Parkinson's Disease: Overview, Genes And Animal Models

Parkin

Parkinson's disease (PD) is a type of neurodegenerative ailment and is caused due to the lack of dopaminergic nerve cells. It diminishes in PD patients. The signs and symptoms of Parkinson's disease include motor deficits. These types of motor deficits are rigidity, bradykinesia, and resting tremors. Dopaminergic neurons are put inside the “substantia nigra pars compacta”, which is the midbrain area of the brain (Julienne et al. 2017).

Three genes, “PINK1, Parkin, and DJ1” play an important function in the expression of disease evident from animal models. Mutation in the genes in PINK1, Parkin, and DJ1 bring about Parkinson's illness. Some wide researches had been done to determine the positions of the genes. The park2 position is used for coding the “E3 ubiquitin ligase parkin”; “PINK1, a mitochondrial kinase” that separates and PARK7, which is used to code for the “protein DJ-1”.

In various experiments, it has been demonstrated that all the three proteins have mitochondrial characteristics and are responsive to stress. The genes are thought to be related to the generation of oxidative strain in neurons: PINK1, Parkin, and DJ-1. The researchers keep on looking at the connections with a greater intensity, and utilization of various animal models to better comprehend those relationships.

For the study of the Parkinson's disease numerous animal model had been used particularly in Drosophila, mice, monkeys, and C. Elegans. During the comparison between the genes, mice had been the most used animal and this might be on the grounds that the natural pathways of Parkinson's ailment are extremely preservationist, which has been demonstrated in Drosophila during the study of this disease. When the researchers are studying about the Parkinson’s disease with the animals, they are only allowed to for using the smallest animal which can resemble the disease of the humans. Among all the animals the rat is the only animal which is smallest and shows similarity with the human being. This is the reason that the animal models are being used to recognize the Parkinson's disease (Winklhofer, 2014). That data has thought of medicines causes, however on the grounds that the wide assortment of patients with familial PD is uncommonly high contrasted with the number with sporadic PD, hereditary research in influenced human families are high, thusly if a hereditary research is proficient it would not be founded on history inside the family or not. Concentrate the sporadic type of the illness serves to infection rapidly without going through various processes to discover the issue. An invertebrate is routinely utilized as a part of treatment. Indeed, even invertebrate creatures, for instance, Drosophila melanogaster, are valuable models for reviews of human PD. growing a creature show, an extraordinary number of genes and atomic transduction pathways are saved amongst Drosophila and individuals (Kazlauskaite et al., 2014).

ROS Formations

Latest researches demonstrate that the ligase movement of parkin may have capacities, which give a clarification to the absence of increase of some putative substrates in Parkin invalid mice. Overexpression of wild-sort parkin decreases generation of the mitochondrial ROS. This decrease occurs by increasing the mitochondrial coating potential, while over-expression of mutant parkin.

 In the gene named parkin, the loss-of-functional mutants of Drosophila show the Parkinson’s disease (early onset). PD is portrayed ordinarily by the accumulation of “a-synuclein protein” in cytoplasm neuronal considerations, called “Lewy bodies” (LB) in various cerebrum territories (Durcan, & Fon, 2015). Further, parkin is available in the influenced mind districts of PD brains and co-localizes with LBs (Van, d. et al. 2015). In vivo records propose that parkin has a neuroprotective component in PD. Parkin mutant flies show an absence of a subset of neurons (dopaminergic).

Parkin uses the “endolysosomal pathway”, especially the organization of the tubular areas, which additionally affect the retromer pathway and exosome discharge. Records reveal that there is a single feature of Parkin in regulating this pathway. It is by means of the law of retromer and endosomal organization. It lifts the possibility that the interruption of this pathway adds to the pathogenesis of PD in relation with Parkin.

It was investigated and confirmed that Parkin interceded “ubiquitination of Eps15”, a connector protein associated with early endocytosis (Tang et al., 2017). It indicates the function for Parkin inside the endocytic pathway. To analyze the Parkin endolysosomal pathway, the morphology and endosomal markers were surveyed in persistent inferred Parkin-insufficient fibroblasts. In spite of the fact that we didn't watch noteworthy contrasts in the example of “EEA1 and LAPMP” in Parkin-lacking cells, a detailed observation of particular endosomal film areas uncovered a huge loss of the tubular components marked by “SNX16, a PX space” containing nexin and reservoirs (Scarffe et al., 2015). To additionally affirm this perception, examine was led with live cell co-focal pictures and found an emotional reduction in endosomal tubulation in Parkin-insufficient fibroblasts. It was contrasted and controls proposing that Parkin is engaged with endosomal layer tubulation (Koyano et al. 2014), characteristic of the hindrance of the retromer work. To get more understanding of the retromer status, examinations of layer relationship of the “retromer proteins SNX1 and VPS35” utilizing cell fractionation test (Koyano et al. 2014). The outcomes demonstrated a diminished proportion of layer related and cytosolic “SNX1 and VPS35 in Parkin-insufficient cells” contrasted and controls, additionally authenticating adjusted retromer work in Parkin-insufficient cells.

Pink 1

 

(Endolysosomal pathway; Song et al. 2016)

To analyze this examination, the researchers disconnected the exosomes from the cell culture media by ordinary centrifugation (West et al., 2015). The outcomes demonstrated that exosomes were fundamentally expanded in Parkin-insufficient fibroblasts. They next wished to affirm their discoveries in DA neurons, which are exceptionally influenced in patients conveying parkin mutations. To additionally build up that this impact was Parkin-particular, they gauged “exosome discharge from HEK293 cells” in which Parkin articulation levels were adjusted. The outcomes demonstrated that shRNA-interceded quieting of parkin resulted in expanded exosome discharge, while overexpression of wild-sort however not mutant Parkin prompted a lessening in the discharge of exosomes, proposing that Parkin is adversely associated with exosome era. Together, these outcomes exhibited the inclusion of Parkin in exosome emission in different cell models.

 

(Patient-derived Parkin-deficient fibroblasts; Song et al., 2016)

The PINK1 gene encoding a protein called PTEN, portrayed by an N-terminal mitochondrial focusing on the exceptionally monitored serine-threonine kinase, and a C-terminal area (Pickrell & Youle, 2015). PINK1 is distinguished in various cell sorts all through the human mind with the most astounding articulation in the substantia nigra, hippocampus and cerebellar Purkinje cells (Pickrell & Youle, 2015). Inside the cell, the PINK1 protein is tremendously confined at the inward mitochondrial film, proposing a critical part in mitochondrial work (Ryan et al. 2015). Rakovic et al., built up a rundown of potential restricting genes of PINK1, four of which are situated in the mitochondria and are imperative for ideal mitochondrial work (Moisoi et al., 2014). Further researches demonstrate that PINK1 assumes a vital part in a few biological forms, including mitochondrial digestion, oxidative anxiety, oxidative phosphorylation, mitochondrial progression, and abnormal protein freedom by proteasomal corruption. PINK1 changes are the second most basic reason for autosomal passive PD after Parkin and are in charge of some sporadic instances of PD (Lehmann, Loh, & Martins, 2017). In vivo, “PINK1 KO mice” show comparative manifestations as found in PD. This includes weakened corticostriatal synaptic versatility, and mitochondrial brokenness in dopaminergic neurons diminished dopamine flood from nigrostriatal terminals (Costa et al., 2013). The mitochondrial buildup of a-synuclein happens transcendently in PD-influenced mind districts, recommending that PINK1 could be related with a-synuclein pathology (Shiba-Fukushima et al., 2014). Besides, PINK1 inadequacy advances a-synuclein total by disabled proteosome work (Inoshita et al., 2017). Proteosome capacity can be controlled by PINK1 by means of phosphorylation of the internal film protease HtrA2, the movement of which is diminished in brains of PD patients conveying PINK1 changes contrasted with PD.

PINK1 mutant protein is not appropriately balanced to contemplate the impacts of endogenous mutant PINK1 in cells. They evaluated PINK1 mRNA levels previously, then after the fact mitochondrial depolarization with the K+ ionophore valinomycin by quantitative invert transcriptase PCR, however, found no huge contrast amongst WT and mutant PINK1 fibroblasts (Chen et al., 2016). Without energy, the PINK1 protein was not really distinguishable by Western smear (WB) (endogenous conditions). Reliably, the PINK1 flag was impressively weaker in p.I368N mutant cells contrasted with WT controls are S1A. Notwithstanding fundamentally diminished protein levels, limitation of the mutant “PINK1 p.I368N” to harmed mitochondria appeared to be unaltered. This was additionally validated by sub-cellular fractions, where both “WT and mutant PINK1” were identified in the mitochondrial portion upon depolarization (Chen et al., 2016). Taken together, “p.I368N mutant cells” demonstrated no adjustments in mRNAs levels, however essentially decreased levels of the total length of PINK1 protein on mitochondria upon depolarization.

 

(The effects of endogenous mutant PINK1 in cells.  Ando et al. 2017)

Research has embroiled mitochondria in the pathogenesis of PD. PD patients show electron transport chain (ETC.) (Hewitt & Whitworth, 2017). This data recommends a mitochondrial segment in the etiology of PD. Regardless of the unmistakable ramifications of mitochondria, considering the start and movement of PD has demonstrated hazardous.

The PD models are better at mirroring the end-phases of PD as opposed to the movement (Winklhofer, 2014). By utilizing the PINK1 KO demonstrate, it might be conceivable to think about the movement of PD and recognize novel symptomatic and remedial focus amid the asymptomatic period of PD. A noteworthy constraint of PD hereditary models is that most models don't reiterate the dynamic neurodegenerative signs of the illness, for example, the loss of midbrain dopaminergic neurons in the substantia nigra (Kazlauskaite et al., 2014). All things considered, the pertinence of the discoveries in mouse models to human PD is sketchy. To focus on this issue, a novel rodent display that is insufficient in the PINK1 protein and presents a dynamic development issue was acquired (Gautier, Corti & Brice, 2014). Dopaminergic neurons express abnormal amounts of tyrosine hydroxylase on the grounds that this protein catalyzes the last and rate-constraining response of dopamine blend (Lopez-Fabuel et al., 2017). In light of tyrosine hydroxylase recoloring, dopaminergic neurons in the SNPC were diminished in PINK1 rats. A relating diminish in the extent of the SNPC was likewise recognized. The information states that the PINK1 gene of rodent model restates the midbrain dopaminergic cell normal for PD.

 

(Dopaminergic neurons in the SNPC. Villeneuve et al. 2016)

DJ-1 (Park 7)

DJ-1, otherwise called PARK7 is situated on the chromosome, with a transcript of 949 bp with 7 exons that encodes a protein comprises of 189 A.A. (Grenier, McLelland & Fon, 2013). DJ-1 was at first recognized as an oncogene and its appearance was observed to be improved in a few sorts of tumors (Burbulla et al., 2014). DJ-1 protein is pervasively communicated in numerous cell sorts and prevalently limits in the cytosol, yet additionally in the core and connected with mitochondria (Walden & Muqit, 2017). Immuno-histochemical investigation exhibited that the DJ-1 protein was communicated by neurons, in any case, likewise by astrocytes in mouse cerebrum (O'flanagan et al. 2015). In the same way, in typical human cerebrum DJ-1 is overwhelmingly communicated by astrocytes and to a significantly lesser degree in neurons.

 

(DJ-1 protein was expressed by neurons. Goa et al. 2012)

Combining the Genes

Transformations are a loss of capacity, a sensible approach to attempt to demonstrate the problem is decreased PINK1, Parkin, or DJ-1 (Kim et al., 2013). Extraordinarily, these impacts seem, to be expected to mitochondrial damage (Alcalay et al. 2014). It was found that Drosophila parkin mutants demonstrate the expanded affectability to oxidative anxiety (Drapalo & Jozwiak, 2017). Despite the fact that the phenotypes were exceptionally remarkable and not just loss of dopamine neurons was not found in any of the models (Ariga et al. 2013).

PINK1-genes that are examined autonomously demonstrates that Drosophila without the single PINK1 homolog had similar sorts of muscle degeneration, male barrenness, and mitochondrial phenotypes as the mutants (Dias, Junn & Mouradian, 2013). These phenotypes were PINK1 subordinate in light of the fact that the human homolog could protect the PINK1-insufficiency phenotypes, which additionally demonstrates that the Drosophila and human qualities were practically preserved. Moreover, in spite of the fact that overexpression of parkin could in any event somewhat protect PINK1 phenotypes, the turn around was not valid, suggesting a hereditary pathway in which PINK1 is a component of parkin (Dias, Junn & Mouradian, 2013). This is a necessary outcome since it infers that the phenotypes seen in various quality changes are not phenotypes but rather can be utilized to show something particular with respect to quality connections. Besides, this putative connection amongst PINK1 and parkin appears to fortify the idea that parkin has an impact in the control of mitochondrial work. Interestingly, the connection between DJ-1 and the other two qualities examined here is more intricate (Redmann et al. 2016). However, the recent experiments of matured flies have uncovered mitochondrial abandons and demonstrated that expanded articulation of DJ-1 can supplement the loss of PINK1, but not the parkin gene (Prasad, 2016). Generally speaking, this proposes DJ-1 acts in parallel, or may be downstream from PINK1, however, is most likely not a focal piece of the PINK1/parkin pathway. Despite the fact that this information was hence unfathomably essential in creating thoughts with respect to connections between various qualities for Parkinsonism, they didn't promptly give a biochemical clarification to why these proteins may have a comparable impact (Hewitt & Whitworth, 2017). In spite of the fact that this is a dynamic territory of research, there have been a few advancements that have started to determine this issue. No substrates for Pink1 kinase movement have been distinguished till date. yet the ubiquitin ligase action can be adjusted by phosphorylation (Fleming, 2014). Pink1 may control Parkin gene, either by coordinating phosphorylation or by the enactment of transitional proteins. Then, it has been accounted for that knockdown of pink1 by RNAi in Drosophila brings about decrease in the Parkin protein. Jagmag, et al. (2015), proposed that Pink1 capacities straightforwardly or by implication to keep up Parkin levels. The previously mentioned hereditary information is additionally predictable with a model in which Pink1 and Parkin act in an arrangement on shared targets (Zhang, Duan & Yang, 2015).

Parkinson’s	Parkin	PINK1	DJ1
C.Elegans	9	7	4
Mice	391	212	306
Monkey	10	0	0
Drosophila	314	245	114

The table was prepared by utilizing the web index from the “Wright State libraries”, a propelled look for the criteria of Parkinson's infection, with every gene “Parkin, PINK1 and DJ-1” with each model. The indexed lists are appeared in the above table, indicating mice and Drosophila as the most well-known creature models utilized for contemplates in every one of the three qualities (Zhang, Duan & Yang, 2015). The monkey as a creature demonstrate in PD ponders was just finished with Parkin, not the others. The best models that were utilized by the table are mice and Drosophila.

This present audit's attention is on the qualities and the examination encompassing PD, especially the creature models used to ponder the ailment. Drugs were not an essential concentration; in any case, explore demonstrates no known cure or treatment to reduce the sickness (Bonifati, 2014). Comprehension of the pathophysiology of Parkinson sickness has progressed quickly finished the most recent two decades through fundamental and clinical examinations utilizing present day neuroanatomical, clinical appraisal, neuropathological and useful mind imaging strategies. The clinical signs of Parkinson's disease, at the time of their onset, reflect degeneration of some particular neurons in the substantia nigra anticipating through the nigrostriatal pathway with some changes occurring in the frameworks (Pringsheim et al. 2014). Positron discharge tomography with particular ligands for the dopamine framework is a capable apparatus for investigation of both degenerative and compensatory forms in the pathophysiology of Parkinson infection in vivo and can be utilized to affirm the conclusion of dopamine insufficient Parkinson sickness. The expanding information of the pathogenesis of Parkinson's illness at a sub-atomic level will have vital ramifications for the improvement of individual helpful procedures to anticipate malady movement (Ref.10).

Conclusion

The paper is based on the qualities and the investigation about PD, especially the animal models used to discover illness. The genuinely generous group of work in the writing on “PINK1, parkin, and DJ-1” has featured a few basic pathways that are most likely engaged with passive Parkinsonism. This is drawn from various exploratory frameworks, and understanding what each of them lets us know includes some learning the transformative connections between the living beings concentrated and how the qualities work in each. The things which need to be clear is that at any rate a few capacities are preserved. There are uncertain inquiries with respect to the capacity of Parkin to protect PINK1 inadequacy. The information in flies and in cell culture should be accommodated. There are likewise noteworthy holes with respect to the development of the mammalian brain, especially in dopaminergic neurons. The enzymatic elements of PINK1 and parkin are known, but the exact biochemical capacity of DJ-1 remain unclear.  It is required to understand the elements that prompt dopamine cell misfortune. It is of genuinely significant worry that little of this information has affected the general population who has any of these illnesses. To some degree, this basically legitimizes knowing all the more with respect to the science so we can grow fittingly focused on approaches, on the grounds that natural procedures as wide as “oxidative anxiety or mitochondrial work” have not yet yielded much in the method for therapeutics. In any case, moreover, this fortifies the thought that albeit human hereditary qualities has revealed to us an incredible arrangement. Regardless, there is a need to discover approaches to apply it back to people, and it is really challenging.

References

Alcalay, R. N., Caccappolo, E., Mejia-Santana, H., Tang, M. X., Rosado, L., Reilly, M. O., ... & Bressman, S. B. (2014). Cognitive and motor function in long-duration PARKIN-associated Parkinson disease. JAMA neurology, 71(1), 62-67.

Ariga, H., Takahashi-Niki, K., Kato, I., Maita, H., Niki, T., & Iguchi-Ariga, S. M. (2013). Neuroprotective function of DJ-1 in Parkinson’s disease. Oxidative medicine and cellular longevity, 2013.

Bonifati, V. (2014). Genetics of Parkinson's disease–state of the art, 2013. Parkinsonism & related disorders, 20, S23-S28.

Burbulla, L. F., Fitzgerald, J. C., Stegen, K., Westermeier, J., Thost, A. K., Kato, H., ... & Rapaport, D. (2014). Mitochondrial proteolytic stress induced by loss of mortalin function is rescued by Parkin and PINK1. Cell death & disease, 5(4), e1180.

Chen, Y., Deng, J., Wang, P., Yang, M., Chen, X., Zhu, L., ... & Xu, Q. (2016). PINK1 and Parkin are genetic modifiers for FUS-induced neurodegeneration. Human molecular genetics, 25(23), 5059-5068.

Costa, A. C., Loh, S. H. Y., & Martins, L. M. (2013). Drosophila Trap1 protects against mitochondrial dysfunction in a PINK1/parkin model of Parkinson's disease. Cell death & disease, 4(1), e467.

Dias, V., Junn, E., & Mouradian, M. M. (2013). The role of oxidative stress in Parkinson's disease. Journal of Parkinson's disease, 3(4), 461-491.

Drapalo, K., & Jozwiak, J. (2017). Parkin, PINK1 and DJ1 as possible modulators of mTOR pathway in ganglioglioma. International Journal of Neuroscience, (just-accepted), 01-23.

Durcan, T. M., & Fon, E. A. (2015). The three ‘P’s of mitophagy: PARKIN, PINK1, and post-translational modifications. Genes & development, 29(10), 989-999.

Fleming, M. L. L. P. M. (2014). Deciphering the molecular role of DJ-1 in the etiology of Parkinson’s and Huntingtons’s disease.

Gautier, C. A., Corti, O., & Brice, A. (2014). Mitochondrial dysfunctions in Parkinson's disease. Revue neurologique, 170(5), 339-343.

Grenier, K., McLelland, G. L., & Fon, E. A. (2013). Parkin-and PINK1-dependent mitophagy in neurons: will the real pathway please stand up?. Frontiers in neurology, 4.

Hewitt, V. L., & Whitworth, A. J. (2017). Chapter Five-Mechanisms of Parkinson's Disease: Lessons from Drosophila. Current topics in developmental biology, 121, 173-200.

Inoshita, T., Shiba-Fukushima, K., Meng, H., Hattori, N., & Imai, Y. (2017). Monitoring mitochondrial changes by alteration of the PINK1-Parkin signaling in Drosophila. Methods Mol Biol. doi, 10, 1007.

Julienne, H., Buhl, E., Leslie, D. S., & Hodge, J. J. (2017). Drosophila PINK1 and parkin loss-of-function mutants display a range of non-motor Parkinson's disease phenotypes. Neurobiology of Disease, 104, 15-23.

Kazlauskaite, A., Kondapalli, C., Gourlay, R., Campbell, D. G., Ritorto, M. S., Hofmann, K., ... & Muqit, M. M. (2014). Parkin is activated by PINK1-dependent phosphorylation of ubiquitin at Ser65. Biochemical Journal, 460(1), 127-141.

Kim, N. C., Tresse, E., Kolaitis, R. M., Molliex, A., Thomas, R. E., Alami, N. H., ... & Winborn, B. J. (2013). VCP is essential for mitochondrial quality control by PINK1/Parkin and this function is impaired by VCP mutations. Neuron, 78(1), 65-80.

Koyano, F., Okatsu, K., Kosako, H., Tamura, Y., Go, E., Kimura, M., ... & Endo, T. (2014). Ubiquitin is phosphorylated by PINK1 to activate parkin. Nature, 510(7503), 162.

Lopez-Fabuel, I., Martin-Martin, L., Resch-Beusher, M., Azkona, G., Sanchez-Pernaute, R., & Bolaños, J. P. (2017). Mitochondrial respiratory chain disorganization in Parkinson's disease-relevant PINK1 and DJ1 mutants. Neurochemistry International.

Morais, V. A., Haddad, D., Craessaerts, K., De Bock, P. J., Swerts, J., Vilain, S., ... & Klein, C. (2014). PINK1 loss-of-function mutations affect mitochondrial complex I activity via NdufA10 ubiquinone uncoupling. Science, 344(6180), 203-207.

O'flanagan, C. H., Morais, V. A., Wurst, W., De Strooper, B., & O'Neill, C. (2015). The Parkinson’s gene PINK1 regulates cell cycle progression and promotes cancer-associated phenotypes. Oncogene, 34(11), 1363-1374.

Pickrell, A. M., & Youle, R. J. (2015). The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson’s disease. Neuron, 85(2), 257-273.

Prasad, K. N. (2016). Simultaneous Activation of Nrf2 and Elevation of Dietary and Endogenous Antioxidants for Prevention and Improved Management of Parkinson’s Disease. In Inflammation, Aging, and Oxidative Stress (pp. 277-301). Springer International Publishing.

Pringsheim, T., Jette, N., Frolkis, A., & Steeves, T. D. (2014). The prevalence of Parkinson's disease: A systematic review and meta?analysis. Movement disorders, 29(13), 1583-1590.

Redmann, M., Dodson, M., Boyer-Guittaut, M., Darley-Usmar, V., & Zhang, J. (2014). Mitophagy mechanisms and role in human diseases. The international journal of biochemistry & cell biology, 53, 127-133.

Ryan, B. J., Hoek, S., Fon, E. A., & Wade-Martins, R. (2015). Mitochondrial dysfunction and mitophagy in Parkinson's: from familial to sporadic disease. Trends in biochemical sciences, 40(4), 200-210.

Scarffe, L. A., Stevens, D. A., Dawson, V. L., & Dawson, T. M. (2014). Parkin and PINK1: much more than mitophagy. Trends in neurosciences, 37(6), 315-324.

Shiba-Fukushima, K., Inoshita, T., Hattori, N., & Imai, Y. (2014). PINK1-mediated phosphorylation of Parkin boosts Parkin activity in Drosophila. PLoS genetics, 10(6), e1004391.

Tang, M. Y., Vranas, M., Krahn, A. I., Pundlik, S., Trempe, J. F., & Fon, E. A. (2017). Structure-guided mutagenesis reveals a hierarchical mechanism of Parkin activation. Nature Communications, 8.

Thomas, R. E., Andrews, L. A., Burman, J. L., Lin, W. Y., & Pallanck, L. J. (2014). PINK1-Parkin pathway activity is regulated by degradation of PINK1 in the mitochondrial matrix. PLoS genetics, 10(5), e1004279.

Toyoda, Y., Erkut, C., Pan-Montojo, F., Boland, S., Stewart, M. P., Müller, D. J., ... & Kurzchalia, T. V. (2014). Products of the Parkinson's disease-related glyoxalase DJ-1, D-lactate and glycolate, support mitochondrial membrane potential and neuronal survival. Biology open, BIO20149399.

Vincow, E. S., Merrihew, G., Thomas, R. E., Shulman, N. J., Beyer, R. P., MacCoss, M. J., & Pallanck, L. J. (2013). The PINK1–Parkin pathway promotes both mitophagy and selective respiratory chain turnover in vivo. Proceedings of the National Academy of Sciences, 110(16), 6400-6405.

Walden, H., & Muqit, M. M. (2017). Ubiquitin and Parkinson's disease through the looking glass of genetics. Biochemical Journal, 474(9), 1439-1451.

West, R. J., Furmston, R., Williams, C. A., & Elliott, C. J. (2015). Neurophysiology of Drosophila models of Parkinson’s disease. Parkinson’s Disease, 2015.

Winklhofer, K. F. (2014). Parkin and mitochondrial quality control: toward assembling the puzzle. Trends in cell biology, 24(6), 332-341.

Zhang, H., Duan, C., & Yang, H. (2015). Defective autophagy in Parkinson’s disease: lessons from genetics. Molecular neurobiology, 51(1), 89-104.

Moisoi, N., Fedele, V., Edwards, J., & Martins, L. M. (2014). Loss of PINK1 enhances neurodegeneration in a mouse model of Parkinson's disease triggered by mitochondrial stress. Neuropharmacology, 77, 350-357.

Lehmann, S., Loh, S. H., & Martins, L. M. (2017). Enhancing NAD+ salvage metabolism is neuroprotective in a PINK1 model of Parkinson's disease. Biology open, 6(2), 141-147.

Jagmag, S. A., Tripathi, N., Shukla, S. D., Maiti, S., & Khurana, S. (2015). Evaluation of models of Parkinson's disease. Frontiers in neuroscience, 9.