Genetic Predisposition to Parkinson's Disease and Cancer

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Current Cancer Drug Targets, 2014, 14, 310-321

Genetic Predisposition to Parkinson’s Disease and Cancer Zhiming Li1,#, Qing Lin1,2,#, Qilin Ma2, Congxia Lu2 and Chi-Meng Tzeng1,* 1

School of Pharmaceutical Sciences, Xiamen University, Xiamen 361005, Fujian, China; 2Department of Neurology, The First Affiliated Hospital of Xiamen University, Xiamen 361003, Fujian, China Abstract: Parkinson’s disease (PD) and cancer are often thought of as two sides of the same coin. At first glance, cancer and PD appear to have little in common. PD is caused by the degeneration of dopaminergic neurons, whereas cancer results from the uninhibited growth of tumor cells. Increasing numbers of genetic studies suggest that the pathogenesis of PD and cancer may involve similar genes, pathways, and mechanisms. The differences in the pathological and cellular mechanisms, and the associated genetic mutations, may result in two such divergent diseases. In this article, we highlight some molecular mechanisms and key biomarkers which might cause those two diseases from misfolding and degradation of proteins, mitochondrial damage, oxidative stress response, cell cycle control and DNA repair, and the PI3K/AKT/ mTOR pathway, in order to provide help to the understanding and treatment of these two diseases.

Keywords: Cancer, genes, parkinson’s disease, pathways. INTRODUCTION Parkinson's disease (PD) is the second most common neurodegenerative disease, after Alzheimer's disease [1]. PD is mainly caused by the degeneration of dopaminergic neurons in the midbrain. In contrast, cancer is a disease caused by the clonal proliferation of selectively advantageous cells. Although the two may appear distinct, epidemiological studies have revealed some parallels. The presence of a lower cancer risk among patients with PD was first recorded over 60 years ago [2]. Since then, convincing case-controlled and large prospective studies suggested a decreased frequency of smoking- and non-smoking-related cancers in patients with PD. In the recent meta-analysis of 29 studies, the aggregate risk for cancer among 107,598 PD patients was 0.73 (95% CI=0.63–0.83) for any cancer, 0.61 (95% CI=0.58–0.65) for smoking-related cancer, and 0.80 (95% CI=0.77–0.84) for non-smoking-related cancers [3]. Although most cancers were less common, some types of cancer including melanoma, thyroid, and breast cancer, were reported to have increased incidence in PD patients [4]. Nevertheless, more data are needed to confirm the epidemiological relationship between PD and cancer. The unusual epidemiological relationship between PD and cancer has been the subject of many investigations. Genetic assessments allowed additional understanding, since many familial PD genes have been associated with cancer (Table 1). Specifically, mutations in parkin (PARK2), PINK1 (PARK6), DJ-1 (PARK7), and LRRK2 (PARK8) may cause distinct effects in PD and cancer in different cell types [5]. PD and cancer share the PI3K/AKT/mTOR pathway, which is a central pathway that regulates cell growth and

*Address correspondence to this author at the School of Pharmaceutical Sciences, Xiamen University, Xiamen 361005, Fujian, China; Tel: 86-5922187226; Fax: 86-592-2182453; E-mail: [email protected] #

These Authors contributed equally

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proliferation, predominantly by modulating protein synthesis and by promptly responding to intrinsic and environmental stresses [6]. Currently, more than 12 loci are known to be related to familial PD [7], of which six genes have been cloned. PD-related genes are involved in a variety of cellular processes, including the misfolding and degradation of proteins, mitochondrial damage, and the response to oxidative stress, cell cycle control, and DNA repair. These processes all play a vital role in the pathogenesis of both PD and cancer. Understanding of the functions of these genes in cell survival and death may therefore help to reveal the connection between the two diseases. The recent discoveries on PD and cancer collectively showed genetic predisposition to two diseases [6, 8-12], besides, ubiquitin-omics also revealed novel networks and associations with human diseases including PD and cancer [13]. In this article, we focus on the cellular pathways and mechanisms that involve genes common to PD and cancer. This will provide increased understanding and improved treatment options for these two diseases. To emphasize the multiple pathological functions of these gene mutations, they are discussed separately. THE MISFOLDING PROTEINS

AND

DEGRADATION

OF

Most neurodegenerative diseases are associated with the death of specific neuronal populations due to perturbations of protein folding proceedings, leading to the misfolding, aggregation, and cytotoxicity of certain proteins [4, 14]. In PD, protein aggregates are formed in the brain, which leads to neurodegeneration. Point mutations or increased expression of the α -synuclein gene lead to a dominant form of the familial disease due to a presumably toxic gain-of-function pathogenesis from cytosolic aggregates that consist of either wild-type or variant α -synuclein, components of the UPS, and other cellular proteins. The misfolding and aggregation of α -synuclein and its associated familial mutation are a © 2014 Bentham Science Publishers

Genetic Predisposition to Parkinson’s Disease and Cancer

Table 1.

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Parkinson’s disease involved genes identified in cancerization.

Gene

PD locus

Chromosome Location

Inheritance in PD*

Expression in Cancer

Proliferation in Cancer†

Cancer

α-Synuclein

PARK1/PARK4

4q21-q23

AD

Overexpressed (not express in normal tissue)

＋

Brain tumors [28], Melanoma [126], Ovary cancer [127]

Parkin

PARK2

6q25.2–q27

AR

Decreased§

－

Glioblastoma [5], Colon cancer [5], Lung cancer [5]

UCHL1

PARK5

4p14

AD

Silenced (via CpG methylation)

－

Nasopharyngeal carcinoma [128], Colorectal cancer [129]

PINK1

PARK6

1p35-p36

AR

Decreased§

－

Breast cancer [130]

DJ-1

PARK7

1p36

AR

Overexpressed

＋

Non-small-cell lung cancer [81]

LRRK2

PARK8

12p11.2–q13.1

AD

Overexpressed

＋

Papillary renal cell carcinoma [118], Thyroid cancer [118]

*Abbreviations: AD, autosomal dominant; AR, autosomal recessive. §The telomeric end of chromosome 1p is subject to frequent deletion and rearrangement in many cancers. †＋/－denotes proliferation and antipoliferation.

major component of Lewy bodies (LBs), which strongly correlates with PD. Protein misfolding can occur randomly, at any time, and in any cell. Neurons are particularly disposed to damage caused by misfolded proteins. Because they are terminally differentiated cells, neurons cannot use cell division to decrease the concentration of misfolded proteins. Instead, they rely on protein degradation mechanisms such as the UPS and the autophagy lysosomal pathway (ALP). The UPS, which is believed to be the major protective system against protein misfolding and aggregation, plays an important role in the etiology of PD [4, 15]. Mutations of key genes are involved in UPS such as parkin, DJ-1, and PINK1, can cause the aggregation of misfolded proteins and neurotoxicity. Furthermore, the misfolding and aggregation of these proteins can also lead to cancer by activating oncoproteins [16]. Many cancers are associated with the abnormal accumulation of aggregated wild type and mutant p53, a three domain protein that plays a key role in tumor suppression. The nature of the intracellular aggregates of p53 remains unclear, although it was reported that wild-type p53 and the p63 and p73 homologs aggregate into cellular inclusions, which disrupts the transcription of apoptosis-related genes, preventing the apoptosis of cancer cells [17]. These data suggest that p53 may be involved in tumorigenesis in two ways: 1) loss of the anti-tumor effects of the wild type or mutated inactive protein, and 2) a gain of function mutation, leading it to be assembled into aggregates that are able to recruit the functional molecules in the cell, in a manner similar to prion protein [18]. α-SYNUCLEIN Examination of the midbrains of deceased PD patients has revealed that a type of abnormal protein aggregates in the cytoplasm of dopaminergic cells. LBs are mainly composed of misfolded α -synuclein [19], and are closely

related to neuronal loss in PD. As such, they are considered to be pathological markers of PD. The gene that encodes α synuclein, SNCA (PARK1/PARK4), was the first genetic factor found to induce PD. PARK1 is a locus associated with a monogenic form that accounts for only 1% of PD cases [20]. Three missense point mutations in the α-synuclein gene were identified in familial cases of early onset PD: A53T [21], A30P [22], and E46K [23]. Additionally, the other two missenses G51D [24] and H50Q [25] on SNCA were discovered in 2013. Mutations in α-synuclein therefore tend to generate a disease that is more progressive, with an earlier onset than sporadic PD [26]. PARK4 refers to SNCA multiplication, which has a dose-dependent relationship with the clinical phenotype and age of onset of PD. Because of the numerous structural adjustments, interactions, and functions that are attributed to α -synuclein, it seems reasonable to suggest that this protein is potentially prone to misfolding. Indeed, aggregated α-synuclein frequently detected in autonomic plexi of the gastrointestinal tract of neurologically intact individuals who are suspected of having preclinical PD [27], might be the initial site of α-synuclein misfolding. α-synuclein is also widely expressed in a variety of brain tumors. Positive immunostaining for α-synuclein was observed in ganglioglioma, meduloblastoma, neuroblastoma, primitive neuroectodermal tumor, pineocytoma/pineoblastoma, and central neurocytoma [28]. Specifically, the expression of α-synuclein was predominantly observed in the cytoplasm of the tumors as well as in the cellular processes. In α-synuclein-overexpressing human osteosarcoma MG63 cells, the proteasome and protein kinase C activity were decreased significantly, whereas the activity of the lysosome was upregulated [29]. These results suggest that the effects of α-synuclein on tumor differentiation may be attributed to downregulation of proteasome. The mechanisms by which αsynuclein regulates tumor differentiation and exerts neuropathological effects may therefore overlap considerably.

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PARKIN The first genetic mutation found to induce PD in adolescents is the homozygous mutation of parkin, which encodes an E3 ubiquitin ligase [30]. It provides specificity for degradation in the UPS by labeling proteins with ubiquitin [31]. Parkin mutations disturb the ubiquitinligating function of the protein, rendering UPS unable to undergo ubiquitin-mediated degradation [32]. In addition, Parkin protein also binds to the promoter domain of TP53, which encodes p53, inhibiting the transcription of p53 [33]. PD-related parkin mutations therefore prevent the binding of Parkin to the TP53 promoter, allowing p53 expression to become elevated beyond the normal levels [6]. A large number of Parkin substrates have been identified. However, it remains unclear which substrate is the cause of the neuronal death. Nevertheless, it is evident in cancer cells that mutated parkin cannot ubiquitinate cyclin E, which allows the accumulation of cyclin E. Cyclin E then causes the cell to enter A and G2/M phases. During this process, there is increased likelihood of multipolar spindles, abnormal mitosis, and abnormal karyotypes [5]. The Parkin gene was proposed as a putative candidate for a tumor suppressor gene, since entire exon deletions and duplications of this gene have been identified in ovarian and other cancers [34-36]. PARK2 is approximately 1.4 Mb, and is located at the fragile site FRA6E of chromosome 6q25q27, which is a mutational hotspot [37]. High-frequency somatic mutations of parkin have been detected in blastoma, colon cancer, and lung cancer, all of which occur in the same structural domain [5]. This suggests that whereas germline mutations in parkin cause PD, somatic mutations of parkin contribute to cancer. Although, parkin is a very large gene that is prone to deletions and mutations, it is still unclear whether somatic mutations in PARK2 are primarily involved in tumor development. Notably, only a few alterations that have been identified in cancer were homozygous, with most being heterozygous. Importantly, these mutations affect the ability of Parkin to promote tumor growth. These data therefore suggest that, in cancer, Parkin may act in a haploinsufficient manner. The functions of Parkin may be different in cancer cells and neurons. The inactivation of one copy of the gene may be sufficient to promote cancer cell growth, but the brains of PD patients carrying heterozygous parkin mutations are normal. It is therefore generally accepted that loss of both copies of parkin is required to cause PD, and that heterozygous parkin mutations only increase susceptibility [38]. UBIQUITIN CARBOXYL-TERMINAL HYDROLASE L1 (UCH-L1) UCH-L1, also known as PGP9.5, is a cysteine hydrolase composed of 223 amino acids. It can remove the peptide bond from the carbon-terminus of polyubiquitin chains to recycle ubiquitin. Studies indicate that it also functions as an ubiquitin ligase [39] and a mono-ubiquitin stabilizer [40]. It is one of the most abundant proteins in the brain (1–2% of the total soluble protein), and immunohistochemical experiments revealed that it is exclusively localized in neurons, and it is a component in LBs [41]. Thus, its role in neuronal cell function and/or dysfunction was predicted. Downregulation

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and extensive oxidative modifications of UCH-L1 have been observed in the brains of PD patients [42]. However, disease-causing mutations in UCH-L1 appear to be very rare [43]. A single nucleotide polymorphism (SNP) S18Y in UCH-L1 was linked to decreased susceptibility to PD in Chinese [44] and Japanese populations [4, 45]. This variant form of UCH-L1 is characterized by a greater hydrolase, but lower E3 activity than wild type. Under normal conditions, UCH-L1 is expressed only in the brain and testes [46]. UCH-L1 is not expressed in normal lung tissue, but is expressed significantly in both primary lung cancer and lung cancer cell lines [47], as well as in invasive colorectal [48] and pancreatic cancers [49]. Additional studies reported that UCH-L1 is a tumor antigen that provokes a humoral immune response in lung cancer, and further proposed that UCH-L1 could be a biomarker of lung tumorigenesis [50]. The de-ubiquitination pathway in which UCH-L1 plays a role is not only vital to UPS, but also affects the cell cycle, apoptosis, and signal transduction. Recent evidence also suggested that UCH-L1 plays a key role in regulating tumor-cell invasion by the upstream activation of Akt [51]. These findings are consistent with the hypothesis that UCH -L1 affects cell migration upstream of the mTOR/Akt cascade. Taken together, these studies suggest that UCH-L1 has a potent oncogenic role and drives tumor development. MITOCHONDRIAL DAMAGE AND THE RESPONSE TO OXIDATIVE STRESS Oxidative stress and impaired electron transport chain function have been linked to the pathogenesis of PD, ever since exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) occurred. In the 1980’s, drug addicts in California, USA who received intravenous injections of the neurotoxin MPTP developed PD [52]. Since then, the importance of mitochondria in maintaining the normal function of dopaminergic neurons has been intensively studied. The MPTP metabolite MPP+ can inhibit the electron transport chain complex I in mitochondria, increasing the concentration of intracellular calcium ions and free radicals, and reducing ATP production [53]. The autopsies of patients with sporadic PD have shown that the activity of mitochondrial complex I is decreased. Reactive oxygen species (ROS) levels can also be enhanced by hypoxia when electron transport complexes are in the reduced state [54]. The hypoxic environment of proliferating tumor tissue also promotes ROS production. ROS in tumor cells can be increased to an extent that could induce damage to vital cellular components, including mitochondrial DNA, which encodes several proteins essential for the function of the mitochondrial respiratory chain. Extensive research during the past two decades has revealed the mechanism that continued oxidative stress can lead to chronic inflammation, which in turn could mediate most chronic diseases including neurodegeneration diseases and cancer. Oxidative stress can activate a variety of transcription factors which lead to the expression of over 500 different genes, including those for growth factors, inflammatory cytokines, chemokines, cell cycle regulatory molecules, and anti-inflammatory molecules [55].


Metallothioneins (MTs) inhibit Charnoly bodies formation in the degenerating neurons by acting as free radical scavengers, suggesting that they provide mitochondrial neuroprotection [56]. MTs antioxidant properties mainly derive from sulfhydryl nucleophilicity, but also from metal complexation. Besides, recently our group found a novel mutation P268S on NOD2 may be a risk factor for Chinese PD patients [57]. Interestingly, epidemiological studies show that smoking is associated with a lower incidence of PD. A neuroprotective role of nicotine is considered, because this chemical stimulates brain dopaminergic systems and modulating dopamine release [58]. In addition to the important function of dopamine as the major neurotransmitters in the mammalian brain, some recent reports also indicate its novel role in regulating malignant cell proliferation [59]. Dopamine regulates cell cycle regulatory proteins via cAMP, Ca(2+)/PKC, MAPKs and NF-κB in mouse embryonic stem cells [60]. In contrast to the well recognized immunomodulatory effects of noradrenaline and adrenaline, the influence of dopamine on inflammatory responses are incompletely defined and controversially discussed [61]. These discoveries are important because they could provide clues about therapeutic strategies for different diseases. Taken these data together indicates an important role of chromic inflammation on the development of PD and cancer. PHOSPHATASE AND TENSIN HOMOLOG (PTEN)INDUCED PUTATIVE KINASE (PINK1) Since the identification of PINK1 as a PD associated gene in 2004, a number of studies have sought to identify the biological roles of this serine-threonine kinase to aid therapeutic advances for the treatment of PD. PINK1 is a mitochondrially-targeted kinase that protects cells from oxidative stress-induced apoptosis. Mutations associated with PD are located throughout the PINK1 protein, but the majority of these are found within the kinase domain. The location of these mutations, including one that resides within the adenosine triphosphate (ATP) binding pocket of PINK1, suggests that the loss of PINK1 kinase activity is responsible for the initiation of PD. In addition, mutations in the C-terminus of the protein affect optimal kinase activity. Homozygous PINK1 mutations cause 1–2% of early-onset cases of PD, and are the second most common autosomal recessive mutation, next to parkin [62]. Most PINK1 mutations change or eliminate kinase activity, although some disrupt the mitochondrial-targeting motif. These mutations render cells sensitive to stress, and result in mitochondrial dysfunction. Initial reports revealed that a key function of PINK1 is to protect cells from stress-induced death. Specifically, PINK1-deficient cells in vitro were shown to be more susceptible to apoptosis after exposure to mitochondrial toxins [63]. In addition, the overexpression of wild type PINK1 protein could protect cells against death mediated by chemical insults such as MPTP, but this effect was abrogated when the protein carried either a PD-associated mutation or a kinase inactivating mutation [62]. Because the mitochondrial DNA is located at the same site where ROS production takes place within the mitochondrion, it is particularly vulnerable to ROS-mediated mutations. The increase in ROS may therefore account for the identification of mitochondrial DNA mutations in PINK1 in PD patients [64]. Functional


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studies of PINK1 and Parkin in animal and cellular model systems revealed that both proteins play important roles in maintaining mitochondrial integrity [65, 66]. Genetic studies of PINK1 and Parkin in Drosophila have shown that PINK1 acts upstream of Parkin in a common pathway that appears to regulate mitochondrial morphology and altered membrane potential [66, 67]. It is therefore tempting to speculate that PINK1 mutations could impair the function of the UPS. PINK1 can be transcriptionally activated by PTEN. The PTEN gene is a tumor suppressor gene encoding a multifunctional phosphatase, which plays an important role in inhibiting the PI3K/Akt pathway. Mutations in PTEN have been found in many human cancers. Germline loss-offunction mutations in PTEN underlie a broad spectrum of syndromes characterized by benign neoplasms and neuronal hypertrophy. Loss of heterozygosity at the PTEN locus has also been described in prostate cancer, glioblastoma, and breast cancer. PTEN deficiency leads to the downregulation of PINK1. PINK1 was therefore a novel candidate for mediating the PTEN growth-suppressive signaling pathway. Inhibition of the PI3K/Akt pathway and the upregulation of PINK1 by PTEN suggest that PTEN is involved in both cancer and PD [68]. However, PINK1 exerts effects not only in the mitochondria, but also in the cytoplasm. PINK1 phosphorylates a number of different substrates, including parkin and mTOR2 (mammalian target of rapamycin complex 2) [69]. PINK1 that is targeted to different intracellular locations may play a role in various diseases. DJ-1 DJ-1 is the third of four genes known to be definitively causal in familial PD, the other three being SNCA, parkin, and the recently identified PINK1. DJ-1 is located on chromosome 1p36, and contains 8 exons distributed over 24 kb. It encodes the cytoplasmic protein DJ-1, which is composed of 189 amino acids [70]. It is conserved across many species and expressed both in the brain and peripheral tissues [71]. Under normal conditions, DJ-1 is localized in the cytoplasm. Under oxidative conditions, it is transported to the mitochondria [72]. DJ-1 has significant anti-oxidative activities. Due to dopamine metabolism, neurons in the nigrostriata are exposed to high concentrations of ROS. DJ-1 is considered a sensor of oxidative stress [73]. In the normal human brain, DJ-1 is moderately expressed in neurons and astrocytes throughout the CNS [74]. DJ-1 accumulates in the neuropathological hallmark lesions of PD; the LBs. Examination of sporadic neurodegeneration patients revealed that DJ-1 is strongly expressed in the reactive astrocytes of PD patients [75]. Wild-type DJ-1 can alleviate the neuronal death induced by 6-hydroxydopamine (6-ODHA) in rats [76]. PD patients who carry DJ-1 mutations have an earlier disease onset and react significantly to levodopa treatment. Specifically, positron emission tomography neuroimaging demonstrated severe dopamine depletion in homozygous DJ1 mutation carriers [77, 78]. Biochemically, DJ-1 exists in a more acidic (oxidized) form in the PD brain. Oxidized DJ-1 has been recognized as a biomarker for neurodegenerative diseases and cancer [79]. As well as protecting nerves, DJ-1 also acts as a carcinogen. DJ-1 was initially described as a putative

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oncogene that could weakly transform cells alone, and more strongly in combination with Ras [80]. DJ-1 is highly expressed in primary lung and prostate cancer biopsies [81, 82], and its expression is negatively correlated with clinical outcome in non-small cell lung carcinoma patients [81]. DJ-1 inhibits PTEN and the PI3K/Akt/mTOR pathway, and altering p53 activity [83]. Overexpression of DJ-1 in mammalian cells decreases the expression of Bax, which reduces p53 transcription and inhibits caspase activation [4, 84]. The overexpression of DJ-1 and reduction of p53 transcription may facilitate the development of cancer. Recent evidence showed that without intact DJ-1, Nrf2 (nuclear factor erythroid 2-related factor) protein is unstable, and so transcriptional responses are reduced both basally and after induction. The effect of DJ-1 on Nrf2 and the subsequent antioxidant responses may explain how DJ-1 affects the etiology of both cancer and PD [71]. CELL CYCLE CONTROL AND DNA REPAIR Classically, the cell cycle is regarded as the pathway leading to cellular proliferation. In most cells, both in vivo and in vitro, the activation of the cell cycle by mitogenic factors leads to DNA replication (S phase) and mitosis (M phase). However, evidence has mounted that nerve cell death in the CNS is often intimately linked to the process of cell division. Studies have shown that experimentally driving the cell cycle in a mature neuron leads to cell death rather than cell division, and that blocking cell-cycle initiation can prevent many types of neuronal cell death [85]. This cell cycle reentry by post-mitotic neurons leads to neuronal death, and inhibiting such ectopic cell-cycle activity protects neurons [85]. Even when neurons divide, their structure and functions become irregular. For these reasons, neurons cannot divide. Moreover, endogenous and environmental agents can cause DNA damage in cells. The accumulation of DNA damage can lead to the inhibition of DNA replication, genetic instability, and cytotoxicity [86]. The withdrawal of neurons from the cell cycle has disadvantages. Several mechanisms by which deficient DNA repair in neurons triggers their apoptosis have been proposed. For instance, the post-mitotic status of differentiated neurons may make them more vulnerable to DNA damage compared with cycling cells. The DNA repair mechanisms that can be used by neurons are therefore limited, and accumulative mutations are likely to occur. This excess burden of DNA damage may overwhelm endogenous repair mechanisms and, in turn, trigger the production or activation of “check-point” proteins that commit a neuron to apoptosis. Indeed, genetic deficiencies in the enzymes that detect or repair DNA damage can induce apoptosis in specific neuronal populations, or further sensitize them to genotoxic stresses. The absence of mitosis means that the lack of sufficient DNA repair may be an important factor that causes PD. The discovery of cell cycle-related events, primarily DNA repair in the pathogenesis of chronic neurodegenerative disorders opened new lines of research in neuroscience. There is still much debate and controversy, but the number of studies examining the role of the cell cycle in the formation of specific pathologies and the related cell death in the brain is increasing.

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CYCLIN-DEPENDENT KINASE 5 (CDK5) The proline-directed serine threonine kinase, Cdk5, is an unusual protein that belongs to the well-known large family of Cdks. The Cdk5 protein is a 33-kDa protein that possesses kinase activity when bound to its activators. Activated Cdk5 phosphorylates serine and threonine residues that have a proline immediately downstream. Although its cloning based on sequence homology to a cell cycle kinase, Cdk5 does not play a critical role in cell cycle progression [87]. The majority of known substrates of Cdk5 are cytoskeletal elements, signaling molecules, or regulatory proteins. Cdk5 is currently the only functional Cdk found in healthy mature neurons of the CNS, where it orchestrates multiple processes including membrane trafficking, transport, and neurotransmission. In the developing CNS, Cdk5 plays a crucial role in axonal migration by modulating actin-based motility and cell adhesion. Dysregulation of Cdk5 has been implicated in Alzheimer’s disease, amyotrophic lateral sclerosis, PD, Huntington’s disease (HD), and acute neuronal injury. Cdk5 may cause neuronal apoptosis by two distinct mechanisms: a cytoplasmic mechanism that leads to disruption of the cytoskeleton, and a nuclear mechanism that interferes with pro-survival genes. Cdk5 mediates these functions in association with its neuronal-specific co-activators. Cdk5 is normally activated by p35 or p39, and the basal activity of CDK5–p35 or CDK–p39 might be required for neuronal survival and development [88]. In 1995, Brion and Couck found that Cdk5 was present in LBs in the midbrain of PD patients [89]. Smith et al., reported an increase in Cdk5 activity in PD mouse models, whereas dominant negative Cdk5 or general kinase inhibitors prevented the loss of dopaminergic neurons [90]. Recently evidence indicated that apurinic/apyrimidinic endonuclease 1, which plays a predominant role in this DNA repair pathway, was a novel target of Cdk5 [91]. This is consistent with a growing link between Cdk5 and DNA damage [92, 93]. Cdk5 is highly conserved and ubiquitously present, with the highest levels of expression seen in post-mitotic neurons and glial cells. This made Cdk5 of special interest to neuroscientists, and so it has been studied extensively with a focus on its role in the brain during the development of the CNS. CYCLIN E Cyclin-dependent kinases control cell cycle transition. These enzymes contain two subunits: a catalytic Cdk subunit, and a regulatory cyclin subunit that activates the Cdk. Two types of cyclin-Cdks regulate the transition of mammalian cells from quiescence into S phase: the D-type cyclins, which activate Cdk4/6, and cyclin E, which activates Cdk2. The regulation of cyclin, and specifically cyclin E, was implicated in kainate excitotoxin-induced neuronal apoptosis [94]. Cyclin E-Cdk2 activity is highest in G1–S, and lowest in quiescent cells. The expression of cyclin E increases during adulthood. The protein is translocated from the nucleus to the cytoplasm of neurons. Cyclin E-Cdk2 is often dysregulated in cancer cells, and this likely contributes to the development of cancer. One downstream function of cyclin E is to phosphorylate the tumor suppressor protein retinoblastoma (Rb), and so remove its inhibition of S-phase


transcription factor E2F1 (E2 promoter binding factor 1) [95]. The mass of accumulated data studying these effects led to a model whereby cyclin E-Cdk2 is an essential and master regulator of the G1/S transition, and that cyclin E executes its cell cycle functions via Cdk2-dependent phosphorylation of its substrates. This allows the cells to pass the G1/S checkpoint, and begin DNA synthesis. In PD patients and MPTP-induced PD mouse models, the activation of the RB/E2F1 pathway can lead to the replication of nuclear DNA. However, this results in neuronal death, not cell division [96]. Mutations in parkin or other UPS members can lead to the accumulation of cyclin E, and so dopaminergic neurons re-enter the cell cycle. However, neurons are not capable of dividing, and they subsequently die. Cyclin E is an unstable protein that is degraded by the UPS. Overexpression of wild type parkin attenuates the accumulation of cyclin E and promotes survival in excitotoxin-treated cultured neurons [94]. Cancer is frequently considered to be a disease of the cell cycle. Cyclin E has been extensively studied in human cancers. Many cancers overexpress cyclin E protein or mRNA, including carcinomas (breast, lung, cervix, endometrium, and gastrointestinal tract), lymphoma, leukemia, sarcomas, and adrenocortical tumors [97]. It is therefore often considered to be a marker of cancer prognosis. Cyclin E not only promotes cell division but also, when overexpressed, drives cells to enter the cell cycle before completing chromosome replication, forming dysploidy. The dysregulation of cyclin E is therefore an important event in cancer development. Several mechanisms can dysregulate cyclin E expression in tumors. A large number of oncogenes function within the mitogenic signal transduction pathways that regulate the Rb pathway, and oncogenic mutations within these pathways may increase the abundance of cyclin E via increased E2F activity. The most common means of activating cyclin E expression in cancers may thus involve mutations in regulatory pathways, rather than within cyclin E itself. As the downstream effector of many cancer-associated pathways, cyclin E-Cdk2 is an attractive therapeutic target. REGULATION OF THE PI3K/AKT/mTOR PATHWAY The mTOR protein, a key component of the PI3K/AKT/ mTOR signaling pathway, may also have a role in neurodegenerative diseases as a regulator of autophagy. The role of mTOR signaling in protein homeostasis appears to be particularly important in the brain [98]. There are two different forms of mTOR: mTORC1 and mTORC2. mTORC1 is responsible for protein translation and autophagy, and can be inhibited by rapamycin. mTORC2 controls cell growth and cannot be inhibited by rapamycin, but it is activated by PI3K and AKT. Usually, the function of the UPS is to ubiquitinate single proteins for proteasomal hydrolysis. However, the degradation of protein aggregates with relatively large structures and organelles requires ALP. mTORC1 is an ALP inhibitor, and so when rapamycin is used to inhibit mTORC1, ALP is upregulated [99]. It has been shown in Drosophila and mouse models of HD that rapamycin can block neuronal degradation via the autophagy pathway, and induce the ALP pathway to degrade α synuclein aggregates [100]. mTOR signaling is therefore linked to several neurodegenerative diseases via its role in


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autophagy. However, studies suggest there may be a complex relationship between PD pathologies and mTORC1 activity [101]. For example in PC12 cells, rapamycin could reduce 6-OHDA toxicity, a drug that induces dopaminergic cell death [102]. Interestingly, an additional report suggests that rapamycin might be useful to alleviate side effects of levodopa [103]. The mTOR-regulating intracellular signaling components that are mutated in many cancer types include PI3K, PTEN, Akt, Ras, and Raf. Emerging evidence suggests that mTOR signaling is dysregulated by oncogenes and miRNA, and that tumor suppressors are commonly mutated in these cancer types [104, 105]. The combined use of rapamycin and an Akt inhibitor can block the growth and proliferation of tumor cells. This signaling pathway is important to both protein synthesis and cell growth [106]. Interestingly, rapamycin was originally developed as an immunosuppressive agent, suggesting that mTOR signaling plays a role in the immune system [107]. In monocytes, mTOR inhibits the production of the NF-κB -dependent pro-inflammatory cytokine interleukin-12 (IL-12), and activates signal transducer and activator of transcription 3 (STAT3)-dependent antiinflammatory IL-10 production, indicating that mTOR has an anti-inflammatory role [108]. LEUCINE-RICH-REPEAT KINASE 2 (LRRK2) LRRK2 is a large gene, 144 kb in length, containing 51 exons and encoding a multi-domain kinase composed of 2527 amino acids. LRRK2 is expressed in many organs and tissues, including the brain. In 2004, two laboratories reported that LRRK2 mutations were related to PD [109, 110]. More than 40 LRRK2 mutations, almost all missense, have been identified [111]. However, the pathogenesis of many mutations remains unclear. LRRK2 is a large protein (280 KDa) that can activate Akt, an upstream element of the mTOR pathway, decreasing the anti-apoptotic activity of AKT and promoting neuronal death [112]. Sequence analysis indicates that LRRK2 comprises several independent domains, including a leucine-rich repeat (LRR) domain, a Roc GTPase domain followed by its associated C terminal of Roc (COR) domain, a kinase domain of the tyrosine kinaselike (TKL) subfamily, and a C-terminal WD40 domain [113, 114]. LRRK2 contains multiple sets of internal repeats, each of which is predicted to adopt a distinct structure. Such repeats, which occur in 14% of all prokaryotic and eukaryotic proteins, commonly serve as platforms for protein-protein interactions [115]. LRRK2 was discovered as part of an evolutionarily conserved family of proteins marked by GTPase (Guanosine triphosphatase) domains that are usually encoded together with kinase domains [113]. The G2019S mutation of LRRK2 is the single most common autosomaldominantly inherited PD gene mutation. The LRRK2 protein is a scaffolding-type protein kinase, and G2019S is thought to lead to PD by increasing the kinase activity of LRRK2, resulting in increased phosphorylation of as yet mostly hypothetical targets. Besides G2019S, there are only a handful of proven pathogenic mutations in LRRK2, which is rather surprising given its large size. Multiple pathogenic mutations (I1371V, R14441C, R1441G, R1441H, Y1699C, Y1699G, G2019S, and I2020T) are located within the GTPase and the kinase domains, or within the COR domain

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Fig. (1). Schematic representation of the domain structure of LRRK2 and coding changes linked to disease. LRRK2 contains several conserved domains: ARM (Armadillo), ANK (Ankyrin repeat), LRR (leucine rich repeat), Roc (Ras of complex protein), COR (C-terminal of Roc), MAPKKK (mitogen activated kinase kinase kinase), and WD-40. Recurrent proven pathogenic mutations are in gray, whereas amino acid substitutions segregated by disease are shown in brown, and the corresponding exon (Ex) numbers are shown in black. The risk of cancer is higher in individuals with the G2019S mutation [125], and several LRRK2 coding changes have been identified in tumors [121]. The M2397T mutation was linked to CD in recent genome-wide association studies [122]. This figure was modified from Mata et al., [116].

(Fig. 1). This structural feature can be used as a target in the design of drugs that treat PD [116]. Many of the LRRK2 kinase inhibitors identified to date were discovered using libraries of defined kinase inhibitors [117]. As with the development of any kinase inhibitor for human use, issues related to safety will need to be carefully evaluated. This is particularly important for a chronic disease such as PD.

different diseases. Every protein may have more than one function, and may play completely different roles in different diseases. Targeted therapies with minimal side effects may therefore need to be developed based on the functions of these proteins on different signaling pathways.

More directly supporting a role of LRRK2 in cancer, chromosomal amplification of the LRRK2 locus is required for oncogenic signaling in papillary renal and thyroid carcinomas [118]. Genetic studies have implicated LRRK2 in the pathogenesis of several human diseases, including cancer and Crohn’s disease (CD) [119-121]. In 2011, Liu et al., found that LRRK2 could suppress the activity of the transcription factor NFAT (nuclear factor of activated Tcells). The overexpression of LRRK2 led to increased retention of NFAT in the cytosol. When LRRK2 was knocked out, NFAT in the cytosol was translocated to the nucleus, where it transcriptionally activated the expression of genes encoding cytokines and other key proteins involved in triggering inflammatory responses. It was first proposed that LRRK2 might play an important role in the signaling pathways that induce CD [122]. In addition, the structure of LRRK2 is similar to that of carcinogen B-RAF. A complex role for LRRK2 in multiple cellular processes is perhaps not surprising, because LRRK2 has multiple domains and is both an active kinase and a GTPase [123]. The binding of different LRRK2 domains and ligands may have different functions, preventing them from connecting closely with PD, inflammation, or cancer. The discovery of additional LRRK2 functions and a deeper understanding of its pleiotropism should provide the research community with more insight into the pathological functions of this important protein in

Advances in our understanding of genetics predisposition may well eventually provide useful biomarkers for PD and cancer. Recently introduced novel biomarkers including metallothioneins, α-Synuclein index (a ratio of nitrated αSynuclein vs. native α- Synuclein), ubiquinone and charnoly body are beneficial to improve PD diagnosis for early and effective treatment [124]. Given that many signalling molecules that crosstalk in multiple pathways, one can not exclude that these overlaps could be coincidental. Novel PD biomarkers might turn out to have an important role in cancer and vice versa. Cancer research has been extremely prolific over the decades and neurodegeneration research will benefit from breakthrough studies in cancer. Therefore, unraveling the link between PD and cancer may open a diagnostic and therapeutic window for both diseases.

PERSPECTIVE

CONCLUSION Although many epidemiologic studies have found a relationship between cancer and neurodegeneration, in particular in PD, data have been inconsistent. Variations in the design, methods, and quality of the studies assessing cancer risk in patients with PD have made it difficult to ascertain the link between the two disorders. Our understanding of the regulation of signaling pathways is more advanced in cancer studies compared with PD. These will help us develop an understanding of these two diseases


from opposing angles. The more we understand about the underlying molecular genetics and cell biology of cancer and PD, the greater the predisposition between these disorders appears. Both cancer and PD are thought to be the result of the interaction of genetic factors. The key difference is that different reactions occur based on the different cellular backgrounds of cell division and cell death. It is therefore possible that neurodegenerative research will benefit from breakthrough studies in cancer. The extensive therapeutic developments in cancer research may therefore allow the identification of prognostic markers for cancer and neurodegeneration, which could result in improved treatments for both disorders.


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NFAT

=

Nuclear factor of activated T-cells

ARM

=

Armadillo

ANK

=

Ankyrin repeat

LRR

=

Leucine rich repeat

Roc

=

Ras of complex proteins

MAPKKK

=

Mitogen activated kinase kinase kinase

COR

=

C-terminal of Roc

Ex

=

Exon

Rb

=

Retinoblastoma

E2F1

=

E2 promoter binding factor 1

SNc

=

Substantia nigra pars compacta

NF-κB

=

Nuclear factor kappa B

COX

=

Cyclooxygenase

Apaf-1

=

Apoptotic protease activating factor 1

SNPs

=

Single nucleotide polymorphisms

TLR

=

Toll-like receptors

LIST OF ABBREVIATIONS

ATP

=

Adenosine triphosphate

PD

=

Parkinson’s disease

Metallothioneins

=

MTs

LBs

=

Lewy bodies

REFERENCES

ALP

=

Autophagy lysosomal pathway

[1]

UCH-L1

=

Ubiquitin carboxy-terminal hydrolase L1

[2]

ROS

=

Reactive oxygen species

MPTP

=

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

[4]

PINK1

=

PTEN-induced putative kinase

[5]

6-ODHA

=

6-Hydroxydopamin

BBB

=

Blood–brain barrier

CD

=

Crohn’s disease

NOD2

=

nucleotide-binding oligomerization domain containing 2

[6]

IL

=

Interleukin

[7]

STAT

=

Signal transducer and activator of transcription

[8]

mTOR

=

Mammalian target of rapamycin

[9]

Cdks

=

Cyclin-dependent kinases

HD

=

Huntington’s disease

Nrf2

=

Nuclear factor erythroid 2-related factor

[11]

LRRK2

=

Leucine-rich-repeat kinase 2

[12]

GTPase

=

Guanosine triphosphatase

[13]

CONFLICT OF INTEREST The authors declare that they have no conflict of interest. ACKNOWLEDGEMENTS This work is supported by grants from Science and Technology Project of Fujian Province (No. 2012D062), Xiamen Science and Technology Bureau (No. 350Z20121153), the National Natural Science Foundation of China (No. 81272445). We thank the reviewers for their constructive suggestions.

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Revised: February 06, 2014

Accepted: March 10, 2014