The Genetics of Parkinson Disease: Implications for Neurological Care

Christine Klein; Michael G. Schlossmacher


Nat Clin Pract Neurol. 2006;2(3):136 

In This Article

Monogenic Variants of Parkinson Disease

Disease phenotypes associated with the PARK1-9 chromosomal loci follow a typical MENDELIAN pattern of inheritance ( Table 1 ), whereas PARK10 and PARK11 represent susceptibility loci with as yet undefined modes of transmission. In Mendelian genetics, the relationship between genotype and phenotype is not always readily apparent; for example, as illustrated in Figure 2, single heterozygous mutations in 'recessive' genes can act as susceptibility factors, thereby appearing pseudodominant. Similarly, dominant forms can present in a pseudorecessive fashion, and heritability should be suspected even in early-onset patients with a negative family history (Figure 2). An apparent lack of heritability might be explained by small family size, nonpaternity, adoption, variable clinical characteristics, reduced PENETRANCE, or de-novo mutations. Conversely, because sporadic PD is a relatively common condition, familial PD might be phenocopied by an occurrence of sporadic PD in a pedigree with a well-established genetic background of the disease.[9,12]

Figure 2.

Examples of pedigrees, to illustrate mode of inheritance in monogenic Parkinson disease (PD). Mendelian modes of inheritance for known monogenic forms of PD are represented schematically. Definitely affected family members are shaded in black, probably affected members in gray. A dot in the pedigree symbol represents an unaffected mutation carrier. The two bars next to the pedigree symbols represent the two alleles of the gene of interest. A mutation is indicated by the star symbol. PD associated with α-synuclein (SNCA) and leucine-rich repeat kinase 2 (LRRK2) is transmitted in an autosomal dominant fashion (A). In cases of reduced penetrance, the mode of inheritance may appear pseudorecessive (B) or even sporadic. In several families with recessively inherited PD associated with mutations in Parkin, phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1), or DJ1 genes (C), a number of heterozygous mutation carriers have been reported to be probably or definitely affected. The inheritance might, therefore, appear pseudodominant (D), mimicking the scenario outlined in (A).

When evaluating a patient for a possible monogenic form of PD, more information than simply the family history needs to be considered, including the age at onset, distribution of symptoms, disease course, therapeutic response, geographic history, consanguinity, and careful accounting for and, if possible, neurological examination of first-degree and second-degree relatives. For example, when compared with patients without mutations in the Parkin gene (also known as PARK2), Parkin-mutation carriers tend to have an earlier age of onset, a slower disease progression, a more symmetrical onset, dystonia as a more frequently encountered initial sign (in addition to hyperreflexia), and the tendency to respond to low doses of levodopa.[7,15] To the informed neurologist, these features might represent important clues to heritable PD ( Table 3 ). Clear-cut predictions cannot, however, be made in the individual patient solely on clinical grounds, as considerable overlap with idiopathic PD has been described clinically. Furthermore, the natural evolution of each phenotype in mutation carriers (identified in cross-sectional studies) remains to be delineated.

Recessively Inherited Parkinson Disease: Probable Loss-of-Function Mechanism

Parkin-Associated Parkinson Disease. Mutations in the Parkin gene[16] represent the commonest known factor responsible for early-onset PD (10-20%; Figure 1) and have been shown in numerous families of different ethnic backgrounds.[17] The large number and wide spectrum of Parkin mutations include alterations in each of its 12 exons. Importantly, about 50% of carriers of this mutation have exon rearrangements that, in the heterozygous state, are not detectable by conventional screening methods, such as sequencing alone.[18]

The Parkin gene is expressed in presynaptic and postsynaptic processes and cell bodies of many neurons.[19] The Parkin protein is presumed to function as an E3-type, E2-enzyme-dependent ubiquitin ligase that is involved in the proteasomal degradation of target proteins.[20] The available E3 activity is disrupted by mutations associated with PD, thereby supporting the predominant loss-of-function theory.[21] A growing number of putative ('to-be-ubiquitinated') Parkin substrates have been identified, and accumulation of these proteins is proposed to cause the selective death of neurons in the substantia nigra and locus coeruleus in humans.[22] Although these putative substrates await convincing validation in animal models with disrupted parkin alleles, Drosophila melanogaster and mice that are deficient of wild-type parkin revealed unequivocal, systemic signs of increased oxidative stress and mitochondrial dysfunction.[23,24,25] It is currently unclear if these biochemical changes can be attributed solely to the E3-ligase activity of the protein (or lack thereof) or to an—as yet unknown—function of the parkin homologs. An equally contentious issue is whether Parkin expression is essential for formation of neuronal inclusions in vivo, and if so, whether its ubiquitin ligase activity is responsible for the formation of Lewy bodies, as suggested (but not proven) by the abundance of ubiquitinated proteins in Lewy inclusions isolated from human brain.[19] Disappointingly, the pathognomonic loss of human substantia nigra neurons has not been replicated in any of the published mouse models of three monogenic PD variants (α-synuclein [SNCA]-transgenic mice, parkin-null mice and dj1-null mice). By contrast, the fruit fly (D. melanogaster) appears more susceptible to PD-type pathology.[26]

Recently, two biochemical modifications of Parkin (S-nitrosylation and dopamine quinone-adduct formation) were identified in cellular studies and human brain specimens.[27] These data indicated that reduced E3-ligase activity of the wild-type Parkin protein (rather than an autosomal recessive mutation in the two Parkin alleles) could also occur as a result of the principal pathogenetic process that is responsible for the development of sporadic PD.

PINK1-Associated Parkinson Disease.. Two homozygous mutations in the phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1; also known as PARK6) gene were initially detected in three consanguineous families with early-onset PD.[28] The frequency of PINK1 mutations is in the range of 1-9%,[29,30,31,32,33,34] with considerable variation across different ethnic groups. Most of the currently described mutations are localized near or within the functional SERINE/THREONINE PROTEIN KINASE domain of PINK1[33] and are expected to result in loss of function in vivo. Wild-type PINK1 is thought to function as a protein kinase with possible activity inside the mitochondria, thereby strengthening the hypothesized link between mitochondrial dysfunction and oxidative stress in PD pathogenesis.[22,35,36]

DJ1-Associated Parkinson Disease. The DJ1 gene (also known as PARK7)[37] is associated with early-onset PD in about 1-2% of cases.[38] It is presumed that the described mutations have a loss-of-function effect. The DJ1 gene is ubiquitously expressed and was initially described in association with oncogenesis and infertility in male rats. The protein has also been shown to confer CHAPERONE-like activity, however, and to function as an intracellular sensor of oxidative stress.[39] Of probable relevance, the pH-change-induced ELECTROPHORETIC SHIFT of human DJ1, and the sulfoxidation of Cys106-mediated translocation of the protein to the mitochondria in response to oxidative stress, imply a role for the protein in the cellular response to oxidative stress, as recently supported by a mouse model of Dj1 inactivation.[39,40] In addition, Dj1 was found to be involved in in-vivo signaling of the dopamine D2-receptor subtype in mice.[41]

The neurological, brain-imaging and pharmacodynamic patterns of PINK1-linked and DJ1-linked PD are widely interchangeable with those of Parkin-associated cases, but the precise roles of these three proteins in promoting the survival of neurons that are affected in PD remain unknown. Moreover, the findings of brain autopsies in patients with mutations in PINK1 or DJ1 have not yet been published. Nevertheless, it is possible to speculate that Parkin, DJ1 and PINK1 are critically involved in the sensing of a dysregulated redox equilibrium or mitochondrial dysfunction (or both) and, accordingly, in the activation of an integrated cellular-response program.[23,24,25,36,37,39,40] The primary purpose of this integrated response could be the maintenance of both redox homeostasis and mitochondrial integrity, thereby facilitating the sustained survival of at-risk neurons during ≤10 decades of human aging (Figure 3).

Figure 3.

Parkinson disease (PD) as a complex disorder. A model of known pathogenetic events in PD shows a principal imbalance between factors that promote PD (e.g. increased total metal content in the substantia nigra, altered steady-state levels of alpha-synuclein proteins, including its phosphorylation, rise in dopamine-metabolism-related stress, and exposure to neurotoxins) and factors that prevent PD (e.g. cigarette smoking, caffeine consumption, expression of wild-type Parkin, DJ1, and PINK1, and normal levels of glutathione). LRRK2, leucine-rich repeat kinase 2; mt, mutant; phosphor., phosphorylation of α-synuclein at residue Ser129; PINK1, phosphatase and tensin homolog (PTEN)-induced putative kinase 1; Ser18, serine at residue 18; Tyr, tyrosine at residue 18; UCHL1, ubiquitin carboxyl-terminal esterase L1; wt, wild-type.

Dominantly Inherited Parkinson Disease: Probable Gain-of-Function Mechanism

SNCA-Associated Parkinson Disease. The SNCA gene (also known as PARK1) was the first gene to be unequivocally associated with familial PD.[42] In addition to three point mutations, several PD families were recently identified as carrying single-allele triplication (initially assigned a separate locus, PARK4,[43] but later corrected) or duplication events in the wild-type SNCA gene.[44] Interestingly, the severity of the phenotype appears to depend on gene dosage, and patients with SNCA duplications bear a closer clinical resemblance to idiopathic PD patients than do patients with triplications. Nevertheless, both MIS-SENSE and multiplication events are extremely rare.[45]

The SNCA protein is abundantly expressed as a 140-residue cytosolic and lipid-binding phosphoprotein in the vertebrate nervous system, where it is believed to participate in the maturation of presynaptic vesicles and to function as a negative co-regulator of neurotransmitter release.[46] Intriguingly, fibril-forming, phosphorylated species of SNCA were found to be abundant in insoluble inclusions (Lewy bodies and Lewy neurites), prompting neuropathologists to group several SNCA-inclusion-rich diseases together. These 'synucleinopathy disorders' (a term coined by Trojanowski and Lee[47]) primarily encompass sporadic PD, SNCA-linked PD, dementia with Lewy bodies, and multiple-system atrophy,[48] but can also be variably found in other neurodegenerative syndromes.[13] Nevertheless, the elucidation of the relevant neurotoxic SNCA species in vivo and the critical steps required for the gain-of-function mechanism remain areas of intense research activity.

LRRK2-Associated Parkinson Disease. Recently, the leucine-rich repeat kinase 2 (LRRK2; also known as PARK8) gene has been identified by two independent groups.[49,50]LRRK2 is a large gene that consists of 51 exons, and which encodes a 2,527-amino-acid protein named LRRK2 or Dardarin, with various conserved domains recognized in its primary amino-acid sequence. To date, more than 40 variants have been reported in this gene. Owing to reduced penetrance and phenocopies, the role of some of these variants currently remains elusive, although at least 16 variants appear to be pathogenic. These variants, which include eight recurrent mutations, occur in only 10 of the 51 exons of LRRK2,[49,50,51,52,53,54,55,56,57] indicating that it might be justifiable to limit genetic testing to these exons. For the most frequent and well-investigated mutation (c.6055G→A), a common FOUNDER has been suggested.[56,57] This single mutation has been reported in ~1.5% of tested index cases (~100 out of 6,500 cases) and in only 2 out of ~12,000 healthy individuals. More recently, LRRK2 mutations have been detected in ~1% of early-onset PD cases (Hedrich K et al., unpublished data). Post-mortem analysis of four patients from a family with one of the recurrent mutations surprisingly revealed a broad spectrum of abnormalities: Lewy bodies restricted to brainstem nuclei in the first patient; diffuse Lewy bodies in the second patient; NEUROFIBRILLARY TANGLES, but no Lewy bodies, in the third patient; and isolated cell loss without neurofibrillary tangles or Lewy bodies in the fourth patient.[11]

Numerous working models have been proposed to integrate the complexities of environmental, biochemical, genetic and neuropathological evidence, but a more simplistic model of PD pathogenesis depicts a progressive imbalance between the forces that promote the degeneration of at-risk neurons by increasing mitochondrial dysfunction, oxidative stress, iron accumulation and lipid dysregulation during the aging process, and those that encompass individual or integrated cellular-defense mechanisms (Figure 3).