Monday 29 September 2003
Definition: Parkinson disease (PD) is a common neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity, and postural instability, as well as by a clinically significant response to treatment with levodopa. Parkinson disease (PD) is the second most common neurodegenerative disorder after Alzheimer disease.
Parkinson’s disease belongs to a group of conditions called movement disorders. It is characterized by muscle rigidity, tremor, a slowing of physical movement (bradykinesia) and, in extreme cases, a loss of physical movement (akinesia).
The primary symptoms are the results of decreased stimulation of the motor cortex by the basal ganglia, normally caused by the insufficient formation and action of dopamine, which is produced in the dopaminergic neurons of the brain.
Secondary symptoms may include high level cognitive dysfunction and subtle language problems. PD is both chronic and progressive.
In addition to the movement disorder, there are other, less well-characterized changes in mental function, which may include dementia, in a subset of individuals with PD.
Parkinson disease is characterized by loss of dopamine neurons in the substantia nigra and the presence of cytoplasmic inclusions known as Lewy bodies (LBs). Lewy bodies are dense aggregates that include the protein alpha-synuclein.
Parkinson disease in older persons is associated with a high incidence of dementia. At autopsy, the brains of such patients often have the neuropathological hallmarks of both Alzheimer disease and Parkinson disease.
A genetic basis for most cases of Parkinson disease has not yet been identified, but mutations in alpha-synuclein have been associated with at least one rare form of the disease, and mutations in another protein, the parkin gene, are associated with another inherited form of Parkinson disease.
Familial forms with autosomal-dominant or autosomal-recessive inheritance exist. Although these make up a limited number of cases, they have contributed to our understanding of the pathogenesis of the disease.
Mutations in the gene for alpha-synuclein (SNA) have been found in patients with familial Parkinson disease. In both sporadic and familial cases, antibodies to alpha-synuclein (SNA), a presynaptic intracellular protein, stain Lewy bodies in neurons of the substantia nigra.
Whereas the inheritance of Parkinson disease due to mutations in the alpha-synuclein (SNA) gene is autosomal dominant, a childhood form of the disease due to mutations in the gene for ubiquitin–protein ligase (parkin) is a recessive disorder.
Parkin seems to promote the degradation of certain neuronal proteins, and selective nitration of alpha-synuclein (SBCA) has been observed in Lewy bodies.
About 10% to 15% of patients with PD develop dementia, with increasing incidence with advancing age. Characteristic features of this disorder include a fluctuating course, hallucinations, and prominent frontal signs.
While many affected individuals also have pathologic evidence of Alzheimer disease (or, less frequently, other degenerative diseases associated with cognitive changes), the dementia in others is attributed to widely disseminated Lewy bodies that are less distinct but still demonstrable by immunohistochemistry for ubiquitin and α-synuclein, particularly in the cerebral cortex but also involving the amygdala and brainstem neurons.
Similar pathology, with this distribution of cortical Lewy bodies, can also be found in individuals with symptoms of dementia as their primary complaint-this is the disorder recognized as dementia with Lewy bodies (DLB). The relationship between DLB and PD with subsequent development of dementia remains to be clarified.
On pathologic examination, the typical macroscopic findings are pallor of the substantia nigra and locus ceruleus. On microscopic examination, there is loss of the pigmented, catecholaminergic neurons in these regions associated with gliosis.
Lewy bodies may be found in some of the remaining neurons. These are single or multiple, cytoplasmic, eosinophilic, round to elongated inclusions that often have a dense core surrounded by a pale halo.
Ultrastructurally, Lewy bodies are composed of fine filaments, densely packed in the core but loose at the rim. These filaments are composed of α-synuclein, as was realized after the gene for this protein was linked to familial PD; neurofilament antigens, parkin, and ubiquitin are also present in the Lewy body.
Lewy bodies may also be found in the cholinergic cells of the basal nucleus of Meynert, which is depleted of neurons (particularly in patients with abnormal mental function), as well as in other brainstem nuclei.
Immunohistochemical studies showing the presence of alpha-synuclein in cortical Lewy bodies have helped resolve the conundrum of how a patient could have insufficient numbers of plaques and neurofibrillary tangles (NFTs) for the diagnosis of Alzheimer disease but still have dementia.
The presence of these alpha-synuclein deposits, alone or in combination with changes that are characteristic of Alzheimer disease, may be the second most common form of neurodegeneration, accounting for 20 to 30 percent of cases of dementia among persons over the age of 60 years. A small number of younger persons with Parkinson’s disease also have dementia due to diffuse Lewy body disease.
The dopaminergic neurons of the substantia nigra project to the striatum, and their degeneration in Parkinson disease is associated with a reduction in the striatal dopamine content. The severity of the motor syndrome is proportional to the dopamine deficiency, which can, at least in part, be corrected by replacement therapy with l-DOPA (the immediate precursor of dopamine).
The symptoms of Parkinson’s disease result from the loss of pigmented dopamine-secreting (dopaminergic) cells in the pars compacta region of the substantia nigra (literally "black substance").
These neurons project to the striatum and their loss leads to alterations in the activity of the neural circuits within the basal ganglia that regulate movement, in essence an inhibition of the direct pathway and excitation of the indirect pathway.
The direct pathway facilitates movement and the indirect pathway inhibits movement, thus the loss of these cells leads to a hypokinetic movement disorder.
The lack of dopamine results in increased inhibition of the ventral anterior nucleus of the thalamus, which sends excitatory projections to the motor cortex, thus leading to hypokinesia.
There are four major dopamine pathways in the brain; the nigrostriatal pathway, referred to above, mediates movement and is the most conspicuously affected in early Parkinson’s disease. The other pathways are the mesocortical, the mesolimbic, and the tuberoinfundibular. Disruption of dopamine along the non-striatal pathways likely explains much of the neuropsychiatric pathology associated with Parkinson’s disease.
The mechanism by which the brain cells in Parkinson’s are lost may consist of an abnormal accumulation of the protein alpha-synuclein bound to ubiquitin in the damaged cells. The alpha-synuclein-ubiquitin complex cannot be directed to the proteosome. This protein accumulation forms proteinaceous cytoplasmic inclusions called Lewy bodies.
The latest research on pathogenesis of disease has shown that the death of dopaminergic neurons by alpha-synuclein is due to a defect in the machinery that transports proteins between two major cellular organelles—the endoplasmic reticulum (ER) and the Golgi apparatus. Certain proteins like Rab1 may reverse this defect caused by alpha-synuclein in animal models.
Iron and ROSs
Excessive accumulations of iron, which are toxic to nerve cells, are also typically observed in conjunction with the protein inclusions. Iron and other transition metals such as copper bind to neuromelanin in the affected neurons of the substantia nigra. Neuromelanin may be acting as a protective agent. The most likely mechanism is generation of reactive oxygen species. Iron also induces aggregation of synuclein by oxidative mechanisms.
Similarly, dopamine and the byproducts of dopamine production enhance alpha-synuclein aggregation. The precise mechanism whereby such aggregates of alpha-synuclein damage the cells is not known.
The aggregates may be merely a normal reaction by the cells as part of their effort to correct a different, as-yet unknown, insult. Based on this mechanistic hypothesis, a transgenic mouse model of Parkinson’s has been generated by introduction of human wild-type alpha-synuclein into the mouse genome under control of the platelet-derived-growth factor-β promoter.
An acute parkinsonian syndrome and destruction of neurons in the substantia nigra follows exposure to MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a contaminant in the illicit synthesis of psychoactive meperidine analogs.
Action by monoamine oxidase B is required for the toxicity of MPTP. The use of this toxin in experimental animals has proved highly useful in studies of therapeutic interventions for PD, including transplantation.
Epidemiologic evidence has also suggested that pesticide exposure may increase the risk of PD, while caffeine and nicotine may be protective.
SNA and alpha-synuclein-associated Parkinson disease
Studies of PD took a major step forward when the gene encoding α-synuclein, an abundant lipid-binding protein associated with synapses, was identified as the basis for an inherited autosomal-dominant form of PD, prompting the recognition that it was a major component of the Lewy body. To date, a few mutations (A53T, A30P, and E46K) have been characterized as causal for PD.
However, only rare cases of PD have mutations in α-synuclein. Families with autosomal dominant PD and genomic triplication of the region containing the gene for α-synuclein (as well as flanking genes) have been found.
This suggests that gene dosage may also be related to PD, similar to the relationship between AD and trisomy 21. A second gene, encoding the protein parkin, was linked with a juvenile autosomal recessive form of PD.
Parkin-associated Parkinson disease
Alterations including deletions and nonsense and missense mutations resulting in loss of parkin functions have been found in various families. These mutations are most prevalent in the population of young-onset PD patients.
The pathology of parkin-linked PD is similar to that of α-synuclein-linked or sporadic PD except for the absence of Lewy bodies in most but not all cases.
Parkin functions as an E3 ubiquitin ligase, with α-synuclein as one of its substrates. A third genetic locus connected with PD encodes the deubiquitination enzyme UCH-L1. The mutant protein (I93M) has decreased activity and is linked with inherited PD in a single family. It has also been suggested that this enzyme can catalyze the reverse reaction as well.
Another locus for autosomal recessive Parkinson disease has been mapped to the gene for a multifunctional protein, DJ-1, that is expressed mainly in astrocytes in the brain.
Thus, the genetics of PD have begun to explain the presence of the diagnostic inclusions and to suggest a link between altered protein degradation and the disease.
Numerous other genetic loci are linked to Parkinson disease but the relevant genes remain to be mapped; their identification will undoubtedly lead to additional insights into the disease.
familial Parkinson disease
Six familial PD-associated proteins have been identified so far:
autosomal dominant PD
- alpha-synuclein (SNCA) (MIM.163890)
- LRRK2 (leucine-rich repeat kinase 2/dardarin) (MIM.609007)
early-onset recessive PD
- PARK2 (parkin)
- DJ1 (DJ-1) (MIM.602533)
- PINK1 (PTEN-induced kinase-1) (MIM.608309)
- ATP13A2 (MIM.9610513).
A number of genetic studies have shown that 50% of the recessive forms are linked to mutations on parkin gene (PARK2), followed by PINK1 (8-15%) and DJ1 (1%).
Mutations in parkin (PARK2) cause autosomal recessive juvenile parkinsonism (AR-JP) that is distinct from sporadic PD by the general absence of LBs.
sporadic Parkinson disease
Gene mutations and susceptibility loci
|PARK1||4p21||MIM.168601||SNCA||alpha-synuclein||autosomal dominant PD|
|PARK2||6q25.2-q27||MIM.602544||PARK2||parkin||autosomal recessive juvenile-onset PD|
|PARK4||4q21||MIM.605543||SNCA||alpha-synuclein||autosomal dominant PD|
9 mutated Parkinson genes known (2008)
Mitochondrial DNA polymorphisms
Dysfunction of ubiquitin-proteasome degradation (UPD) in neurons
Protein clearance appears to be particularly important for the viability of post-mitotic neurons. UPD dysfunction is directly implicated in several neurodegenerative disorders, the most prominent of which is Parkinson disease, the second most common neurodegenerative disorder in humans.
Mutations in the gene that encodes parkin, an E3 ubiquitin-protein ligase that is expressed highly in the brain, causes autosomal recessive juvenile parkinsonism (ARJP).
As an E3 enzyme, parkin targets several proteins for degradation, and in neuroblastoma cell lines it accumulates and is concentrated in the centrosomal region on treatment with lactacystin. Additionally, co-immunoprecipitation assays have demonstrated that parkin physically binds to gamma -tubulin both in vivo in rat brains as well as in vitro in HEK293 cells.
Furthermore, except in ARJP, Parkinson disease is usually associated with Lewy bodies - intracytoplasmic inclusions containing alpha-synuclein and ubiquitin, as well as other components that await biochemical identification.
alpha-Synuclein is a substrate of the UPD system, and the Ala53Thr and Ala30Pro mutant peptides that are found in some patients, are degraded 50% slower than those of the wild type, possibly accounting for their accelerated aggregation into fibrils of the mutant protein.
Additionally, defects in UPD probably affect the clearance of alpha-synuclein in a more generalized way, as increased intracellular protein concentration promotes alpha-synuclein aggregation through a ’molecular crowding’ effect.
As such, even though alpha-synuclein is not itself a centrosomal protein, it seems that the ability of the centrosome-associated UPD system to clear misfolded proteins is central to the pathogenesis of all forms of Parkinson disease.
The emerging theme deduced from the functional properties of the Parkinson disease proteins is that defective protein degradation underlies the pathogenesis of this disease.
Therefore, given that the centrosome is linked to the UPD system both structurally and functionally, it is reasonable to propose that centrosomal dysfunction has a role in the pathogenesis of protein clearance disorders, and that the evaluation of centrosomal integrity and function in progressive phenotypes might yield new functional insights into poorly understood pathologies.
The link between centrosomal dysfunction and protein clearance disorders could be direct, for example by affecting the recruitment and/or anchoring of centrosomally located proteins such as parkin, or indirect, through the destabilization or disorganization of the pericentriolar region, where the bulk of proteasome-dependent protein degradation occurs.
As such, it might be useful to investigate not only a causative link between centrosomal dysfunction and UPD-based disorders, but also to speculate that centrosomal perturbation might be important in modulating the rate of progression and/or severity of such phenotypes.
Treatment does not, however, reverse the morphologic changes or arrest the progress of the disease; and with progression, drug therapy tends to become less effective, and symptoms become more difficult to manage.
Symptomatic response to l-DOPA therapy is one of the features, in addition to clinical signs and symptoms, that support a diagnosis of PD. While l-DOPA therapy is often extremely effective in symptomatic treatment, it does not significantly alter the intrinsically progressive nature of the disease.
Over time, l-DOPA becomes less able to help the patient through symptomatic relief and begins to lead to fluctuations in motor function on its own. As a result, there has been a search for alternative therapies that might alter the disease course.
Given the well-characterized biochemical defect in PD, therapy through neural transplantation has been attempted. Clinical improvement has been reported in patients with PD or MPTP-induced Parkinson disease treated with stereotactic implants of fetal mesencephalic tissue into the striatum.
Other current neurosurgical approaches to this disease include the strategic placement of lesions elsewhere in the extrapyramidal system to compensate for the loss of nigrostriatal function.
Strategic placement of stimulating electrodes (deep brain stimulation) can also provide relief of motor symptoms of PD.
Familial Parkinson diseases
The discovery of Mendelian inherited genes has enhanced our understanding of the pathways that mediate neurodegeneration in Parkinson disease.
One main pathway of cell toxicity arises through alpha-synuclein (SNA), protein misfolding and aggregation. These proteins are ubiquitinated and initially degraded by the ubiquitin–proteasome system (UPS), in which parkin has a crucial role.
However, there is accumulation and failure of clearance by the UPS over time, which leads to the formation of fibrillar aggregates and Lewy bodies.
alpha-Synuclein protofibrils can also be directly toxic, leading to the formation of oxidative stress that can further impair the UPS by reducing ATP levels, inhibiting the proteasome, and by oxidatively modifying parkin. This leads to accelerated accumulation of aggregates.
Phosphorylation of alpha-synuclein-containing or tau-containing aggregates might have a role in their pathogenicity and formation, but it is not known whether leucine-rich repeat kinase 2 (LRRK2) mediates this. Another main pathway is the mitochondrial pathway.
There is accumulating evidence for impaired oxidative phosphorylation and decreased complex I activity in Parkinson’s disease, which leads to reactive oxygen species (ROSs) formation and oxidative stress.
In parallel, there is loss of the mitochondrial membrane potential. This leads to opening of the mitochondrial permeability transition pore (mPTP), release of cytochrome c from the intermembrane space to the cytosol, and activation of mitochondrial-dependent apoptosis resulting in caspase activation and cell death.
There is evidence that recessive-inherited genes, such as phosphatase and tensin homologue (PTEN)-induced kinase 1 (PINK1), Parkinson’s disease (autosomal recessive, early onset) 7 (DJ1) and HtrA serine peptidase 2 (HTRA2, also known as OMI), might all have neuroprotective effects against the development of mitochondrial dysfunction, although the exact site of their action remains unknown.
Parkin has also been shown to inhibit the release of cytochrome c following ceramide-induced stress, and is itself modified by the interacting protein BCL2-associated athanogene 5 (BAG5).
Dysfunction of both pathways leads to oxidative stress, which causes further dysfunction of these pathways by feedback and feedforward mechanisms, ultimately leading to irreversible cellular damage and death.
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