Advances in the genetic studies in Parkinson's disease

Genetic contribution to the etiology of Parkinson's disease (PD) is generally accepted based on the studies of the familial form of the disease and progress in molecular genetic techniques. To date, specific mutations have been identified in five separate genes and several chromosomal loci have been linked for different forms of familial parkinsonism. The discovery of alpha-synuclein, ubiquitin C-terminal hydrolase, parkin, tau and DJ-1 mutations and analysis of the biochemical and molecular properties of these gene products point to the critical role of protein aggregation in dopaminergic neurons of the substantia nigra as the basic mechanism leading to neurodegeneration also in sporadic form of the disease. Lewy bodies, even in sporadic PD, contain some of these gene products, particularly abundant fibrillar alpha-synuclein. Studies of familial parkinsonism provide evidence that PD is genetically heterogeneous. Evidence elucidated from genetic studies in PD suggests that parkinsonism is a complex disorder in which multiple gene-gene and gene-environment interactions play a critical role in the development of the disease and phenotypic variability. Further genetic studies in familial parkinsonism will enhance our knowledge of pathogenesis of PD and allow the development of neuroprotective treatments of PD and perhaps other forms of parkinsonism as well.     

Autosomal-dominantly inherited forms of Parkinson's disease

Today, a genetic contribution to the etiology of Parkinson's disease (PD) is generally accepted, based on the demonstration of a familial aggregation of the disease, as demonstrated by several case-control and twin-studies. However, most cases of PD appear to be sporadic, and in the majority of those with a positive family history, no clear mendelian mode of inheritance can be established. Therefore, a polygenic mode of inheritance or a multifactorial etiology is likely in these cases. On the other hand, a number of families have been identified, in whom parkinsonism is inherited as an apparently monogenic mendelian trait with high penetrance. In several of these families, the disease genes have been mapped and mutations have been identified in some of them. The first gene locus has been mapped to the long arm of chromosome 4 in a small number of families with autosomal-dominant inheritance and typical Lewy-body pathology (PARK 1), and mutations have been identified in the gene for alpha-synuclein in these kindreds. Two other loci in families with dominant inheritance have been mapped, to chromosome 2p13 (PARK 3) and to chromosome 4p, respectively. A gene causing autosomal recessive parkinsonism of juvenile onset has been mapped to chromosome 6 (PARK 2), and the causative gene has been identified and named parkin. Each of these genetically defined familial disorders share clinical characteristics that fulfill the criteria accepted for idiopathic Parkinson's disease but, as in sporadic PD, also show a variability of clinical expressions, both within and between families. At present, there is no direct evidence that any of these genes for familial Parkinsonian syndromes have a direct role in the etiology of the common sporadic form of PD. However, the elucidation of the molecular sequence of events leading to nigral degeneration in these inherited cases is likely to shed light also on the molecular pathogenesis of the common sporadic form of this disorder.     

Olfactory dysfunction in Parkinson's disease

The olfactory system is one of the nonmotor systems severely affected in Parkinson's disease (PD). Olfactory dysfunction occurs early in the disease process, is independent of disease stage, duration, and treatment. However, olfactory dysfunction appears to be dependent on disease subtype. Olfaction is mildly impaired or preserved in most of the parkinsonism-plus syndromes (PPS). This provides a means of differential diagnosis between typical PD and PPS. Olfactory function is impaired also in familial forms of parkinsonism in which the genetic defect is known. In familial parkinsonism, olfactory function is impaired in both typical PD and PPS phenotypes. Olfactory dysfunction does not appear to be a manifestation of dopamine deficiency. Olfactory dysfunction is also associated with other neurodegenerative diseases such as Alzheimer's disease (AD), Huntington's disease (HD), as well as with normal aging. The neuropathological changes observed in the olfactory system in PD and other neurodegenerative diseases appear to be disease-specific, raising the possibility that olfactory dysfunction may be the result of a central rather than a peripheral process. The cellular and molecular mechanisms underlying olfactory dysfunction in PD and other neurodegenerative diseases remain unknown.     

Clinical and pathologic features of families with LRRK2-associated Parkinson's disease

The etiology for Parkinson's disease (PD) remains unknown. Genetic causes have been identified with several distinct mutations. Recently, 9 mutations involving a novel gene, leucine-rich repeat kinase 2 (LRRK2), have been identified as the cause of autosomal dominant PD in kindreds, with some of them previously linked to the PARK8 locus on chromosome 12. LRRK2 mutations are relatively common genetic causes of familial and sporadic PD. In addition, these mutations have been identified in diverse populations. The clinical and pathologic features of LRRK2-associated PD are indistinguishable from idiopathic PD; however, considerable clinical and pathologic variability exists even among kindreds. This short review highlights the clinical and pathologic features in LRRK2-associated parkinsonism.     

Is there a genetic susceptibility to idiopathic parkinsonism?

The search for the etiology of idiopathic parkinsonism (IP) has been difficult and largely unsuccessful. Recently, there has been renewed interest in the possibility that there are genetic susceptibility loci for IP. Part of this interest has been spurred by recent advances in molecular genetics. This review analyzes the available genetic epidemiology and family study data (clinical and molecular genetic) as they relate to IP and parkinsonism plus syndromes (PPS). Analysis of data from families with several members having IP or PPS suggests that this approach may not identify susceptibility genes for IP. When the genes responsible for the syndromes affecting multiplex families are identified, they are likely to provide insight into the pathogenesis of IP and may be the basis for developing a more useful nosology. The molecular genetic study of PPS and the mapping of the wld locus may herald rapid advances in understanding these syndromes.     

Importance of familial Parkinson's disease and parkinsonism to the understanding of nigral degeneration in sporadic Parkinson's disease

We review here familial Parkinson's disease (PD) from clinical as well as molecular genetic aspects. The contribution of genetic factors to the pathogenesis of PD is supported by the demonstration of the high concordance in twins, increased risk among relatives of PD patients in case control and family studies, and the existence of familial PD and parkinsonism based on single gene defects. Recently, several genes have been mapped and/or identified in patients with familial PD. Alpha-synuclein is involved in a rare dominant form of familial PD with dopa responsive parkinsonian features and Lewy body positive pathology. In contrast, parkin is responsible for autosomal recessive form of early-onset PD with Lewy body-negative pathology. This form is identified world-wide among patients with young-onset PD. Furthermore, ubiquitin carboxy terminal hydrolase L1 gene is responsible for an autosomal dominant form of typical PD, although only a single family has so far been identified with a mutation of this gene, and tau has been identified as a causative gene for frontotemporal dementia and parkinsonism. In addition, five other chromosome loci have been identified to be linked to familial PD or dystonia-parkinsonism. The presence of different loci or different causative genes indicates that PD is not a single entity but a highly heterogeneous. Identification and elucidation of the causative genes should enhance our understanding of the pathogenesis of sporadic PD.     

Genetics of parkinsonism.

Parkinson's disease (PD) was noted to have a familial component as early as 1880 (Leroux, 1880). More recently, the discovery of several genetic factors influencing parkinsonism has emphasized the importance of heredity in PD. The clinical spectrum of familial parkinsonism is wide; it includes not only PD, but also dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP), essential tremor, and other disorders. In the general population, it is likely that PD results from combined genetic and environmental factors, most of which are not yet known. The discovery of causal mutations in the gene for alpha-synuclein, parkin, and of genetic linkages to chromosomes 2p4, 4p5, and three loci on 1q6-8 have revolutionized PD research. This review focuses on recent progress in the Mendelian genetics of PD and those diseases in which parkinsonism is a prominent feature, and considers how these discoveries modify our beliefs regarding the etiology and pathogenesis of these disorders.     

Phenotypic commonalities in familial and sporadic Parkinson disease

BACKGROUND: Parkinson disease (PD) is a clinically well-documented neurodegenerative disorder. However, the mechanism or mechanisms of its phenotypic expressions are still unknown. OBJECTIVE: To compare phenotypes by examining demographic and clinical features of patients with familial PD and sporadic PD and with or without a family history of PD. DESIGN: Historical review of patients with sporadic PD in clinic-based samples and individual patients diagnosed with PD from families whose linkage to mutations or loci has been identified. SETTING: Movement disorder clinic in a referral center. PATIENTS: A total of 1277 patients with sporadic PD and 40 patients with familial PD. MAIN OUTCOME MEASURES: Clinical features, including distribution by sex, initial motor symptom, location of initial motor symptom, and frequency of asymmetric motor symptoms. RESULTS: Despite different etiologic backgrounds, both familial and sporadic PD exhibited several interesting commonalities, including a higher incidence in men, tremor as the initial motor symptom (predominantly involving the upper extremities), and asymmetric parkinsonism during disease course. CONCLUSIONS: The increased incidence of parkinsonism in men with familial PD suggests that the sex disparity is more likely the result of a protective effect against development of PD in women than of an increased risk in men that is associated with environmental factors. Phenotypic similarity among familial and sporadic PD indicates that a similar topographic distribution of the nigrostriatal lesion exists in patients with either form of PD regardless of apparent genetic influence.     

Spinocerebellar ataxia type 2 with parkinsonism in ethnic Chinese

OBJECTIVE: To describe the clinical and molecular genetic analysis of a large family of northern Chinese descent with a mutation at the SCA2 locus causing carbidopa-levodopa-responsive parkinsonism. BACKGROUND: Most causes of parkinsonism remain unknown. However, molecular genetic analysis of families with parkinsonism has recently identified five distinct loci and pathogenic mutations in four of those. Additionally, some of the spinocerebellar ataxia syndromes (SCA), particularly Machado-Joseph syndrome (SCA3), are known to cause parkinsonism. Spinocerebellar ataxia type 2 (SCA2) has not previously been described as causing a typical dopamine-responsive asymmetric PD phenotype. METHODS: A large family was evaluated clinically and molecularly for apparent autosomal dominant parkinsonism. RESULTS: The phenotype includes presentation consistent with typical dopamine-responsive parkinsonism. Other presentations in this family include a parkinsonism/ataxia phenotype, which is classic for SCA2 and parkinsonism, resembling progressive supranuclear palsy. CONCLUSIONS: Patients presenting with a family history of parkinsonism, including familial progressive supranuclear palsy and PD, should be tested for the spinocerebellar ataxia type 2 expansion.     

Familial Lewy body diseases

Lewy body disease includes clinically and pathologically defined disorders in which Lewy bodies occur in the nervous system. In recent years, the molecular features of these disorders have been emerging. Several genetic loci have been identified in association with familial Lewy body disease; however, the genetic risks underlying most cases of familial Lewy body disease remain to be discovered. The fact that Lewy bodies stain strongly with antibodies to asynuclein and that mutations in the alpha-synuclein gene lead to syndromes in which parkinsonism and dementia occur gives us important clues regarding the biologic processes leading to disease. Pursuit of additional mendelian causes of familial Lewy body disease and study of the factors contributing to the complex phenotypes associated with Lewy body disorders will elucidate underlying disease pathways and, thus, possible targets for therapeutic intervention.     

Clinical genetics of Parkinson's disease and related disorders

Our knowledge regarding the genetics of Parkinson's disease (PD) and parkinsonism has evolved dramatically during the past decade, with the discovery of numerous loci and genes. The LRRK2 gene has emerged as the most commonly involved in both familial and sporadic PD. Several variants in LRRK2 and SNCA have been associated with an increased risk of sporadic PD. PRKN, PINK1 and DJ1 mutations cause early-onset recessively inherited PD. Autosomal dominant dementia and parkinsonism is caused by mutations in the MAPT gene, and in the most recently discovered PGRN gene.     

LRRK2 in Parkinson's disease: protein domains and functional insights

Parkinson's disease (PD) is the most common motor neurodegenerative disease. Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) have been linked recently with autosomal-dominant parkinsonism that is clinically indistinguishable from typical, idiopathic, late-onset PD. Thus, the protein LRRK2 has emerged as a promising therapeutic target for treatment of PD. LRRK2 is extraordinarily large and complex, with multiple enzymatic and protein-interaction domains, each of which is targeted by pathogenic mutations in familial PD. This review places the PD-associated mutations of LRRK2 in a structural and functional framework, with the ultimate aim of deciphering the molecular basis of LRRK2-associated pathogenesis. This, in turn, should advance our understanding and treatment of familial and idiopathic PD.     

Genetics of Parkinson's disease

Over the past few years, several genes for monogenically inherited forms of Parkinson's disease (PD) have been mapped and/or cloned. In a small number of families with autosomal dominant inheritance and typical Lewy-body pathology, mutations have been identified in the gene for α-synuclein. Aggregation of this protein in Lewy-bodies may be a crucial step in the molecular pathogenesis of familial and sporadic PD. On the other hand, mutations in the parkin gene cause autosomal recessive parkinsonism of early onset. In this form of PD, nigral degeneration is not accompanied by Lewy-body formation. Parkin-mutations appear to be a common cause of PD in patients with very early onset. Parkin has been implicated in the cellular protein degradation pathways, as it has been shown that it functions as a ubiquitin ligase. The potential importance of this pathway is also highlighted by the finding of a mutation in the gene for ubiquitin C-terminal hydrolase L1 in another small family with PD. Other loci have been mapped to chromosome 2p and 4p, respectively, in a small number of families with dominantly inherited PD, but those genes have not yet been identified. These findings prove that there are several genetically distinct forms of PD that can be caused by mutations in single genes. On the other hand, there is at present no direct evidence that any of these genes have a direct role in the aetiology of the common sporadic form of PD. Epidemiological, case control, and twin studies, although supporting a genetic contribution to the development of PD, all suggest a clear familial clustering only in a minority of cases. It is therefore widely believed that a combination of interacting genetic and environmental causes may be responsible in this majority of PD-cases. However, studies of gene-environment interactions have not yet produced any convincing results. Nevertheless, the elucidation of the molecular sequence of events leading to nigral degeneration in clearly inherited cases is likely to shed light also on the molecular pathogenesis of the common sporadic form of this disorder. Received: 27 March 2001, Accepted: 5 April 2001     

Gene therapy for Parkinson's disease

Advances in molecular biology and virology in recent years have enabled the technology of gene transfer to proceed forward. Parkinson's disease (PD) is a particularly appropriate target for gene therapy since the brain pathology is fully characterized and relatively well circumscribed largely within the nigrostriatal dopaminergic neurons. In addition, the search for genetic mutations responsible for familial forms of PD has accelerated in recent years with several genes or loci already identified. Mutations in the parkin gene are linked to the autosomal recessive form known as autosomal recessive juvenile parkinsonism, park2. Therefore, parkin gene therapy can be effective in PD caused by parkin gene mutations, which are inherited as an autosomal recessive trait. Intriguingly, several studies, including our reports, have suggested the possibility that parkin gene therapy could treat a subset of patients with PD who have mutations in the alpha-synuclein gene. Furthermore, if indeed parkin overexpression broadly corrects anatomical degeneration in the substantia nigra and striatum, this might be a potential therapy for alpha-synucleinopathy.     

Autosomal recessive juvenile parkinsonism: A key to understanding nigral degeneration in sporadic Parkinson's disease

The contribution of genetic factors to the pathogenesis of Parkinson's disease (PD) is supported by the demonstration of the high concordance in twins studies using positron emission tomography (PET), the increased risk among relatives of PD patients in case–control and family studies, and the existence of familial PD and parkinsonism by single gene defect. Recently several genes have been mapped and/or identified. α‐Synuclein is involved in a rare dominant form of familial PD with dopa‐responsive parkinsonism features and Lewy body‐positive pathology. In contrast, parkin is responsible for the autosomal recessive form (AR‐JP) of early onset PD with Lewy body‐negative pathology. The clinical features of this form include early onset (in the 20s), levodopa‐responsive parkinsonism, diurnal fluctuation, and slow progression of the disease. Parkin consists of 12 exons and the estimated size is over 1.5 Mb. To date, variable mutations such as deletions or point mutations resulting in missense and nonsense changes have been reported in AR‐JP patients. In addition, the localization of parkin indicates that parkin may be involved in the axonal transport system. More recently we have found that parkin interacts with the ubiquitin‐conjugating enzyme E2 and is functionally linked to the Ub‐proteasome pathway as a ubiquitin ligase, E3. These findings fit the characteristics of a lack of Lewy bodies (these are cytoplasmic inclusions that are considered to be a pathological hallmark). Our findings should enhance the exploration of the mechanisms of neuronal death in PD as well as other neurodegenerative disorders of which variable inclusion bodies are observed.     

Synuclein, dopamine and oxidative stress: co-conspirators in Parkinson's disease?

The etiology of Parkinson's disease (PD) is presently unknown. The unifying hallmark of disease is depletion of dopamine and loss of nigrostriatal dopamine neurons. Familial and sporadic forms of the disease are described. The familial mutations occur within alpha-synuclein and molecules involved in protein degradation and mitochondrial function. Sporadic PD is thought to involve the interplay of genetic and environmental factors. Despite disparate initiating triggers, a convergent pathobiologic model for this common neurodegenerative disease has been proposed. Likely players have emerged that may form the basis for this common pathway model of disease. In this review, we examine the role of three most implicated PD pathogenic conspirators: synuclein, dopamine and oxidative stress.     

Oxidative stress and genetics in the pathogenesis of Parkinson's disease

Parkinson's Disease (PD) is the second most common chronic neurodegenerative disease characterized by the progressive loss of dopamine neurons, leading to rigidity, slowness of movement, rest tremor, gait disturbances, and imbalance. Although there is effective symptomatic treatment for PD, there is no proven preventative or regenerative therapy. The etiology of this disorder remains unknown. Recent genetic studies have identified mutations in alpha-synuclein as a rare cause of autosomal dominant familial PD and mutations in parkin as a cause of autosomal recessive familial PD. The more common sporadic form of PD is thought to be due to oxidative stress and derangements in mitochondrial complex I activity. Understanding the mechanism by which familial linked mutations and oxidative stress cause PD has tremendous potential for unraveling the mechanisms of dopamine cell death in PD. In this article, we review recent advances in the understanding of the role of genetics and oxidative stress in the pathogenesis of PD.     

Familial parkinsonism: Our experience and review

There is substantial interest in the possible role of genetic factors in the etiology of idiopathic parkinsonism (IP) and parkinsonism-plus syndromes (PPS). We have longitudinally investigated eight large kindreds from North America. Five families demonstrated IP features, two families represented PPS and in one family, neither a diagnosis of IP or PPS could be established. A literature review supported our findings; only half of the published kindreds presented with a clinical picture typical of IP. Genetic DNA analysis is in progress on our kindreds and on many families in our literature review. The results may clarify the etiology and classification of IP and PPS.     

Parkin gene and its function; a key to understand nigral degeneration]

In most patients with Parkinson's disease (PD), the contribution of genetic factors as well as environmental factors remains to be elucidated. But, it has become clear that genetic factors contribute to the pathogenesis of PD after identification of the distinct genetic loci for certain forms of familial PD. We recently identified the novel large gene "parkin" responsible for an autosomal recessive form of familial parkinsonism (AR-JP). AR-JP is a distinct clinical and genetic entity characterized by early onset before 40 years. Pathological changes in this form revealed selective degeneration of the pigmented neurons in the substantia nigra and locus coeruleus, but no Lewy bodies were found. The parkin gene encodes a novel protein of 465 amino acids. The parkin gene is mildly homologous to ubiquitin at the N-terminal portion and has a RING-finger motif at the C-terminal portion. We found variable different homozygous deletions involving exons 3, 4, 5, 3 to 4, 3 to 5, and 3 to 7 in AR-JP families from Japan. In addition to exonic deletions, we identified a one base deletion in exon 5 in two AR-JP families. Although we have identified several mutations in parkin gene, characterization of its gene product, "Parkin protein" has not yet been established. To elucidate the molecular mechanism underlying the disease, we have analyzed the subcellular localization of the Parkin protein by immunohistochemical and immunoblotting studies on patients with AR-JP and sporadic PD using two antibodies. Parkin protein was absent in all regions of the brains of AR-JP patients. Parkin protein was not decreased in brains of sporadic PD patients. Parkin protein was located in both Golgi complex and cytosol. Taken together, the Parkin protein may play a role in vesicular transport system in association with the Golgi complex.     

Gene–environment interactions in Parkinson's disease and other forms of parkinsonism

It is widely recognized that both genetic and environmental factors are likely to contribute to the pathogenesis of human parkinsonism. While the identification of specific predisposing conditions and mechanisms of disease development remain elusive, new discoveries coupled with technological advances over the past decade have provided important clues. From the genetic standpoint, both causal and susceptibility genes have been identified, with some of these genes pointing to gene–environment interactions. The application of emerging genomic technologies, such as Genome Wide Association Studies (GWAS), will certainly further our knowledge of Parkinson's disease (PD)-related genes. From the environmental perspective, toxicant-induced models of parkinsonian syndromes, such as those associated with exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or β-N-methylamino-l-alanine (BMAA), have revealed potential mechanisms of increased susceptibility based on genetic predisposition. Finally, new hypotheses on mechanisms of disease development include the possibility that exposure to neurotoxicants triggers an upregulation and pathological modifications of α-synuclein. Mutations in the α-synuclein gene are responsible for rare familial cases of parkinsonism, and polymorphisms in the promoter region of this gene confer a higher susceptibility to idiopathic PD. Thus, toxicant–α-synuclein interactions could have deleterious consequences and play a role in pathogenetic processes in human parkinsonism.