Until about a decade ago, PD was thought to have little or no genetic component. However, the identification of several genes for monogenically inherited forms of the disease, although rare, and accounting for only 5-10% of the cases, has accelerated the study of molecular pathways leading to PD (13). Mutations in at least five genes have been strongly linked to autosomal dominant or recessive forms of PD, including a-synuclein, parkin, DJ-1, PTEN-induced kinase 1 (PINK1), and Leucine-rich repeat kinase 2 (LRRK2) (14-19). So far only two of these genes - a-synuclein and parkin - have been connected to UPS dysfunction.
Immunohistochemical data show that a-synuclein aggregates may be a principal component of Lewy bodies in idiopathic and genetic forms of PD (20,21). Thus if Lewy bodies are structures that segregate unwanted and potentially toxic proteins, then a-synuclein accumulates in Lewy bodies either because it is insufficiently degraded due to UPS dysfunction or mutations in a-synuclein result in misfolding or excessive production leading to proteolytic stress (22). These observations and implications to PD are discussed in detail in Chapter 12. Parkin, on the other hand, is more directly related to the UPS. Parkin functions as an E2-dependent E3 ubiquitin ligase, catalyzing the addition of ubiquitin molecules to specific substrate molecules (23-25). Mutations in parkin have been linked to an autosomal recessive form of juvenile parkinsonism (AR-JP), a distinct clinical entity from sporadic PD in spite of overlapping clinical symptoms (15,26).
An early onset form of PD, AR-JP is characterized by the selective loss of dopaminergic neurons in the substantia nigra and locus coerulus, usually with the absence of Lewy bodies (11,27,28). While sporadic PD and AR-JP have common characteristics such as dystonia, sufficient response to levodopa, lack of dementia and classic parkinsonism symptoms, the two forms can be separated based on sleep benefit for parkinsonian symptoms, female predominance, retropulsion, dystonia of the feet, hyperreflexia and pathological findings (26). Some PET studies have shown similar patterns of metabolism between sporadic and parkin-liked PD patients (29,30). However, Portman et al performed PET studies on AR-JP patients with mutations in the parkin gene and noted a marked reduction in fluorodopa uptake in the caudate nucleus and cerebellum, indicating a different nigrostriatal dopaminergic pattern from sporadic PD patients and a distinct pathophysiology for AR-JP (31). The same study concluded that the cerebral energy metabolism in AR-JP patients was comparable to sporadic cases. Another PET study corroborates the difference in dopaminergic dysfunction between sporadic and parkin-linked PD patients, suggesting a more severe synaptic disruption for parkin-linked patients (32). The heterogeneity in clinical symptoms and neuropathology of parkin-associated PD cases is further complicated by marked variation observed in the age of onset (33,34).
Linkage analysis of several Japanese families with ARJP localized the causative gene of this most common form of familial PD to a locus on chromosome 6, PARK 2 (35). Since the initial identification of large deletions in parkin associated with ARJP, a multitude of mutations have been identified, including deletions of single or multiple exons, duplications or triplications of exons, frame shift mutations, and point mutations (36). Numerous parkin mutations occur as homozygous or compound heterozygous mutations; however, in spite of extensive screening, several published cases appear to have only one of the alleles mutated (37,38). While this could reflect the insensitivity of the genetic analyses, especially with a locus as large and complex as PARK2, it is also likely that haploinsufficiency of parkin due to loss of one copy of the gene constitutes a risk factor for the onset of PD. Such heterozygous mutations may lead to disease when coupled with environmental conditions, such as oxidative or nitrosative stress, or may be a toxic gain-of-function mutant or have a dominant negative effect (39-41).
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