Thesis of The Parkinsons disorder : 619788

Question:

Introduction

• What is Parkinson’s disease
• Define and talk about the four genes (PINK1, Parkin and DJ-1) that causes Parkinson’s disease
• Parkin and PINK1 causes Parkinson’s disease but plays a normal role or function in cells
• Research paper summarized about different models used including human studies, mouse models, drosophila, invitro (neurons, C. elegans
• What is mitochondria
• What is mitophagy

Body

• PINK1, and Parkin have normal role in the cell
• Papers on models used
• Although Parkin and PINK1 causes Parkinson’s disease in cells, changing the gene eg. Parkin gene can have different results in these other models, state and know that these genes are important because they affect all cells (mention the controls used in each model figure study and include figures in paper)
• Talk about other factors that can lead to Parkinson’s disease besides the genetics (for example other people do not have the genes, so other can lead to Parkinson’s disease
• Argue that although Parkin and PINK1 are known to cause Parkinson’s disease in humans it can also have effect in other models (models mentioned)
• Critique what happens if a gene is changed in other models and its results (Can PINK1, Parkin and DJ-1 be studied in other models other than humans’ models? What can be manipulated to potentially influence in Parkinson’s disease?
• Make sure that the figures that I have included is coherent to the study, or put the appropriate figures and explain them so I can understand what is going on in the figures.

Conclusion

• State and argue the results of each model

Future studies

• What can be done, other factors that can potentially cause Parkinson’s disease, potentially cure, gene manipulation

In addition, the document will ultimately need a signature page, a table of contents, a list of figures, and an abstract. These pages are numbered using “i, ii,”, etc., although the numbers are not printed on the first two pages. The page numbers should appear at the bottom center of the document. The Reference page formatted consistently. List of all journal titles and figures with titles, and reference page and reference should include a journal,  volume, or page numbers.

Each of the figures needs a Figure legend that you have written; this legend must make sense in the absence of the paper. At the end of the legend, the paper must be cited as “adapted from Author, et al., date”.

Write the paper starting with a discussion of Parkinson’s disease or mitophagy in general and then present the information in a logical sequence. Papers should be critiqued where appropriate in paper.

Answer:

Abstract

Parkinson’s disorder is due to the loss of dopaminergic neurons within the midbrain. Autosomal recessive early onset of PD is as a result of mutations in these three genes PINK1, Parkin and DJ1. Animal and cell models have demonstrated a direct link between parkin and PINK1, whereby PINK1 phosphorylates and turns on parkin at the outer mitochondrial membrane, resulting in elimination of dysfunctional mitochondria via mitophagy. Although there is an overwhelming evidence for this interaction, few research had been able to perceive a link for DJ-1 with parkin or PINK1. The purpose of this study is to summarize the functions of PINK1, Parkin and DJ-1 and to research the prevailing evidence for direct interactions between them. DJ-1 is able to rescue the phenotype of PINK1-knockout Drosophila models, however not of parkin-knockouts, suggesting that DJ-1 may additionally act in a parallel pathway to that of the PINK1/parkin pathway. On this evaluation, biological pathways related to PINK1, Parkin and DJ1 that triggers Parkinson’s disease may also be recognized. Questions consisting of what those genes do to trigger Parkinson’s disease and the way that is all carried out in different forms and comparisons in the models used could be analyzed. Interestingly., expression of these proteins and their associated transcription factors are found to be drastically down-regulated in PD patients in comparison to healthy controls. In summary, this review provides insight in common pathways linking three PD-causing genes and highlights a few key questions, the answers to which may additionally provide critical insight into the disease process.

Introduction

Parkinson’s disease is a neurodegenerative disease and it is due to the lack of dopaminergic neurons which decreases in Parkinson’s disease patients. Its signs and symptoms include motor deficits such as resting tremors, rigidity, and bradykinesia. Dopaminergic neurons are placed inside the substantia nigra pars compacta, which is the midbrain section of the brain (Spillantini et al., 1997; Klein and Krainc, 2012; Pickrell and Youle 2015).

Three genes, PINK1, Parkin and DJ1 are known to play a function  in the disease expression and animal model used to look at the disease. Mutations in PINK1, Parkin and DJ1 genes results in Parkinson’s disease. The position of the genes has been extensively researched.  PARK2 position is to encode the E3 ubiquitin ligase parkin; PINK1, a mitochondrial kinase that breaks down and PARK7, which codes for the protein DJ-1.

In numerous experimental systems, it has been proven that everyone in three proteins impact mitochondrial characteristic and/or oxidative stress responses. The relationship between the genes is assumed to be associated with the production of oxidative strain in neurons: PINK1, Parkin and DJ-1 work together as outlined later on this paper.  Researchers continue to look at the relationships in greater intensity, and use a variety of animal model to better understand those relationships.

Numerous animal model had been used for the study of Parkinson’s disease specifically mice, drosophila, C. Elegans and monkeys.  In comparison of the genes, mice had been the most animal model used and this may be because the biological pathways of Parkinson’s disease are very conservative, which has been proven in drosophila up throughout the study.  When researchers are doing research with animal models, they must get permission to use the lowest animal to be able to mimic the disorder in humans.  I am curious as to why mice, drosophila, C. elegans and monkeys are used in studies; it may be due to the fact these animal models have phenotypes close to that of humans. Animal models have been used to better recognize Parkinson’s disease (Chakraborty, S., Bornhorst, J., Nguyen, T. T., & Aschner, M. 2013). That information has helped to come up with treatments causes, however because the wide variety of patients with familial PD is extraordinarily high compared to the number with sporadic PD, genetic research in affected human families are very high, therefore if a genetic research is accomplished it would not be based on history within the family or not. Studying the sporadic form of the disease helps to disease quickly without having to go through different processs to find out the problem.  An invertebrate is regularly used in treatment. Even invertebrate animals, as an example, Drosophila melanogaster, are beneficial models for surveys of human PD. growing an animal model, a great number of genes and molecular transduction pathways are conserved between Drosophila and people (Pickrell and Youle, 2015).

Parkin

Recent research show that the ubiquitin ligase activity of parkin may have proteasome-unbiased functions, which may additionally provide an explanation for the lack of accumulation of some putative substrates in Parkin null mice. A part from lysine48 (K48) -related poly-ubiquitination, parkin is also able to catalyze both mono-ubiquitination and K63-linked poly-ubiquitination. Overexpression of wild-type parkin has been proven to lessen mitochondrial ROS production in neuronal cells by improving the mitochondrial membrane potential, while overexpression of mutant parkin induced.

ROS formations. In parkin loss-of-characteristic mutants in Drosophila, dramatic mitochondrial defects brought on by using the absence of purposeful parkin are located, in energy in depth tissues. PD is characterized commonly by innovative degeneration of melanized neurons inside the midbrain and brainstem, and accumulation of aggregated a-synuclein protein in cytoplasmic neuronal inclusions, called Lewy bodies (LB) in diverse brain areas (Van, d. et al. 2015). The primary hyperlink between parkin and autosomal recessive familial PD turned into the discovery of the T240R mutation, a threonine to arginine substitution, within the parkin gene (Van, d. et al. 2015). Further, parkin is present in the affected mind regions of PD brains (Van, d. et al. 2015). and colocalizes with LBs (Van, d. et al. 2015). In vivo records suggest that parkin has a neuroprotective feature in PD, in view that parkin mutant flies demonstrate a lack of a subset of dopaminergic neurons.

In this study, Parkin regulates the endolysosomal pathway, particularly the company of the tubular and multivehicular regions, which further have an effect on the retromer pathway and exosome secretion. furthermore, Parkin ubiquitinates overdue-endosomal GTPase Rab7, thereby regulating its activity and stability. Records reveal a singular feature of Parkin in modulating the endo-lysosomal pathway via the law of retromer feature and endosomal company, and lift the posible that the disruption of this pathway contributes to the pathogenesis of Parkin-related PD.

A preceding take a look at verified that Parkin mediated ubiquitination of Eps15, an adaptor protein involved in early endocytosis (Fallon et al., 2006), suggesting a function for Parkin inside the endocytic pathway. . To examine in more detail the endolysosomal pathway in the presence of mutant Parkin, we first assessed the morphology and distribution of several early and late endosomal markers in patient-derived Parkin-deficient fibroblasts. Although we did not observe significant differences in the pattern of EEA1 and LAPMP1 in Parkin-deficient cells (Fig. 1A, B), a more detailed inspection of the specific endosomal membrane regions revealed a significant loss of tubular elements labelled by SNX16, a PX domain-containing sorting nexin specifically enriched on late endosomal tubules and cisterns (Brankatschk et al., 2011) (Fig. 1C). To further confirm this observation, research was conducted with live cell confocal images and found a dramatic decrease in endosomal tubulation in Parkin-deficient fibroblasts compared with controls suggesting that Parkin is involved in endosomal membrane tubulati   on observed a decrease in the levels of the late endosomal marker M6PR, which is a main cargo of retromer (Arighi et al., 2004) (Fig. 1D), indicative of the impairment of the retromer function. To get more insight in the retromer status, analyses of membrane association of the retromer proteins SNX1 and VPS35 using cell fractionation assay (Seaman et al., 2009). The results showed a decreased ratio of membrane-associated and cytosolic SNX1 and VPS35 in Parkin-deficient cells compared with controls (Fig. 1E), further corroborating altered retromer function in Parkin-deficient cells.

Endolysosomal pathway in the presence of mutant Parkin. Retrieved from Song et al. 2016

To test this study, the authors isolated exosomes from the cell culture media of Parkin-deficient or control fibroblasts by conventional centrifugation and measured the number of exosomes by nanoparticle tracking analysis (Dragovic et al., 2011; Tsunemi et al., 2014). The results showed that exosomes were significantly increased in Parkin-deficient fibroblasts (Fig. 3A). To confirm this finding, the authors conducted Western blot analysis using established markers of exosomes, TSG101 and Flotillin-1, and confirmed increased exosome secretion from Parkin-deficient fibroblasts. They next wished to confirm their findings in DA neurons, which are highly affected in patients carrying parkin mutations. To that they also differentiated Parkin-deficient and control iPS cells into DA neurons, which are considered as the most relevant neuronal model to DA neurons in human brains. Both nanoparticle tracking and Western blot analysis with TSG101 and Flotillin-1 revealed a similar increase in secretion of exosomes in Parkin-deficient DA neurons (Fig. 3B). To further establish that this effect was Parkin-specific, they measured exosome release from HEK293 cells in which Parkin expression levels were modulated. The results showed that shRNA-mediated silencing of parkin resulted in increased exosome release (Fig. 3C), whereas overexpression of wild-type but not mutant Parkin led to a decrease in secretion of exosomes (Fig. 3D), suggesting that Parkin is negatively involved in exosome generation. Together, these results demonstrated the involvement of Parkin in exosome secretion in multiple cellular models.

Patient-derived Parkin-deficient fibroblasts. Retrieved from Song et. Al 2016

PINK1

The PINK1 gene encodes a protein called PTEN-induced putative kinase 1 (PINK1), characterized by an N-terminal mitochondrial targeting motif, a highly conserved serine-threonine kinase domain, and a C-terminal autoregulatory domain (Wilhelmus et al. 2012). PINK1 is detected in different cell types throughout the human brain with the highest expression in the hippocampus, substantia nigra, and cerebellar Purkinje cells (Wilhelmus et al. 2012). It has been shown that PINK1 mRNA expression is abundantly found in neurons, but not in glial cells (Wilhelmus et al. 2012). However, immunohistochemical analysis demonstrated PINK1-immunopositive glial cells, predominantly astrocytes (Wilhelmus et al. 2012). In addition, endothelial and vascular smooth muscle cells in both white and gray matter are positive for PINK1 (Wilhelmus et al. 2012).  Intracellularly, the PINK1 protein is predominantly localized at the inner mitochondrial membrane, suggesting an important role in mitochondrial function (Wilhelmus et al. 2012). Only a few substrates of PINK1 are known to this date, although it is likely that many more proteins can interact with this kinase. Recently, Rakovic et al. established a list of potential binding targets of PINK1, four of which are located in the mitochondria and are important for optimal mitochondrial function (Wilhelmus et al. 2012). Recent studies now show that PINK1 plays an important role in several cell (patho)biological processes, including mitochondrial metabolism, oxidative stress, oxidative phosphorylation, calcium homeostasis, mitochondrial dynamics, and aberrant protein clearance by proteasomal degradation. PINK1 mutations are the second most common cause of autosomal recessive PD after parkin and are responsible for some sporadic cases of PD. Similar to parkin, colocalization of PINK1 with LBs has been observed (Wilhelmus et al. 2012). In vivo, PINK1 KO mice exhibit similar symptoms as seen in PD, including reduced dopamine overflow from nigrostriatal terminals, impaired corticostriatal synaptic plasticity and mitochondrial dysfunction in dopaminergic neurons (Wilhelmus et al. 2012). Mitochondrial accumulation of a-synuclein occurs predominantly in PD-affected brain regions, suggesting that PINK1 could be associated with a-synuclein pathology (Wilhelmus et al. 2012).  In fact, overexpression of PINK1 in Drosophila rescues a-synuclein pathology, and restores a-synucleininduced fusion (Wilhelmus et al. 2012).  Furthermore, PINK1 deficiency promotes a-synuclein aggregation by impaired proteasome function (Wilhelmus et al. 2012). Proteasome function can be manipulated by PINK1 via phosphorylation of the inner membrane protease HtrA2, the activity of which is decreased in brains of PD patients carrying PINK1 mutations compared to idiopathic PD brain.

PINK1 p.I368N mutant protein is not properly stabilized upon dissipation of the mitochondrial membrane potential. To study the effects of endogenous mutant PINK1 in cells, the authors analyzed primary skin fibroblasts from controls and both patients carrying the homozygous p.I368N mutation. They quantified PINK1 mRNA levels before and after mitochondrial depolarization with the K+ ionophore valinomycin by quantitative reverse transcriptase PCR (qRT-PCR), but found no significant difference between WT and mutant PINK1 fibroblasts (Fig. 3a). Next, they examined PINK1 protein levels under basal conditions and upon mitochondrial damage (Fig. 3b). In the absence of stress, PINK1 protein was hardly detectable by Western blot (WB) under endogenous conditions. While full-length PINK1 WT robustly accumulated in controls upon treatment with the mitochondrial uncoupler CCCP, stabilization of p.I368N mutant PINK1 protein was significantly impaired (Fig. 3b, c). To confirm these findings, fibroblasts were subjected to immunofluorescence (IF) with antibodies against PINK1 and the mitochondrial marker protein TOM20. Consistently, PINK1 signal was considerably weaker in p.I368N mutant cells compared to WT controls (Additional file 5: Figure S1A). Despite significantly reduced protein levels, localization of the mutant PINK1 p.I368N to damaged mitochondria seemed unaltered. This was further corroborated by subcellular fractionations, where both WT and mutant full-length PINK1 were detected in the mitochondrial fraction upon depolarization (Additional file 5: Figure S1B). Taken together, p.I368N mutant cells showed no changes in mRNAs levels, but significantly reduced levels of the full-length PINK1 protein on mitochondria upon depolarization.

The effects of endogenous mutant PINK1 in cells.  Retrieved from Ando et al. 2017

Research has implicated mitochondria in the pathogenesis of PD. PD patients exhibit electron transport chain (ETC.)  (Ando et al. 2017), Several drugs including 1-methyl-4-phenylpyridinium, rotenone, and paraquat inhibit mitochondrial function producing Parkinsonian symptoms put in drug section. (Ando et al. 2017). This information suggests a mitochondrial component in the etiology of PD. Despite the clear implication of mitochondria, studying the initiation and progression of PD has proven problematic.

In general, PD models are better at mimicking the end-stages of PD rather than the progression (Ando et al. 2017). Recently, the Michael J. Fox Foundation produced several rat models lacking PD-associated proteins. PINK1 knockout (PINK1 KO) rat model, displays a progressive movement disorder (Ando et al. 2017).  By using the PINK1 KO model, it may be possible to study the progression of PD and identify novel diagnostic and therapeutic target during the asymptomatic phase of PD. A major limitation of PD genetic models is that most models do not recapitulate the progressive neurodegenerative hallmarks of the disease such as the progressive movement disorder or the loss of midbrain dopaminergic neurons in the substantia nigra (Villeneuve et al. 2016). As such, the relevance of the findings in mouse models to human PD is questionable. To target this issue, a novel rat model that is deficient in the PINK1 protein and presents a progressive movement disorder was obtained (Villeneuve et al. 2016).  To confirm the loss of midbrain dopaminergic neurons in the substantia nigra, the authors performed stereology of tyrosine hydroxylase positive neurons in wild-type Long Evans Hardy (LEH) and PINK1 KO (produced on the LEH background) animals at 9 months of age (Fig. 1a). Dopaminergic neurons express high levels of tyrosine hydroxylase because this enzyme catalyses the final and rate-limiting reaction of dopamine synthesis. Based on tyrosine hydroxylase staining, the number of dopaminergic neurons in the SNPC was decreased in PINK1 KO rats (Fig. 1b). A corresponding decrease in the size of the SNPC was also detected (Fig. 1c). These data demonstrate that the PINK1 knockout rat model recapitulates the midbrain dopaminergic cell death characteristic of PD.

Dopaminergic neurons in the SNPC was decreased in PINK1 KO rats.  Retrieved from Villeneuve et al. 2016)

DJ-1 (Park 7)

DJ-1, also known as PARK7 is located on chromosome 1p36.23, with a transcript length of 949 bp with 7 exons and encodes a protein consisting of 189 amino acids (Wilhelmus et al. 2012). DJ-1 was initially identified as an oncogene and its expression was found to be enhanced in several types of cancers (Wilhelmus et al. 2012). DJ-1 protein is ubiquitously expressed in many cell types and predominantly localizes in the cytosol, but also in the nucleus and associated with mitochondria.   (Wilhelmus et al. 2012).  Immuno histochemical analysis demonstrated that the DJ-1 protein was expressed by neurons, however, also by astrocytes in mouse brain (Wilhelmus et al. 2012).  Likewise, in normal human brain DJ-1 is predominantly expressed by astrocytes and to a much lesser extent in neurons.

DJ-1 protein was expressed by neurons. Retrieved from Goa et al. 2012.

Combining the genes

Mutations are loss of function, a reasonable way to try to model the disease would be to reduce or stop PINK1, parkin, or DJ-1. For reasons that are not clear, this has not led to striking results in mice because even triple knockouts of all three genes did not have loss of dopaminergic neurons when aged to 2 years old (Kitada et al. 2009). Furthermore, in Drosophila models, knockout of parkin had dramatic effects. Although there are many E3 ligases, there appears to be one reasonably clear homolog of human parkin in flies. Genomic knockout of this homolog led to loss of flight muscles and male sterility. Interestingly, and surprisingly, these effects both appeared to be due to mitochondrial damage (Greene et al. 2003). What was also interesting was the report that Drosophila parkin mutants show increased sensitivity to oxidative stress (Pesah et al. 2004). Therefore, knockout of parkin in this simple organism seemed to link the two theories regarding loss of dopamine neurons discussed above, although the phenotypes were very striking and not simply loss of dopamine neurons; in fact, loss of neurons was not seen in one of the models (Pesah et al. 2004).

Unbiased assays of the proteome also highlighted mitochondrial dysfunction in parkin knockout mice, although without such dramatic morphological effects as seen in flies (Palacino et al. 2004).

PINK1-deficient flies were made. Two groups independently showed that Drosophila lacking the single PINK1 homolog had the same types of muscle degeneration, male infertility, and mitochondrial phenotypes as the parkin mutants (Clark et al. 2006; Park et al. 2006). These phenotypes were PINK1 dependent because the human homolog could rescue the PINK1-deficiency phenotypes, which also shows that the Drosophila and human genes were functionally conserved. Furthermore, although overexpression of parkin could at least partially rescue PINK1 phenotypes, the reverse was not true, implying a genetic pathway in which PINK1 is upstream of parkin. This is an important result because it implies that the phenotypes seen in different gene mutations are not phenocopies but can be used to indicate something specific regarding gene relationships. Furthermore, this putative relationship between PINK1 and parkin seems to strengthen the concept that parkin has an effect in the control of mitochondrial function. In contrast, the relationship between DJ-1 and the other two genes discussed here is more complex. The original reports of DJ-1 knockout flies did not show such dramatic mitochondrial phenotypes, although they were reported to have altered sensitivity to oxidative stressors (Menzies et al. 2005; Meulener et al. 2005; Park et al. 2005; Yang et al. 2005; Lavara-Culebras and Paricio 2007). However, more recent examinations of aged flies have revealed mitochondrial defects and shown that increased expression of DJ-1 can complement loss of PINK1, but not parkin function (Hao et al. 2010). Overall, this suggests that DJ-1 acts in parallel, or perhaps downstream from PINK1, but is probably not a central part of the PINK1/parkin pathway. Although these data were therefore incredibly important in developing ideas regarding relationships between different genes for parkinsonism, they did not immediately provide a biochemical explanation for why these proteins might have a similar effect. Although this is an active area of research, there have been several developments that have begun to resolve this issue. Dodson et al. have found that Pink1 and Parkin can physically interact in cultured Drosophila cells (R Feldman and M Guo, unpublished data), although the functional consequences of this interaction remain unclear. No substrates for Pink1 kinase activity have been identified to date but the ubiquitin ligase activity of Parkin can be modulated by phosphorylation (Dodson et al. 2007). Thus, Pink1 might regulate Parkin activity post-translationally, either by direct phosphorylation or by activation of intermediate signaling proteins. Alternatively, it has been reported that knockdown of pink1 by RNA interference (RNAi) in Drosophila results in reduced abundance of the Parkin protein (Dodson et al. 2007).  suggesting that Pink1 functions directly (perhaps through modulation of Parkin autoubiquitination and degradation) or indirectly (through actions on other proteins) to maintain Parkin levels. The aforementioned genetic data are also consistent with a model in which Pink1 and Parkin act in series on shared targets. For example, Pink1- dependent phosphorylation of a substrate might facilitate the interaction of this protein with Parkin (Dodson et al. 2007).

Animal models

The table above was created using the search engine from Wright State libraries, an advanced search for the criteria Parkinson’s disease, with each gene (Parkin, PINK1 and DJ-1 with each model (mice, drosophila, c. elegans and monkeys). The search results are shown in the above table, showing mice and drosophila as the most common animal models used for studies in all three genes. The monkey as an animal model in PD studies was only done with Parkin, not the others. The best models that was used according to the table are mice and drosophila. These models were mainly used because they mimic humans, they are inexpensive, and Animal Use Protocols require the researcher to use the lowest class of animal that best vertebrates when invertebrates can be used researched and summarized in this paper.

Treatment

This review’s focus is on the genes and the research surrounding PD, particularly the animal models used to study the disease. Medications were not a primary focus; however, research shows no known cure or treatment to lessen the disease. Medications for Parkinson’s disease act, in one way or another, to increase dopamine levels to make up for its loss caused by the death of the dopamine producing cells. Understanding of the pathophysiology of Parkinson disease has advanced rapidly over the last two decades through basic and clinical studies using modern neuroanatomical, clinical assessment, neuropathological and functional brain imaging methods. The clinical manifestations of Parkinson’s disease, at least in early stages, reflect selective degeneration of dopamine neurons in the substantia nigra projecting through the nigrostriatal pathway to the caudal putamen with compensatory changes in this and related systems. Positron emission tomography with specific ligands for the dopamine system is a powerful tool for analysis of both degenerative and compensatory processes in the pathophysiology of Parkinson disease in vivo and can be used to confirm the diagnosis of dopamine deficient Parkinson disease. The increasing knowledge of the pathogenesis of Parkinson’s disease at a molecular level will have important implications for the development of individual therapeutic strategies to prevent disease progression (Ref.10).

Conclusion

The review focused on the genes and the research surrounding PD, particularly the animal models used to study the disease. The fairly substantial body of work in the literature on PINK1, parkin, and DJ-1 has highlighted several critical pathways that are probably involved in recessive parkinsonism. This is drawn from a number of experimental systems, and understanding what each of them tells us involves some knowledge the evolutionary relationships between the organisms studied and how the genes function in each. What is clear is that at least some functions are conserved, but there are likely to be subtleties in usage that have driven the relative phenotypes in each model system. What still needs to be resolved are the fine-grained details of mechanisms by which PINK1/ parkin and DJ-1 function. There are unresolved questions regarding the ability of parkin to rescue PINK1 deficiency, where the data in flies and in cell culture need to be reconciled. There are also significant gaps in our knowledge regarding which of these functions can be shown to be active in the mature mammalian brain, particularly in dopaminergic neurons. Finally, whereas the enzymatic functions of PINK1 and parkin are known, the precise biochemical function of DJ-1 is still somewhat mysterious, and this might be important in understanding which functions of the overall pathway lead to dopamine cell loss, with the important caveat that DJ-1 appears to be in a parallel pathway and therefore might partially be a phenocopy of PINK1/parkin deficiency. As a final thought, it is of fairly substantial concern that little of this knowledge has impacted the people who have any of these diseases. In part, this simply justifies knowing more regarding the biology so that we can develop appropriately targeted approaches, because biological processes as broad as oxidative stress or mitochondrial function have not yet yielded much in the way of therapeutics. But in addition, this reinforces the notion that although human genetics has told us a great deal, we still need to find ways to apply it back to humans, and this constitutes the biggest challenge we face.

References

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George, S., Mok, S. S., Nurjono, M., Ayton, S., Finkelstein, D. I., Masters, C. L., . . . Dong, Z. J. (2012). α-Synuclein transgenic mice reveal compensatory increases in parkinson’s disease-associated proteins DJ-1 and parkin and have enhanced α-synuclein and PINK1 levels after rotenone treatment. United States: Humana Press. doi:10.1007/s12031-010-9378-1

George, S., Mok, S., Nurjono, M., Ayton, S., Finkelstein, D., Masters, C., . . . Culvenor, J. (2010). α-Synuclein transgenic mice reveal compensatory increases in parkinson’s disease-associated proteins DJ-1 and parkin and have enhanced α-synuclein and PINK1 levels after rotenone treatment. Journal of Molecular Neuroscience, 42(2), 243. Retrieved from http://ezproxy.libraries.wright.edu/login?url=http://search.ebscohost.com.ezproxy.libraries.wright.edu/login.aspx?direct=true&db=edb&AN=52793078&site=eds-live

Gubellini, P., & Kachidian, P. (2015). Update in neurosciences: Animal models of parkinson’s disease: An updated overview. Revue Neurologique, 171, 750-761. doi:10.1016/j.neurol.2015.07.011

Haque, M. E., Mount, M. P. 1., Safarpour, F., Abdel-Messih, E., Callaghan, S., Mazerolle, C., . . . Park, David S.1,5, [email protected]. (2012). Inactivation of Pink1 gene in vivo sensitizes dopamine-producing neurons to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and can be rescued by autosomal recessive parkinson disease genes, parkin or DJ-1. Journal of Biological Chemistry, 287(27), 23162-23170. doi:10.1074/jbc.M112.346437

Hauser, D. N., Primiani, C. T., & Cookson, M. R. (2016). The effects of variants in the PARK2 (parkin), PINK1, and PARK7 (DJ-1) genes along with evidence for their pathogenicity. Current Protein & Peptide Science, Retrieved from http://ezproxy.libraries.wright.edu/login?url=http://search.ebscohost.com.ezproxy.libraries.wright.edu/login.aspx?direct=true&db=mnh&AN=26965687&site=eds-live

Hewitt, V. L., & Whitworth, A. J. (2017). Mechanisms of parkinson’s disease: Lessons from drosophila. Current Topics in Developmental Biology, 121, 173-200. doi:10.1016/bs.ctdb.2016.07.005

Jean-Francois eTrempe, & Fon, E. A. (2013). Structure and function of parkin, PINK1 and DJ-1, the three musketeers of neuroprotection. Frontiers in Neurology, Vol 4 (2013), doi:10.3389/fneur.2013.00038/full; 10.3389/fneur.2013.00038

Kamp, F., Exner, N., Lutz, A. K., Wender, N., Hegermann, J., Brunner, B., . . . Haass, C. (2010). Inhibition of mitochondrial fusion by α-synuclein is rescued by PINK1, parkin and DJ-1. EMBO Journal, 29(20), 3571-3589. doi:10.1038/emboj.2010.223

Kamp, F., Exner, N., Lutz, A. K., Wender, N., Hegermann, J., Brunner, B., . . . Moore, D. J. (2012). Inhibition of mitochondrial fusion by α-synuclein is rescued by PINK1, parkin and DJ-1 John Wiley & Sons, Inc. doi:10.1038/emboj.2010.223

Karla Cristina, V. M., Mário, C. J., Ana Lúcia Zuma, d. R., Denise, H. N., João, S. P., Delson José Silva, . . . Culvenor, J. G. (2010). Exon dosage variations in brazilian patients with Parkinson’s disease: Analysis of SNCA, PARKIN, PINK1 and DJ-1 genes Hindawi Publishing Corporation. doi:10.3233/DMA-2011-0873

Kim, C. Y., & Alcalay, R. N. (2017). Genetic forms of parkinson’s disease. Seminars in Neurology, 37(2), 135-146. doi:10.1055/s-0037-1601567

Klein, C., Djarmati, A., Hedrich, K., Schäfer, N., Scaglione, C., Marchese, R., . . . Pramstaller, P. P. (2005). PINK1, parkin, and DJ-1 mutations in italian patients with early-onset parkinsonism. European Journal of Human Genetics, 13(9), 1086-1093. doi:10.1038/sj.ejhg.5201455

Le Grand, J., Gonzalez-Cano, L., Pavlou, M., & Schwamborn, J. (2015). Neural stem cells in parkinson’s disease: A role for neurogenesis defects in onset and progression. Cellular & Molecular Life Sciences, 72(4), 773-797. doi:10.1007/s00018-014-1774-1

Le Grand, J., Gonzalez-Cano, L., Pavlou, M., & Schwamborn, J. (2015). Neural stem cells in parkinson’s disease: A role for neurogenesis defects in onset and progression. Cellular & Molecular Life Sciences, 72(4), 773-797. doi:10.1007/s00018-014-1774-1

Le Grand, J., Gonzalez-Cano, L., Pavlou, M., & Schwamborn, J. (2015). Neural stem cells in parkinson’s disease: A role for neurogenesis defects in onset and progression. Cellular & Molecular Life Sciences, 72(4), 773-797. doi:10.1007/s00018-014-1774-1

Lev, N., Roncevic, D., Ickowicz, D., Melamed, E., & Offen, D. (2006). Role of DJ-1 in parkinson’s disease. Journal of Molecular Neuroscience: MN, 29(3), 215-225. Retrieved from http://ezproxy.libraries.wright.edu/login?url=http://search.ebscohost.com.ezproxy.libraries.wright.edu/login.aspx?direct=true&db=mnh&AN=17085780&site=eds-live

Liang, C., Wang, T. T., Luby-Phelps, K., German, D. C., Guo, M., Cookson, M. R., . . . Schwamborn, J. C. (2015). Mitochondria mass is low in mouse substantia nigra dopamine neurons: Implications for parkinson’s disease Elsevier Inc. doi:10.1016/j.expneurol.2006.08.015

Liang, J., Luo, J., & Jin, J. (2013). [Study of parkinson’s disease based on drosophila model]. Zhejiang Da Xue Xue Bao.Yi Xue Ban = Journal of Zhejiang University.Medical Sciences, 42(6), 685-692. Retrieved from http://ezproxy.libraries.wright.edu/login?url=http://search.ebscohost.com.ezproxy.libraries.wright.edu/login.aspx?direct=true&db=mnh&AN=24421238&site=eds-live

Lill, C. M. (2016). Review: Genetics of parkinson’s disease. Molecular and Cellular Probes, 30, 386-396. doi:10.1016/j.mcp.2016.11.001

Low, K., Aebischer, P., Liang, C. L., Wang, T. T., Luby-Phelps, K., & German, D. C. (2007). Use of viral vectors to create animal models for parkinson’s disease Retrieved from http://ezproxy.libraries.wright.edu/login?url=http://search.ebscohost.com.ezproxy.libraries.wright.edu/login.aspx?direct=true&db=edswsc&AN=000307911400004&site=eds-live; http://ezproxy.libraries.wright.edu/login?url=http://search.ebscohost.com.ezproxy.libraries.wright.edu/login.aspx?direct=true&db=edswsc&AN=000244046000009&site=eds-live

McInnes, J. (2013). Insights on altered mitochondrial function and dynamics in the pathogenesis of neurodegeneration. Translational Neurodegeneration, 2(1), 12-12. doi:10.1186/2047-9158-2-12

Merwe, C., Jalali, S. D., Christoffels, A., Loos, B., & Bardien, S. (2015). Evidence for a common biological pathway linking three parkinson’s disease-causing genes: Parkin, PINK1 and DJ-1. European Journal of Neuroscience, 41(9), 1113-1125. doi:10.1111/ejn.12872

Minakawa, E. N., Yamakado, H., Tanaka, A., Uemura, K., Takeda, S., & Takahashi, R. (2013). Chicken DT40 cell line lacking DJ-1, the gene responsible for familial parkinson’s disease, displays mitochondrial dysfunction.Neuroscience Research, 77, 228-233. doi:10.1016/j.neures.2013.09.006

Moura, K. C. V., Junior, M., de Rosso, Ana Lúcia Zuma, Nicaretta, D. H., Pereira, J. S., José Silva, D., . . . Pimentel, M. (2012). Exon dosage variations in brazilian patients with parkinson’s disease: Analysis of SNCA, PARKIN, PINK1 and DJ-1 genes. Disease Markers, 32(3), 173-178. doi:10.3233/DMA-2011-0873

Puschmann, A., Wang, X. L., Petrie, T. G., Liu, Y. C., Liu, J., Fujioka, H., . . . Berman, S. B. (2013). Review: Monogenic parkinson’s disease and parkinsonism: Clinical phenotypes and frequencies of known mutationsElsevier Ltd. doi:10.1016/j.parkreldis.2013.01.020

Rochet, J., Hay, B. A., & Guo, M. (2012). Chapter 5: Molecular insights into parkinson’s disease. Progress in Molecular Biology and Translational Science, 107, 125-188. doi:10.1016/B978-0-12-385883-2.00011-4

Rochet, J., Hay, B. A., & Guo, M. (2012). Molecular insights into parkinson’s disease. Progress in Molecular Biology and Translational Science, 107, 125-188. doi:10.1016/B978-0-12-385883-2.00011-4

Sai, Y., Zou, Z., Peng, K., Dong, Z., Abdel-Salam, O., Guo, M., . . . Moore, D. J. (2012). Review: The parkinson’s disease-related genes act in mitochondrial homeostasis Elsevier Ltd. doi:10.1016/j.neubiorev.2012.06.007

Sanchez, G., Varaschin, R. K., Büeler, H., Marcogliese, P. C., Park, D. S., & Trudeau, L. (2014). Unaltered striatal dopamine release levels in young parkin knockout, Pink1 knockout, DJ-1 knockout and LRRK2 R1441G transgenic mice. Plos One, 9(4), 1-7. doi:10.1371/journal.pone.0094826

Sanchez, G., Varaschin, R. K., Büeler, H., Marcogliese, P. C., Park, D. S., Trudeau, L., . . . Park, D. S. (2010). Unaltered striatal dopamine release levels in young parkin knockout, Pink1 knockout, DJ-1 knockout and LRRK2 R1441G transgenic mice Public Library of Science. doi:10.1371/journal.pone.0094826

Segura-Aguilar, J., Paris, I., Muñoz, P., Ferrari, E., Zecca, L., Zucca, F. A., . . . Moore, D. J. (2012). Protective and toxic roles of dopamine in parkinson’s disease. England: Wiley on behalf of the International Society for Neurochemistry. doi:10.1111/jnc.12686

Seon-Heui Cha, Yu, R. C., Cheol-Ho Heo, Seo-Jun Kang, Eun-Hye Joe, Jou, I., . . . Sang, M. P. (2015). Loss of parkin promotes lipid rafts-dependent endocytosis through accumulating caveolin-1: Implications for parkinson’s disease. Molecular Neurodegeneration, 10, 1-13. doi:10.1186/s13024-015-0060-5

Shen, J., Cookson, M. R., Wood-Kaczmar, A., Gandhi, S., & Wood, N. W. (2006). Mitochondria and dopamine: New insights into recessive parkinsonism Retrieved from http://ezproxy.libraries.wright.edu/login?url=http://search.ebscohost.com.ezproxy.libraries.wright.edu/login.aspx?direct=true&db=edswsc&AN=000223156900004&site=eds-live; http://ezproxy.libraries.wright.edu/login?url=http://search.ebscohost.com.ezproxy.libraries.wright.edu/login.aspx?direct=true&db=edswsc&AN=000242065300004&site=eds-live

Terzioglu, M., Galter, D., Park, J., Kim, Y., Chung, J., Zhang, Q., . . . Yuan, Z. Q. (2012). Parkinson’s disease: Genetic versus toxin-induced rodent models Wiley-Blackwell. doi:10.1111/j.1742-4658.2008.06302.x

Van, d. M., Dashti, Z. J. S., Christoffels, A., Loos, B., & Bardien, S. (2015). Evidence for a common biological pathway linking three parkinson’s disease‐causing genes: Parkin, PINK1 and DJ‐1. European Journal of Neuroscience, 41(9), 1113-1125. doi:10.1111/ejn.12872

van, d. M., Dashti, Z. J. S., Christoffels, A., Loos, B., & Bardien, S. (2015). Evidence for a common biological pathway linking three parkinson’s disease‐causing genes: Parkin, PINK1 and DJ‐1. European Journal of Neuroscience, 41(9), 1113-1125. doi:10.1111/ejn.12872

van, d. M., Jalali, S. D., Christoffels, A., Loos, B., & Bardien, S. (2015). Evidence for a common biological pathway linking three parkinson’s disease-causing genes: Parkin, PINK1 and DJ-1. The European Journal of Neuroscience, 41(9), 1113-1125. doi:10.1111/ejn.12872

van, d. M., Jalali, S. D., Christoffels, A., Loos, B., & Bardien, S. (2015). Evidence for a common biological pathway linking three parkinson’s disease-causing genes: Parkin, PINK1 and DJ-1. The European Journal of Neuroscience, 41(9), 1113-1125. doi:10.1111/ejn.12872

van, d. M., Jalali, S. D., Christoffels, A., Loos, B., & Bardien, S. (2015). Evidence for a common biological pathway linking three parkinson’s disease-causing genes: Parkin, PINK1 and DJ-1. The European Journal of Neuroscience, 41(9), 1113-1125. doi:10.1111/ejn.12872

Wilhelmus, M. M. M., Nijland, P. G., Drukarch, B., de Vries, H. E., & van Horssen, J. (2012). Review article: Involvement and interplay of parkin, PINK1, and DJ1 in neurodegenerative and neuroinflammatory disorders.Free Radical Biology and Medicine, 53, 983-992. doi:10.1016/j.freeradbiomed.2012.05.040

Wilhelmus, M. M. M., Nijland, P. G., Drukarch, B., de Vries, H.,E., & van Horssen, J. (2012). Involvement and interplay of parkin, PINK1, and DJ1 in neurodegenerative and neuroinflammatory disorders. Free Radical Biology & Medicine, 53(4), 983-992. doi:10.1016/j.freeradbiomed.2012.05.040

Yang, Y., Gehrke, S., Imai, Y., & Gasser, T. (2007). Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of drosophila Pink1 is rescued by parkindoi:10.1073/pnas.0602493103

Yonova-Doing, E., Atadzhanov, M., Quadri, M., Kelly, P., Shawa, N., Musonda, S. T. S., . . . Morris, H. R. (2012). Analysis of LRRK2, SNCA, parkin, PINK1, and DJ-1 in zambian patients with parkinson’s disease Elsevier Ltd. doi:10.1016/j.parkreldis.2012.02.018

Yonova-Doing, E., Atadzhanov, M., Quadri, M., Kelly, P., Shawa, N., Musonda, S. T. S., . . . Park, D. S. (2009). Analysis of LRRK2, SNCA, parkin, PINK1, and DJ-1 in zambian patients with parkinson’s disease. England: Elsevier Science. doi:10.1016/j.parkreldis.2012.02.018