Genetic and environmental factors in the cause of Parkinson's disease

Despite being the subject of intense study, the pathogenesis of Parkinson's disease still remains unclear. In recent years, however, there has been increasing evidence to support a role for genetic factors in its cause. This has come from twin and family studies, the mapping and cloning of PARK genes that are associated with the development of PD, and analysis of potential susceptibility genes. There is also evidence indicating that environmental factors may play a role in the disease process. It is likely that for most cases, there is a complex interplay between these genetic and environmental influences in the causation of Parkinson's disease. This article reviews the evidence in support of genetic and environmental factors in the cause of PD.     

Genetic contributions to Parkinson's disease

Sporadic Parkinson's disease (PD) is a common neurodegenerative disorder, characterized by the loss of midbrain dopamine neurons and Lewy body inclusions. It is thought to result from a complex interaction between multiple predisposing genes and environmental influences, although these interactions are still poorly understood. Several causative genes have been identified in different families. Mutations in two genes [α-synuclein and nuclear receptor-related 1 (Nurr1)] cause the same pathology, and a third locus on chromosome 2 also causes this pathology. Other familial PD mutations have identified genes involved in the ubiquitin–proteasome system [parkin and ubiquitin C-terminal hydroxylase L1 (UCHL1)], although such cases do not produce Lewy bodies. These studies highlight critical cellular proteins and mechanisms for dopamine neuron survival as disrupted in Parkinson's disease. Understanding the genetic variations impacting on dopamine neurons may illuminate other molecular mechanisms involved. Additional candidate genes involved in dopamine cell survival, dopamine synthesis, metabolism and function, energy supply, oxidative stress, and cellular detoxification have been indicated by transgenic animal models and/or screened in human populations with differing results. Genetic variation in genes known to produce different patterns and types of neurodegeneration that may impact on the function of dopamine neurons are also reviewed. These studies suggest that environment and genetic background are likely to have a significant influence on susceptibility to Parkinson's disease. The identification of multiple genes predisposing to Parkinson's disease will assist in determining the cellular pathway/s leading to the neurodegeneration observed in this disease.     

Genetics of Parkinson's disease

PURPOSE OF REVIEW: Parkinson's disease is the second most common neurodegenerative disorder and affects 2% of the population over the age of 60 years. Due to the increasing proportion of elderly individuals in developed countries, Parkinson's disease and related neurodegenerative disorders represent a growing burden on the health care system. In the majority of cases, the cause of the disease is still unknown, and its elucidation remains one of the major challenges of the neurosciences. Recent findings in rare genetic forms of Parkinson's disease have allowed the development of novel animal models, providing a basis for a better understanding of the molecular pathogenesis of the disease, setting the stage for the development of novel treatment strategies. RECENT FINDINGS: Several novel genes for monogenic forms of Parkinson's disease, such as PINK-1 for an autosomal-recessive early-onset variant, and LRRK2 for a relatively common late-onset autosomal-dominant form have recently been discovered, and several novel animal models have been generated on the basis of genes that had been found earlier. SUMMARY: The combination of genetic, pathologic and molecular findings provide increasing evidence that the pathways identified through the cloning of different disease genes are interacting on different levels and share several major pathogenic mechanisms.     

Genome-scale methylation analysis of Parkinson's disease patients' brains reveals DNA hypomethylation and increased mRNA expression of cytochrome P450 2E1

Multiple lines of evidence suggest a link between environmental toxins and Parkinson's disease (PD). Although numerous studies reported associations of genetic variants in de-toxifying enzymes, i.e. cytochrome genes, with PD. Epigenetic modifications of genes and subsequent altered expression may confer a yet unappreciated level of susceptibility. We present a genome-wide methylation analysis of PD with quantitative DNA methylation levels of 27.500 CpG sites representing 14.495 genes. We found decreased methylation of the cytochrome P450 2E1 gene and increased expression of CYP2E1 messenger RNA in PD patients' brains, suggesting that epigenetic variants of this cytochrome contribute to PD susceptibility.     

Genetic causes of Parkinson's disease: extending the pathway

The functional characterization of identified disease genes in monogenic forms of Parkinson's disease (PD) allows first insights into molecular pathways leading to neurodegeneration and dysfunction of the nigrostriatal system. There is increasing evidence that disturbance of the ubiquitin proteasome pathway is one important feature of this process underscoring the relevance of protein misfolding and accumulation in the neurodegenerative process of PD. Other genes are involved in mitochondrial homeostasis and still others link newly identified signalling pathways to the established paradigm of oxidative stress in PD. Additional factors are posttranslational modifications of key proteins such as phosphorylation. Also, molecular data support the role of altered iron metabolism in PD. Here we describe known genes and novel genetic susceptibility factors and define their role in neurodegeneration.     

Impulsivity and Parkinson's disease: more than just disinhibition

In the last few years it has become clear that impulsivity is a complex behaviour composed of different domains and dependent on different neural networks. The proposed pathogenetic mechanisms for the emergence of impulsivity disorders in Parkinson's Disease (PD) can be broadly separated into three potentially interacting processes: the contribution of premorbid susceptibility to impulsivity, the contribution of the disease itself to the behaviour and the potential contribution of therapeutic agents. Growing evidence suggests that dopamine and the subthalamic nucleus are playing a certain role in the pathophysiology of different aspects of impulsivity. In this review, we summarise the main concepts defining various components of impulsivity both in healthy subjects and patients affected by PD.     

Genetic susceptibility and the occurrence of Parkinson's disease

A genetic cause of Parkinson's disease is supported by the occurrence of familial disease with identified gene defects, a increased prevalence in homozygous twin pairs and the existence of family clusters. However, familial Parkinson's disease is an interesting but rare form of the disorder and twin studies indicate that heredity may be one of the factors which contribute to the onset of Parkinson's disease. Similarly, the increased risk of Parkinson's disease in relatives of an affected individual suggests a genetic contribution, but alone this is unlikely to explain the onset of nigral cell degeneration. To account for apparently sporadic cases of Parkinson's disease, an involvement of susceptibility genes has been proposed to explain the inherited component of the disorder. However, to date most studies have failed to identify specific genotypic associations with Parkinson's disease. For example, despite extensive investigation no clear association is known between cytochrome P450 isoenzymes, specifically CYP2D6, and Parkinson's disease. Indeed, a genetic component may not be required to explain sporadic Parkinson's disease since environmental factors are associated with an increased prevalence of the illness and the actions of specific toxins are known to induce nigral cell degeneration. In addition, endogenous toxin formation in the brain leads to a variety of processes which may initiate nigral cell death in Parkinson's disease. However, in all probability both genetic and environmental or toxic components contribute to the occurrence of Parkinson's disease and it is likely that an interaction between these factors results in nigral cell degeneration.     

Role of mendelian genes in "sporadic" Parkinson's disease

The molecular mechanisms underlying neuronal degeneration leading to Parkinson's disease (PD) remain unknown. However, it is becoming increasingly clear that genetic factors contribute to its complex pathogenesis. In the past 15 years, the genetic basis of rare forms of PD with Mendelian inheritance, which represent no more than 10% of the cases, has been investigated. More than 18 loci, identified through linkage analysis or genome wide association studies (GWAS), and eight validated genes have been identified so far [parkin, PTEN-induced kinase 1 (PINK1), DJ-1, ATP13A2, SNCA, Leucine-rich repeat kinase 2 (LRRK2), as well as two recently identified possibly causative genes, vacuolar protein sorting 35 (VPS35) and eukaryotic translation initiation factor 4G1 (EIF4G1)]. Many studies have shed light on their implication not only in familial but also in sporadic forms of PD. Recent GWAS have provided convincing evidence that polymorphic variants in these genes also confer an increased risk for late-onset sporadic PD. In addition, heterozygous mutations in GBA have now been well-validated as susceptibility factors for PD. The role of the most relevant associated genes and risk factors in sporadic PD are discussed in this review.     

The pathogenesis of neurodegenerative disease: neurotoxic mechanisms of action and genetics

The role of environmental and occupational exposures to neurotoxicants in the pathogenesis of neurodegenerative disease has not been fully elucidated. Recent published research on whether genetic polymorphisms contribute to individual susceptibility to develop neurodegenerative diseases such as Parkinson's disease have been equivocal at best. This review relates putative mechanisms of neurotoxicant-induced cell damage to polymorphisms in the genes that encode for the enzymes involved in the metabolism of neurotoxicants. The effects that genetically induced alterations in enzyme functioning have on neurotoxicant metabolism and how this relates to the risk of neurotoxic effects among exposed individuals are reviewed. A pragmatic approach to future research in the area of neurodegenerative disease is developed on the basis of the interrelationship between known routes of neurotoxicant metabolism and human genetics.     

Manganese and extrapyramidal disorders (a critical review and tribute to Dr. George C. Cotzias)

In this essay we first review the important contributions of Dr. George Cotzias to the understanding of chronic manganese intoxication and of manganese metabolism in man and animals. We also indicate the original contribution of Dr. John Donaldson to the mechanism of the neurotoxicity of manganese. In a second phase, the author challenges the tenet that Parkinson's disease is a form of chronic manganese intoxication and that manganism is an experimental model for Parkinson's disease. Clinical, pathological, experimental and biochemical evidence are brought to bear on this argument. Thirdly the author proposes that the necessary event to the so-called "depigmentation" of the substantia nigra and subsequent bradykinetic "low dopamine" syndrome is an early enhanced turnover of dopamine. Manganese intoxication is only one of the factors which may serve as a trigger to this event. Many others are also listed. In opposition to current views, who look for causal factors in Parkinson's disease along the pathways for melanogenesis, the author thus proposes a novel hypothesis which envisions a variety of transient "trigger factors" acting at the dopamine synapse to increase dopamine turnover. In turn, this increased synthesis of dopamine favours the production of large quantities of free radicals within the cell bodies in the substantia nigra, eventually overflowing the scavenging capacity of neuromelanin and their protective barrier, and causing cell death. The resulting decreased pool of dopamine-producing cells leads to a self-perpetuating situation of ever increasing demand on the remaining cells, and "progression" of the disease. Finally the author stresses the fact that genetic factors may play a role in an individual's susceptibility to such triggers. Again defective manganese transport, metabolism or binding are only some of the mechanisms possibly underlying such genetic predisposition to induced basal ganglia disorders. Further studies relating to manganese in these disorders and particularly in Parkinson's disease should focus not on the "intoxication" part of the overload and its striatopallidal consequences, but on the intimate mechanism of destabilization of the homeostatic regulator in neuromelanin bearing cells, even after the exposure period.     

How genetics research in Parkinson's disease is enhancing understanding of the common idiopathic forms of the disease

PURPOSE OF REVIEW: Rapid progress in genetics has meant that there are now five genes identified for 'Parkinson's disease'. The detailed phenotypes vary, but generally the dominant genes cause a Lewy body disease spectrum whereas recessive genes cause a milder parkinsonism with variable inclusion body pathology. The subject of this review is to highlight these discoveries and to discuss their relationships to idiopathic Parkinson's disease. RECENT FINDINGS: In January 2004, mutations in PINK1, coding for a mitochondrial kinase, were found to be causal for recessive parkinsonism. Subsequently, several studies have found additional mutations associated with early onset parkinsonism. Some cases have been described with a phenotype much closer to idiopathic Parkinson's disease, but it does not appear that PINK1 is a major risk factor for the sporadic disease. Later in the same year, the LRRK2 gene was shown to cause a dominant disease with a broader phenotype. The protein product was named dardarin and contains GTPase and kinase domains. Lewy bodies have been reported in LRRK2 cases, potentially linking this gene with sporadic Parkinson's disease. One mutation, G2019S, is found in a significant percentage of cases, including sporadic Parkinson's disease. SUMMARY: Mutations in these two genes, along with previously described Mendelian variants, are beginning to yield important information about loss of specific neuronal groups or to protein inclusion pathology. How this relates to sporadic Parkinson's disease, however, is not yet fully defined. There are clear phenotypic overlaps with genetic and sporadic Parkinson's disease, especially for the dominant genes, suggesting that common facets of pathogenesis may exist.     

Molecular chaperones as rational drug targets for Parkinson's disease therapeutics

Parkinson's disease is a neurodegenerative movement disorder that is caused, in part, by the loss of dopaminergic neurons within the substantia nigra pars compacta of the basal ganglia. The presence of intracellular protein aggregates, known as Lewy bodies and Lewy neurites, within the surviving nigral neurons is the defining neuropathological feature of the disease. Accordingly, the identification of specific genes mutated in families with Parkinson's disease and of genetic susceptibility variants for idiopathic Parkinson's disease has implicated abnormalities in proteostasis, or the handling and elimination of misfolded proteins, in the pathogenesis of this neurodegenerative disorder. Protein folding and the refolding of misfolded proteins are regulated by a network of interactive molecules, known as the chaperone system, which is composed of molecular chaperones and co-chaperones. The chaperone system is intimately associated with the ubiquitin-proteasome system and the autophagy-lysosomal pathway which are responsible for elimination of misfolded proteins and protein quality control. In addition to their role in proteostasis, some chaperone molecules are involved in the regulation of cell death pathways. Here we review the role of the molecular chaperones Hsp70 and Hsp90, and the cochaperones Hsp40, BAG family members such as BAG5, CHIP and Hip in modulating neuronal death with a focus on dopaminergic neurodegeneration in Parkinson's disease. We also review current progress in preclinical studies aimed at targetting the chaperone system to prevent neurodegeneration. Finally, we discuss potential future chaperone-based therapeutics for the symptomatic treatment and possible disease modification of Parkinson's disease.     

Polymorphisms of dopamine receptor and transporter genes and Parkinson's disease

Summary Disturbances of the dopamine system are involved in the pathogenesis of idiopathic Parkinson's disease (PD). Although genetic factors may play a role in the etiology of PD, there is little direct evidence implicating a specific gene. We conducted a study to test the hypothesis that allelic variations of the dopamine receptors (D2, D3, D4) and the dopamine transporter (DAT) contribute to the susceptibility to PD. Association analyses of 70 Japanese PD patients and the same number of age-matched controls did not reveal any association between alleles of the D2, D3 or D4 receptor genes or the DAT gene and PD. Thus, our results suggest that factor(s) other than allelic variations of these key proteins in the dopamine system contribute to the susceptibility to PD.     

Genetic and environmental factors of Parkinson's disease

We present a review on the genetic and environmental factors implicated in the aetiology of Parkinson's disease. The environmental hypothesis was strongly suggested about 20 years ago after the report of a parkinsonian syndrome in young adults that were intoxicated by a neurotoxin called MPTP which selectively destroys nigrostriatal dopaminergic neurons. Several chemical products used in herbicides and pesticides are similar structurally to MPTP, including paraquat, diquat and rotenone. Epidemiological studies have revealed an increased risk for Parkinson's disease with the use of pesticides and herbicides or the consumption of well water in rural areas of industrialised countries. However, it has not been possible to identify any causative environmental chemical agent in the aetiology of Parkinson's disease despite intensive research. Comparatively, the genetic hypothesis of Parkinson's disease has gained considerable interest during the last decade. Epidemiological studies reveal a family history in 10-25 p. cent Parkinson's disease patients. Several large kindreds with autosomal dominant Parkinson's disease associated with mutations of alpha-synuclein gene (PARK 1) were recently described. alpha-synuclein is a constituant of Lewy bodies, the hallmark of idiopathic Parkinson's disease. However, alpha-synuclein gene mutations are rare as opposed to parkin gene mutations (PARK 2), which are frequently found in autosomal recessive and sporadic young onset Parkinson's disease patients. Other genes or locus are implicated in autosomal dominant familial cases (PARK 3, 4 and 5). Nevertheless, a pure genetic origin can be demonstrated only in a minority of Parkinson's disease patients. Investigation of the possible interaction between genes and environment and of several candidate genes gave contradictory results, notably concerning the association between allelic variants of CYP2D6 gene and the occurrence of Parkinson's disease. In conclusion, the aetiology of Parkinson's disease remains unknown. There are probably several types or causes of Parkinson's disease. In most cases, this heterogeneity could be attributed both to genetic and environmental factors.     

Lack of Association of the PICALM rs3851179 Polymorphism With Parkinson's Disease in the Greek Population

ABSTRACT Parkinson's disease (PD) is a complex, heterogeneous neurodegenerative disorder, affecting approximately 1% of the population over 60?years of age. The molecular and cellular mechanisms underlying PD pathogenesis are still unknown. Clathrin-mediated endocytosis (CME) is a procedure closely related to the intracellular trafficking of multiple molecules in the cell, including proteins, lipids, and neurotransmitters. Recently, variations in the gene encoding the phosphatidylinositol binding clathrin assembly protein (PICALM) has been associated with Alzheimer's disease (AD), suggesting a possible role of CME in the pathogenesis of neurodegenerative diseases. In this study, we examined for the first time the potential role of the PICALM rs3851179 polymorphism in PD. We studied the PICALM rs3851179 polymorphism in 191 Greek patients with sporadic PD and 118 control subjects, using a PCR-RFLP method. Our results do not provide evidence that the PICALM rs3851179 polymorphism increase susceptibility of PD, in the Greek population.     

Determination of the GSTM1 gene deletion frequency in Parkinson's disease by allele specific PCR

We have examined the occurrence of GSTM1 null, one of the glutathione S-transferase mu genes, in a control and a Parkinson's disease group. By using the polymerase chain reaction (PCR) we found 67% of non-expressors compared with 51% in a control group (chi(1)(2) = 5.535; p < 0.025). These results suggest that a deletion of the GSTM1 gene may be associated with a susceptibility to Parkinson's disease.     

Parkinson's disease and pathological oscillatory activity: Is the beta band the bad guy? — New lessons learned from low-frequency deep brain stimulation

A number of studies have identified pathological neural oscillations in Parkinson's disease and it is widely agreed that these excessive synchronizations are linked to the motor symptoms of Parkinson's disease (PD). However, it is still under debate if there exists a single frequency having a critical negative influence on PD symptoms and what this frequency might be. To provide experimental evidence for a causal link between beta oscillations and bradykinesia, C. C. Chen and coauthors stimulated patients with Parkinson's disease with different low frequencies while the patients were performing a grip force task [C. C. Chen, W. Y. Lin, H.L. Chan, Y.T. Hsu, P.H. Tu, S.T. Lee, S.M. Chiou, C.H. Tsai, C.S. Lu, P. Brown: Stimulation of the subthalamic region at 20 Hz slows the development of grip force in Parkinson's disease, Exp. Neurology, 2011]. In their study the authors could demonstrate a 15% slowing in the grip force task during 20 Hz stimulation, but not during stimulation with other frequencies. The finding of 20 Hz being the driving pathological frequency contrasts with previous studies using e.g. finger tapping, where 5 and 10 Hz had the largest influence. Thus, this study provides evidence that there is no single pathological oscillation frequency that is responsible for all Parkinsonian symptoms. Instead, the results indicate that the modulation of very specific frequencies leads to changes in specific performance parameters evaluated in particular tasks. In this respect, this study also provides more physiological evidence on the involvement of the STN in dynamic force production. Taken together, the study adds a further piece to the puzzle of understanding the pathophysiology of Parkinson's disease and the mechanisms of deep brain stimulation.     

A scientific rationale for protective therapy in Parkinson's disease

Summary The desire to introduce neuroprotective therapy for Parkinson's disease has begun to focus attention on pathogenetic mechanisms responsible for cell death. Considerable theory and some evidence have now accumulated to suggest that factors related to oxidative stress, mitochondrial bioenergetic defects, excitatory neurotoxicity, calcium cytotoxicity, and trophic factor deficiencies acting either singularly or in combination may contribute to the development of cell death in Parkinson's disease. A better understanding of the specific pathogenetic mechanism involved in cell degeneration might provide a scientific basis for testing a putative neuroprotective therapy. This chapter reviews the theory and evidence in support of these different mechanisms and possible strategies that might provide neuroprotection and interfere with the natural progression of Parkinson's disease.     

Molecular pathways in sporadic PD

Over the last decade, several autosomal dominant and recessive genes causative of Parkinson's disease (PD) have been identified. The functional studies on their protein products and the pathogenetic effect related to their mutations have greatly contributed to understand the many cellular pathways leading to neurodegeneration, that include oxidative stress damage, mitochondrial dysfunction, misfolded protein stress and impairment of cellular clearance systems, namely the ubiquitin-proteasome system (UPS) and the autophagy pathway. Although mendelian genes are responsible only for a small subset of PD patients, it is expected that the same pathogenetic mechanisms could play a relevant role also in the more frequent sporadic PD, that is currently recognized as a multifactorial disorder. In this model, different genetic and environmental factors, either playing a protective or a susceptibility role, variably interact to reach a threshold of disease over which PD will become clinically manifest. As an example, mutations or multiplication of the alpha-synuclein gene cause autosomal dominant PD, while common genetic variants at the same locus have been consistently associated to the risk of developing PD by genome-wide association studies. These findings are opening novel interesting perspectives to identify critical molecular pathways leading to neurodegeneration.