures to metals as risk factors for Parkinson's disease. Neurology. 1997;48:650–658 - 61.
Mergler D, Baldwin M: Early manifestations of manganese neurotoxicity in humans: an update. Environ Res. 1997;73:92–100 - 62.
Pal PK, Samii A, Calne DB: Manganese neurotoxicity: a review of clinical features. Neurotoxicology. 1999;20:227–238 - 63.
Dexter DT, Carayon A, Vidailhet M, Ruberg M, et al: Decreased ferritin levels in brain in Parkinson's disease. J Neurochem. 1990;55:16–20 - 64.
Valentea EM, Arenaa G, Torosantuccia L, Gelmettia V: Molecular pathways in sporadic PD. Parkinsonism Related Disorders. 2012;18(1):71–73 - 65.
Trinh K, Moore K, Wes PD, et al: Induction of the phase II detoxification pathway suppresses neuron loss in Drosophila models of Parkinson's disease, J Neurosci. 2008;28(2):465–472 - 66.
Wassef R, Haenold R, Hansel A, Brot N: Methionine sulfoxide reductase A and a dietary supplement S‐methyl‐L‐cysteine prevent Parkinson's‐like symptoms, J Neurosci. 2007;27(47):12808–12816 - 67.
Long JH, Gao L, Sun L, Liu J, Zhao‐Wilson X: Grape extract protects mitochondria from oxidative damage and improves locomotor dysfunction and extends lifespan in a Drosophila Parkinson's disease model. Rejuvenation Res. 2009;12(5):321–331 - 68.
Jimenez‐Del‐Rio M, C Guzman‐Martinez, C Velez‐Pardo: The effects of polyphenols on survival and locomotor activity in Drosophila melanogaster exposed to iron and paraquat. Neurochem Res. 2010;35:227–238 - 69.
Lavara‐Culebras E, Mu˜noz‐Soriano V, G’omez‐Pastor R, Matallana E, and Paricio N: Effects of pharmacological agents on the lifespan phenotype of Drosophila DJ‐1β mutants. Gene. 2010;462(1–2):26–33 - 70.
Wang D, Qian L, Xiong H, et al: Antioxidants protect PINK1‐dependent dopaminergic neurons in Drosophila. Proc Natl Acad Sci USA. 2006a;103(36):13520–13525 - 71.
Chaudhuri A, Bowling K, Funderburk C, Lawal H, et al: Interaction of genetic and environmental factors in a Drosophila Parkinsonism model. J Neurosci. 2007;27(10):2457–2467 - 72.
Hosamani, R., Muralidhara: Neuroprotective efficacy of Bacopa monnieri against rotenone induced oxidative stress and neurotoxicity in Drosophila melanogaster. Neurotoxicology. 2009;30:977–985 - 73.
Hosamani R, Ramesh SR, Muralidhara: Attenuation of rotenone‐induced mitochondrial oxidative damage and neurotoxicity in Drosophila melanogaster supplemented with creatine. Neurochem Res. 2010;35(9):1402–1412 - 74.
Faust K, Gehrke S, Yang Y, Yang L, et al: Neuroprotective effects of compounds with antioxidant and anti‐inflammatory properties in a Drosophila model of Parkinson's disease. BMC Neurosci. 2009;10:109 - 75.
Tain LS, Chowdhury RB, Tao RN, et al: Drosophila HtrA2 is dispensable for apoptosis but acts downstream of PINK1 independently from Parkin. Cell Death Differentiation. 2009;16(8):1118–1125 - 76.
Auluck PK, Chan HY, Trojanowski JQ, Lee VM, Bonini NM: Chaperone suppression of alpha‐synuclein toxicity in a Drosophila model for Parkinson's disease. Science. 2002;295:865–868. - 77.
Auluck PK, Meulener MC, Bonini NM: Mechanisms of suppression of α‐synuclein neurotoxicity by geldanamycin in Drosophila. J Biol Chem. 2005;280:2873–2878. - 78.
Saini N, Schaffner W: Zinc supplement greatly improves the condition of parkin mutant Drosophila. BiolChem. 2010;391(5):513–518 - 79.
Munoz‐Soriano V, Paricio N: Drosophila models of Parkinson's disease: discovering relevant pathways and novel therapeutic strategies. Parkinson's Disease. 2011;1–14. DOI:10.4061/2011/520640 - 80.
Burbulla LF, Kruger R: Converging environmental and genetic pathways in the pathogenesis of Parkinson's disease. J Neurol Sci. 2011;306:1–8 - 81.
Martin I, Dawson VL, Dawson TM: Recent advances in the genetics of Parkinson's disease. Annu Rev Genom Human Genet. 2011;12:301–325 - 82.
Cookson MR, Bandmann O: Parkinson's disease: insights from pathways. Hum Mol Genet. 2010;19:R1–R27 - 83.
Tansey MG, Goldberg MS: Neuroinflammation in Parkinson's disease: its role in neuronal death and implications for therapeutic intervention. Neurobiol Dis. 2010;37:510–518 - 84.
Bilen J, Bonini NM: Drosophila as a model for human neurodegenerative disease. Annu Rev Genet. 2005;39:153–171 - 85.
Cooper AA, Gitler AD, Cashikar A, Haynes CM, et al: α‐Synuclein blocks ER‐Golgi traffic and Rab1 rescues neuron loss in Parkinson's models. Science. 2006;313:324–328 - 86.
Chai C, Lim KL: Genetic insights into sporadic Parkinson's disease pathogenesis. Curr Genomics. 2013;14:486–501. - 87.
De Bellis MD, Baum AS, Birmaher B, Keshavan MS, et al: Developmental traumatology, Part I: Biological stress systems. Biol Psychiatry. 1999;45:1259–1270 - 88.
Kim ST, Choi JH, Chang JW, Kim SW, Hwang O: Immobilization stress causes increase in tetrahydrobiopterin, dopamine, and neuromelanin and oxidative damage in the nigrostriatal system. J Neurochem. 2005;95:89–98 - 89.
Tan EK, Khajavi M, Thronby JI, Nagamitsu S, et al: Variability and validity of polymorphism association studies in Parkinson's disease. Neurology. 2000;5:533–538 - 90.
Warner TT, Schapira AHV: Genetic and environmental factors in the cause of Parkinson's disease. Ann Neurol. 2003;53(3):16–25 - 91.
Yang J, Benyamin B, McEvoy BP, Gordon S, Henders AK, et al: Common SNPs explain a large proportion of the heritability for human height. Nat Genet. 2010;42(7):565–569 - 92.
Yang J, Lee SH, Goddard ME, Visscher PM: GCTA: a tool for genome‐wide complex trait. Am J Hum Genet. 2011;88(1):76–82 - 93.
Keller MF, Saad M, Bras J, Bettella F, et al: Using genomewide complex trait analysis to quantify ‘missing heritability’ in Parkinson's disease. Hum Mol Genet. 2012;21(22):4996–5009 - 94.
Ross CA, Smith WW: Gene‐environment interactions in Parkinson's disease. Parkinsonism Relat Disord. 2007;13(3):309–315. - 95.
Kelada SN, Checkoway H, Kardia SL, Carlson CS, et al: 5’ and 3’ region variability in the dopamine transporter gene (SLC6A3), pesticide exposure and Parkinson's disease risk: a hypothesis‐generating study. Hum Mol Genet. 2006;15:3055–3062 - 96.
Hancock DB, Martin ER, Vance JM, Scott WK: Nitric oxide synthase genes and their interactions with environmental factors in Parkinson's disease. Neurogenetics. 2008;9:249–262 - 97.
Dick FD, De Palma G, Ahmadi A, Osborne A, et al: Gene environment interactions in Parkinsonism and Parkinson's disease: the Geoparkinson study. Occup Environ Med. 2007;64:673–680 - 98.
Piccini P, Burn DJ, Ceravolo R, Maraganore D, Brooks DJ: The role of inheritance in sporadic Parkinson's disease: evidence from a longitudinal study of dopaminergic function in twins. Ann Neurol. 1999;45(5):577–582 - 99.
Wirdefeldt K, Gatz M, Reynolds CA, Prescott CA, Pedersen NL: Heritability of Parkinson disease in Swedish twins: a longitudinal study. Neurobiol Aging. 2011;32(10):1921–1928 - 100.
Feany MB, Bender WW: A Drosophila model of Parkinson's disease. Nature. 2000;404:394–398 - 101.
Hirth F: Drosophila melanogaster in the study of human neurodegeneration. CNS Neurological Disorders. 2010;9:504–523 - 102.
Bonini NM, Fortini ME: Human neurodegenerative disease modeling using Drosophila. Annu Rev Neurosc. 2003;26:627–656 - 103.
Barrientos A, Moraes CT: Titrating the effects of mitochondrial complex I impairment in the cell physiology. J Biol Chem. 1999;274:16188–1619 - 104.
Chauvin C, De Oliveira F, Ronot X, Mousseau M, et al: Ubiquinone analogs: a mitochondrial permeability transition pore‐dependent pathway to selective cell Death J Biol Chem. 2001;276,41394–41398 - 105.
Green DR, Reed JC: Mitochondria and apoptosis. Science. 1998;281:1309–1312 - 106.
Kroemer G, Reed JC: Mitochondrial control of cell death. Nat Med. 2000;6:513–519 - 107.
Wang X: The expanding role of mitochondria in apoptosis. Genes Dev. 2001;15:2922–2933 - 108.
Liu X, Kim CN, Yang J, Jemmerson R, Wang X: Induction of apoptotic program in cell‐free extracts: requirement for dATP and cytochrome c. Cell. 1996;86:147–157 - 109.
Du C, Fang M, Li Y, Li L, Wang X: Smac, a mitochondrial protein that promotes cytochrome c‐dependent caspase activation by eliminating IAP inhibition. Cell. 2000;102:33–42 - 110.
Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, et al: Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell. 2000;102:43–53 - 111.
Li LY, Luo X, Wang X: Endonuclease G is an apoptotic DNase when released from mitochondria. Nature. 2001;412:95–99 - 112.
Susin SA, Lorenzo HK, Zamzami N, Marzo I, et al: Molecular characterization of mitochondrial apoptosis‐inducing factor. Nature. 1999;397:441–446 - 113.
Reed JC: Bcl‐2 and the regulation of programmed cell death. J Cell Biol. 1994;124:1–6 - 114.
Reed JC: Double identity for proteins of the Bcl‐2 family. Nature. 1997;387:773–776 - 115.
Budnik V, White K: Catecholamine containing neurons in Drosophila melanogaster: distribution and development. J Comp Neurol. 1988;268:400–413 - 116.
Nassel DR, Elekes K: Aminergic neurons in the brain of blowflies and Drosophila: dopamine‐ and tyrosine hydroxylase‐immunoreactive neurons and their relationship with putative histaminergic neurons. Cell Tissue Res. 1992;267:147–167 - 117.
Friggi‐Grelin F, Coulom H, Meller M, Gomez D, et al: Targeted gene expression in Drosophila dopaminergic cells using regulatory sequences from tyrosine hydroxylase. J Neurobiol. 2003;54:618–627 - 118.
Cassar M, Issa AR, Riemensperger T, Petitgas C, et al: A dopamine receptor contributes to paraquat‐induced neurotoxicity in Drosophila. Hum Mol Genet. 2015;24(1):197–212 - 119.
Reiter LT, Potocki L, Chien S, Gribskov M, et al: A systematic analysis of human disease‐associated gene sequences in Drosophila melanogaster. Genome Res. 2001;11:1114–1125 - 120.
Girish C, Muralidhara: Propensity of Selaginella delicatula aqueous extract to offset rotenone‐induced oxidative dysfunctions and neurotoxicity in Drosophila melanogaster: implications. NeuroToxicology. 2012;33:444–456 - 121.
Manjunath MJ, Muralidhara: Standardized extract of Withania somnifera (Aswagandha) markedly offsets Rotenone‐Induced locomotor deficits, oxidative impairments and neurotoxicity in Drosophila melanogaster. J Food Sci Technol. 2015;52:1971–1981 - 122.
Johnson ME, Bobrovskaya L: An update on the rotenone models of Parkinson's disease: their ability to reproduce the features of clinical disease and model gene–environment interactions. NeuroToxicology. 2015;46:101–116 - 123.
Marsh JL, Thompson LM: Drosophila in the study of neurodegenerative disease. Neuron. 2006;52:169–178 - 124.
Virmani A, Pinto L, Binienda Z, Ali S: Food nutrigenomics and neurodegeneration‐neuroprotection by what you eat! Mol Neurobiol. 2013;48:353–362 - 125.
Lee WH, Lee CY, Bebaway M, Luk F, et al: Curcumin and its derivatives:their application in neuropharmacology and neuroscience in the 21st century. Curr Neuropharmacol. 2013;11:338–378 - 126.
Kim HJ, Kim P, Shin CY: A comprehensive review of the therapeutic and pharmacological effects of ginseng and ginsenosides in central nervous system. J Ginseng Res. 2013;37:8–29 - 127.
Sun AY, Wang Q, Simonyi A, Sun GY: Resveratol as a therapeutic agent for neurodegenerative diseases. Mol Neurobiol. 2010;41:375–383 - 128.
Chen LW, Wang YQ, Wei LC, Shi M, Chan YS: Chinese herbs and herbal extracts for neuroprotection of dopaminergic neurons and potential therapeutic treatment of Parkinson's disease. CNS Neurol Disord Drug Targets. 2007;6:273–281 - 129.
Chao J, Yu MS, Ho YS, Wang M, Chang RC: Dietary oxyresveratrol prevents Parkinsonian mimetic 6‐hydroxydopamine neurotoxicity. Free Radic Biol Med. 2008;45:1019–1026 - 130.
Ji HF, Shen L: The multiple pharmaceutical potential of curcumin in Parkinson's disease. CNS Neurol Disord Drug Targets. 2014;13:369–373 - 131.
Gadad BS, Subramanya PK, Pullabhatla S, Shantharam IS, Rao KS: Curcumin‐glucoside, a novel synthetic derivative of curcumin, inhibits alpha‐synuclein oligomer formation: relevance to Parkinson's disease. Curr Pharm Des. 2012;18:76–84 - 132.
Phom L, Achumi B, Alone DP, Muralidhara, Yenisetti SC: Curcumin's neuroprotective efficacy in Drosophila model of idiopathic Parkinson's disease is phase specific: implication of its therapeutic effectiveness. Rejuvenation Res. 2014;17(6):481–489 - 133.
Prior RI, Cao G, Martin A, Sofic A, et al: Antioxidant capacity as influenced by total phenolic and anthocyanine content maturity and variety of vaccinium species. J Agri Food Chem. 1998;46:2586–2593 - 134.
Joseph JA, Hale‐Shukitt B, Casadesus G: Reversing the deleterious effect of aging on neuronal communications and behavior: beneficial properties of fruit polyphenol compounds. Am J Clin Nutr. 2005;81:313S–316S - 135.
Krikorian K, Slider MD, Nash TA, Kalt W, et al: Blueberry supplementation improves memory in older patients. J Agri Food Chem. 2010;58:3996–4000 - 136.
Peng C, Yuanyun Z, KinMing K, Yintong L, et al: Blueberry extract prolongs lifespan of Drosophila melanogaster. Exper Gerontol. 2012;47:170–178 - 137.
Lim LM, Ng CH: Genetic models of Parkinson disease. Biochimica Biophysica Acta. 2009;1792(7):604–615 - 138.
Dawson TM, Ko HS, Dawson VL: Genetic animal models of Parkinson's disease. Neuron. 2010;66(5):646–661 - 139.
Dagda RK, Zhu J, Chu CT: Mitochondrial kinases in Parkinson's disease: converging insights from neurotoxin and genetic models. Mitochondrion. 2009;9:289–298 - 140.
Falkenburger BH, Schulz JB: Limitations of cellular models in Parkinson's disease research. J Neural Transm. 2006;70:261–268 - 141.
Jeibmann A, Paulus W: Drosophila melanogaster as a model organism of brain diseases. Int J Mol Sci. 2009;10:407–440 - 142.
Adams MD, Celniker SE, Holt RA, Evans CA, et al: The genome sequence of Drosophila melanogaster. Science. 2000;287:2185–2219 - 143.
Pandey UB, Nichols CD: Human disease models in Drosophila melanogaster and the role of the fly in therapeutic drug discovery. Pharmacol Rev. 2011;63:411–436 - 144.
Cauchi RJ, vanden Heuvel M: The fly as a model for neurodegenerative diseases: is it worth the jump? Neurodegener Dis. 2006;3:338–356 - 145.
Chan HY, Bonini NM: Drosophila models of human neurodegenerative disease. Cell Death Differ. 2000;7:1075–1080 - 146.
Kohler RE: Drosophila: a life in the laboratory. J Hist Biol. 1993;26:281–310 - 147.
Lu B, Vogel H: Drosophila models of neurodegenerative diseases. Annu Rev Pathol. 2009;4:315–342 - 148.
Ambegaokar SS, Roy B, Jackson GR: Neurodegenerative models in Drosophila: polyglutamine disorders, Parkinson disease, and amyotrophic lateral sclerosis. Neurobiol Disease. 2010;40:29–39 - 149.
West RJH, Furmston R, Williams CAC, Elliott CJH: Neurophysiology of Drosophila models of Parkinson's disease. Parkinson's Disease. 2015;ID381281:11. DOI:10.1155/2015/381281 - 150.
Stephenson R, Metcalfe NH: Drosophila melanogaster: a fly through its history and current use. J R Coll Physicians Edinb. 2013;43:70–75 - 151.
Fernandez‐Funez P, Nino‐Rosales ML, de Gouyon B, She WC, et al: Identification of genes that modify ataxin‐1‐induced neurodegeneration. Nature. 2000;408:101–106 - 152.
Ghosh S, Feany MB: Comparison of pathways controlling toxicity in the eye and brain in Drosophila model of human neurodegenerative diseases. Hum Mol Genet. 2004;13:2011–2018 - 153.
Hamamichi S, Rivas RN, Knight AL, Cao S, et al: Hypothesis based RNAi screening identifies neuroprotective genes in a Parkinson's disease model. Proc Natl Acad Sci USA. 2008;105:728–733 - 154.
Kazemi‐Esfarjani P, Benzer S: Genetic suppression of polyglutamine toxicity in Drosophila. Science. 2000;287:1837–1840 - 155.
Menzies FM, Yenisetti YS, Min KT: Roles of Drosophila DJ‐1 in survival of dopaminergic neurons and oxidative stress. Curr Biol. 2005;15(17):1578–1582 - 156.
Merzetti EM, Staveley BE: Spargel, the PGC‐1 alpha homologue, in models of Parkinson disease in Drosophila melanogaster. BMC Neuroscience. 2015; 16(70): 1–8. DOI:10.1186/s12868-015-0210-2. - 157.
Van Ham TJ, Breitling R, Morris A Swertz MA, Nollen EAA: Neurodegenerative diseases: lessons from genome‐wide screens in small model organisms. EMBO Mol Med. 2009;1(8–9):360–370. DOI:10.1002/emmm.200900051 - 158.
Ivatt RM, Sanchez‐Martinez A, Godena VK, Brown S, et al: Genome wide RNAi screen identifies the Parkinson disease GWAS risk locus SREBF1 as a regulator of mitophagy. Proc Nat Acad Sci USA. 2014;111(23):8494–8499