Clinical manifestations. Parkinson disease is a chronic, progressive neurodegenerative disorder characterized by a combination of rest tremor, rigidity, bradykinesia, and postural instability. Other diseases with features of parkinsonism are termed “parkinsonian” or “Parkinson plus” syndromes (see below). Features suggestive of idiopathic Parkinson disease are asymmetric onset, marked levodopa response, lack of early postural instability, and cognitive decline. Pathologically, Parkinson disease is defined by a degeneration of dopaminergic neurons in the substantia nigra pars compacta and the presence of cytoplasmic inclusions termed “Lewy bodies.” In addition, neurodegeneration is found in a wide variety of brain structures, including the locus ceruleus, raphe nuclei, nucleus basalis of Meynert, hypothalamus, cerebral cortex, cranial nerve motor nuclei, and central and peripheral autonomic nervous system. Progression of Parkinson disease has been tied to a specific sequence of neuronal degeneration, but this notion has proven to be controversial (Braak et al 2003). Although idiopathic Parkinson disease usually occurs in the 60s, typical onset is usually earlier, before 40 years of age, in known genetic causes of Parkinson disease. Further, in genetic Parkinson disease, other clinical features such as myoclonus, dystonia, cerebellar findings, or dementia may be seen, which begs the question of whether Parkinson disease is truly one entity. In line with this notion and confounding this picture, Lewy body inclusions are not always present in genetic Parkinson disease (PARK2), whereas they are otherwise considered an important pathological feature of Parkinson disease.
Etiology. Although the specific etiology of Parkinson disease is not known, consensus has been emerging that idiopathic Parkinson disease is likely a combination of environmental and genetic factors. In genetic Parkinson disease, which accounts for a very small minority of cases, the isolated genes have provided great insight into cellular pathways that are involved in the disease, regulating cell survival and cell death of the affected neurons. Key molecular targets, among others, include the ubiquitin-proteasome system, the mitochondria, alpha-synuclein, the lysosomal-autophagy system, oxidative stress regulators, poly ADP-ribose polymerase (PARP) and caspase activators, calcium channels, heat shock proteins, dopamine signaling, and histone deacetylation. For extensive reviews, please refer to the article by Gupta and colleagues (Gupta et al 2008). Notably, even in those genetic cases, environmental factors are often presumed to be important as penetrance is not always complete.
Pathogenesis and pathophysiology. The ubiquitin-proteasome system is the primary system responsible for degradation and clearance of misfolded proteins in a eukaryotic cell. Misfolded proteins are labeled with ubiquitin by a series of enzymatic reactions that target them for degradation by the 26/20 proteasome, which yields constituent peptides and amino acids. Ubiquitin is subsequently recycled. Genetic mutations resulting in the failure of the ubiquitin-proteasome system instigate accumulation of abnormal proteins, which organize in inclusion bodies such as the Lewy body (McNaught and Olanow 2003). The role of the ubiquitin-proteasome system in the development of Parkinson disease has been supported by the observation that local administration of proteosome inhibitors (nigral injection) can produce animal models that are somewhat pathologically reminiscent of idiopathic Parkinson disease (McNaught et al 2004b; Zhu et al 2007); clinically, these models do show some shortcomings, and systemic administration of proteasome inhibitors has not resulted in a reproducible model of Parkinson disease (Bove et al 2006). On the other hand, parkin, a critical gene identified in one of the genetic Parkinson disease cases, has been found to be one of the enzymes (E3 ligase) involved in the ubiquitin-dependent protein degradation. Curiously enough, patients with this mutation did not show any Lewy body formation in pathology, implying that steps beyond parkin activity are necessary for large aggregate formation. These few observations alone show the complexity of protein degradation in the context of Parkinson disease pathogenesis, indicating a need for future research to clarify the nature of the contribution of the ubiquitin system to the pathology of Parkinson disease.
Alpha-synuclein mutations have been implicated in promoting the pathogenesis of Parkinson disease in many ways. The most well-studied are toxic gain-of-function mutations that promote abnormal protein folding and aggregation. Mutant alpha-synuclein may not only circumvent ubiquitin-dependent degradation, but also lysosomal-autophagy degradation via the lysosomal-associated membrane protein 2 (LAMP2A) receptor (Cuervo 2004; Martinez-Vicente 2007), and this may occur by altering affinity to ligands and receptors (Bertoncini et al 2005). It is speculated that oligomeric rather than polymeric alpha-synuclein is the true toxic compound, and strategies utilizing RNA interference, antibodies, or even the oligomerization blocker, rifampicin, have been or are being tested for possible therapeutic benefit (Masliah et al 2005; Fountaine and Wade-Martins 2007; Ono et al 2007). In support of this notion, inhibition of SIRT2, a regulator of histone deacetylation, can ameliorate alpha-synuclein toxicity while promoting large aggregate formation. Aside from implying oligomeric alpha-synuclein in neurotoxicity, it also links histone deacetylation to protein degradation, which is consistent with the observation that histone deacetylation is required for autophagy.
Alpha-synuclein mutations may also damage neuronal membranes by catalyzing the production of hydrogen peroxide (Turnbull et al 2001). Furthermore, alpha-synuclein mutations cause impaired dopamine storage (Lotharius and Brundin 2002). Other identified mechanisms include impairment of the mutant alpha-synuclein with dopamine transmission and synaptic integrity (Chandra 2005), membrane excitability, and vesicular trafficking (Cooper 2006); see the review by Gupta and colleagues (Gupta et al 2008). Clearly, given the complexity of alpha-synuclein interaction, what is needed in the future is to elucidate the main targets of alpha-synuclein to delineate the pathway that critically contributes to the development of Parkinson disease.
The importance of mitochondrial dysfunction in the development of Parkinson disease has been supported by several crucial discoveries over the recent years. Much of this evidence is derived from the observation that some of the recessively inherited genetic Parkinson disease cases encode for genes involved in mitochondrial function, particularly PTEN-induced kinase-1 (PINK1) and DJ-1. Animal models of loss-of-function mutants of PINK1 have shown mitochondrial dysfunction, which, intriguingly, can be rescued by parkin, but not vice versa. This finding is critical in that it suggests a linear pathway, with PINK1 being upstream of parkin, and elucidates a nodal point in signaling that could be very effectively targeted for drug development. A proposed mechanism as to how PINK1 regulates mitochondrial function is by phosphorylating key substrates that are involved in various mitochondrial activities, such as TRAP and HtrA2, proteins both involved in mitochondrial stress signaling (Alremni et al 2007; Plun-Favreau et al 2007; Pridgeon et al 2007). Intriguingly, HtrA2 was found to be associated with the Parkinson disease locus 13 (Strauss et al 2005), indicating yet another Parkinson disease gene in a potentially linear signaling pathway, but this association has recently been challenged (Kruger et al 2011). Along these lines, DJ-1 has been proposed to act as a regulator of oxidative stress by scavenging mitochondrial peroxide (Andres-Mateos et al 2007) and stabilizing the antioxidant master regulator, Nrf2 (Clements et al 2006).
Aside from mitochondrial physiology, DJ-1 and PINK1 were found to have additional roles in cell signaling. DJ-1 affects dopamine signaling by regulating its transcription (Goldberg et al 2005; Zhong et al 2006), which may indicate a synergistic mechanism with alpha-synuclein (see above). It was also shown to regulate apoptosis in dopaminergic neurons by inhibiting the proapoptotic protein Daxx and pyrimidine tract-binding protein-associated splicing factor, which possesses transcriptional silencing activity involved in neuronal apoptosis (Xu et al 2005). Using small interference RNA to target PINK1, wild-type PINK1 participates in the protection of dopaminergic neurons (Deng et al 2005), likely through inhibition of apoptosis (Petit et al 2005).
The gene for leucine-rich repeat kinase 2 (LRRK2), perhaps most significant for sporadic Parkinson disease (see Epidemiology section, below), encodes a kinase that has both autophosphorylation activity and kinase activity and locates primarily to the cytoplasm and outer mitochondrial membrane. Notably, LRRK2 toxicity is linked to increased kinase activity, which is consistent with autosomal dominant inheritance, gain-of-function paradigm, association of increased kinase activity with disease segregation, and association of alleviation of toxicity with reduced kinase activity (Smith et al 2006; West et al 2007). Although relevant LRRK2 substrates and their relationship to distinct molecular pathways are not yet fully understood, GTP binding to its Ras-like binding domains appears to regulate both LRRK2 kinase activity and its phosphorylation by other kinases (Ito et al 2007). Furthermore, LRRK2 interacts with parkin (Smith et al 2005), which may indicate that LRRK2 substrates are targeted to the ubiquitin-proteasome degradation system (Lichtenberg et al 2011). More recently, mitogen-activated protein kinase (MAPK), Wnt signaling, translational processing, microRNA control, and Fas-ligand pathway have all been shown to be altered by changes in LRRK2 kinase activity, but contextual in vivo data to explain the neurotoxicity of LRRK2 mechanistically are limited (Cookson 2010; Lin et al 2011). Novel notions about kinase-independent contributions of LRRK2 have been suggested, including LRRK2 being instrumental in signaling complex assembly given its large protein size and multitude of protein interaction modules (Berwick and Harvey 2011).
Nurr1 is a transcription factor thought to maintain substantia nigra dopaminergic neuronal health. It is expressed early in the development and remains expressed throughout life, and deficits in Nurr1 result in abnormal nigrostriatal dopaminergic function in patients with Parkinson disease and progressive supranuclear palsy (Chu et al 2006). As the precise role of Nurr1 in Parkinson disease is being explored, it appears to regulate the dopamine transporter, tyrosine hydroxylase, and the vesicular monoamine transporter-2 (VMAT-2), indicating a role in synaptic transmission and integrity (Jankovic et al 2005). This notion is supported by the recent analysis of Nurr1-deficient mice (Zhang et al 2012).
Despite the molecular evidence derived from genes causing Parkinson disease, the question remains as to how that knowledge translates into a better understanding of sporadic Parkinson disease. It is assumed that the signaling pathways involved in genetic Parkinson disease are aberrant in sporadic Parkinson disease as well. These alterations may be a complex consequence of polymorphisms or genetic variants of the Parkinson disease genes or genes found to be associated with Parkinson disease (see below) and environmental influences yet to be identified. Recent encouraging evidence also points to a selective vulnerability of neurons in the substantia nigra that is based on channel-mediated calcium influx. It is postulated that a postnatal switch from sodium to calcium channels might make the substantia nigra neurons more susceptible to apoptosis, as compared to other dopaminergic neurons that either don’t have those channels or have additional protective mechanisms (Chan et al 2007). In this respect, calcium antagonist treatment has been postulated to be protective (Surmeier 2007), and active research is ongoing to assess any therapeutic benefit with such medication.
Finally, it is worthwhile to mention a fairly recent advancement in research. The breakthrough of creating any kind of cell type from induced pluripotent stem cells has given rise to enormous promise for understanding neurologic diseases and designing new therapeutic concepts (Jaenisch and Young 2008). In this context, human dopaminergic neurons have been created from Parkinson disease patients by turning fibroblasts from a skin biopsy into pluripotent stem cells and subsequently differentiating them into dopaminergic neurons (Soldner et al 2009). Of note, human fibroblasts have even recently been differentiated directly into dopaminergic cells, without the need to go through the pluripotent stem cell dedifferentiation step (Caiazzo et al 2011). Interestingly, the transcription factor Nurr1 implicated in genetic Parkinson disease and described above has been used as one of the 3 factors required to accomplish this, indicating its central role in developing and maintaining the dopaminergic cell fate. Irrespective of which protocol yields the most suitable dopaminergic neurons, it is now possible to study Parkinson disease in a human cell culture system, enabling the study of the molecular pathogenesis in the human context and the designing of cell-based assays for drug screening to any desired molecular target (Rubin 2008). Without question, this new technology provides great hope for the near future.
Epidemiology. Parkinson disease is the second most common disease encountered in a movement disorder clinic, behind essential tremor. It has a prevalence of 347/100,000. Although genetic causes account for a minority of patients with late-onset Parkinson disease, they are more prevalent in patients with young-onset Parkinson disease (onset younger than 40 years of age); see the article by Di Fonzo and colleagues (Di Fonzo et al 2009). The most common genetic defect in young-onset Parkinson disease is PARK2, with mutations occurring in one third to one half of patients under the age of 40 years (Lucking 2000). On the other hand, with respect to late-onset Parkinson disease, genetic studies indicate that mutations in LRRK2 may be surprisingly prevalent, accounting for up to 7% of genetic and 1.5% to 3% of sporadic cases (Gilks et al 2005; Nichols et al 2005). The prevalence of LRRK2 mutation is particularly high in certain populations: in Ashkenazi Jews with Parkinson disease, the LRRK2 mutation reaches 29.7% in familial cases and 13.3% in sporadic cases (Ozelius et al 2006), whereas in North African Arabs with Parkinson disease, the frequency of the mutation reaches 37% in familial cases and 41% in sporadic cases (Lesage et al 2006). These genetic studies implicate the LRRK2 mutations as a major genetic cause of Parkinson disease. Penetrance is age-dependent for the G2019S mutation, the most common mutation, with cumulative incidence of the disease of 15% at 60 years of age, 21% at 70 years, and 32% at 80 years (Goldwurm et al 2007). For a review on LRRK2, see the article by Gupta and colleagues (Gupta et al 2008).
In addition to clear genetic causes of Parkinson disease that are inherited by Mendelian principles, genetic susceptibility genes were recently identified and studied in genome-wide association (GWA) studies (Yates 2011; Zimprich 2011). Of particular interest are genetic variants in the gene mutated in Gaucher disease, glucocerebrosidase (GBA). Certain GBA variants are linked to Parkinson disease and potentially contribute to earlier disease onset (Nichols et al 2009). However, the degree of this association has not been fully explored as such variants are also present (in much lower frequency) in the general population, raising the question of whether those control subjects are in their preclinical Parkinson disease stage or whether they are resistant to developing Parkinson disease based on their genetic makeup and lack of suspected environmental triggers. Of note, several GWA studies on Parkinson disease in Caucasian and Asian populations have also found strong association signals around SNCA, the gene that encodes alpha-synuclein, MAPT, the gene that codes for tau, and PARK16 (Satake et al 2009; Simon-Sanchez et al 2009; Elbaz et al 2011; International Parkinson Disease Genomics Consortium 2011; Klein and Ziegler 2011). The GWA study conducted by the International Parkinson Disease Genomics Consortium identified 11 loci that surpassed the threshold for genome-wide significance: 6 loci were old, namely MAPT, SNCA, HLA-DRB5, BST1, GAK, and LRRK2, and 5 loci were new, ACMSD, STK39, MCCC1/LAMP3, SYT11, and CCDC62/HIP1R (“combined population-attributable risk” of 60.3%) (International Parkinson Disease Genomics Consortium 2011). In the GWA study conducted by Elbaz and colleagues, a total of 5302 cases and 4161 controls were assessed, and all 4 SNCA single nucleotide polymorphisms and the MAPT H1-haplotype-defining single nucleotide polymorphism (rs1052553) displayed a highly significant marginal association with Parkinson disease (Elbaz et al 2011). MAPT H1 has been found in separate GWA studies to be associated with Parkinson disease and to strongly influence the risk of Parkinson disease dementia (Mata et al 2011; Seto-Salvia et al 2011). In the largest case-control GWA study of Parkinson disease involving 3426 cases and 29,624 controls, 2 novel genome-wide significant associations were found with Parkinson disease, rs6812193 near SCARB2 and rs11868035 near SREBF1/RAI1, in addition to the previously identified associations that include LRRK2, GBA, SNCA, MAPT, GAK, and the HLA region. The association with MAPT raises new questions as to pathogenesis of Parkinson disease and the relationship to tauopathies, such as progressive supranuclear palsy, corticobasal degeneration, and Alzheimer disease. However, caution is warranted with the degree of association in these GWA studies, as they may overestimate the risk related to specific loci due to the inherent bias of the case-control design. Also, the results are not accurate enough to be clinically useful as a basis for Parkinson disease risk assessment (Klein and Ziegler 2011). Nonetheless, with the help of such studies the heritability of Parkinson disease has been estimated to be at least 0.27, suggesting that genetic factors account for at least one fourth of the total variation in liability to Parkinson disease.
Lastly, Parkinson disease has been thought to be associated with a higher frequency of tumors, particularly lipomas, and, clinically more important, melanomas. Recently, interest has focused on finding molecular commonalities in pathways that could affect both Parkinson disease and the generation of such tumors, including the role of autophagy and dopamine synthesis in apoptosis and oncogenesis, respectively (Pan et al 2011).
Diagnostic workup. The diagnosis of Parkinson disease is based on clinical examination and history. Examination should include a general neurologic examination, including pyramidal and cerebellar pathways, ocular motility examination, and orthostatic blood pressure reading, as these may be helpful in distinguishing between Parkinson disease and Parkinson plus syndromes. MRI or CT of the brain are typically normal in idiopathic Parkinson disease. Although PET and SPECT scans are used in a few institutions for research purposes, they are not routinely performed in a diagnostic capacity. PET scanning with L-dopa, however, can be quite helpful in assisting in the diagnosis of early or even preclinical Parkinson disease, demonstrating decreased signal of L-dopa in a particular pattern at the synaptic cleft in the striatum (mostly putaman).
Management. Refer to the separate Parkinson disease clinical summary for disease management. For detailed reviews of the genetics of Parkinson disease, see articles by Vila and Przedborski (Vila and Przedborski 2004) and Huang and colleagues (Huang et al 2004).