Despite apparent differences in causality, the motor phenotypes of both familial and idiopathic PD are very similar. This would suggest common mechanisms of action. Genetic studies are ongoing and have shown some genetic predilections to developing idiopathic PD. However, given its location on neuronal synapses and other evidence, it appears to be involved in neurotransmission, plasticity, and perhaps synaptic vesicle release Ulusoy, Research has shown overexpression or alteration of the protein can interfere with needed proteasomal and lysosomal function, promote mitochondrial injury, increase toxic iron III levels, limit dopamine production by interfering with tyrosine hydroxylase, and worsen neuronal presynaptic vesicle release Ozansoy and Basak, ; Jellinger, ; Ulusoy, ; Olanow and Prusiner, Oxidative stress is a key theory behind PD mechanisms and potentially links many of the following theories.
Here, we will focus predominantly on oxidative stress as it relates to mitochondrial dysfunction but it can occur from a variety of causes. A cell is in oxidative stress when the amount of reactive oxygen species ROS exceeds a certain threshold and the cell no longer functions effectively, leading to cell death Varcin et al. Studies have demonstrated altered markers of oxidative stress in serum and cerebrospinal fluid CSF of PD patients, and dopaminergic neurons are particularly susceptible to high levels of ROS Varcin et al.
Toxic intermediates from the catabolism of dopamine can produce ROS and crucial antioxidants such as glutathione are already low in these neurons, likely accounting for some of their vulnerability Stefanoni et al. Mitochondria , while vital for cell function, are the main producers of ROS in the brain Dumont and Beal, ; Yan et al. Scientists have discovered mitochondrial DNA to be altered in some PD cases and determined that this alteration raises the risk of developing the disease, potentially by increasing ROS formation Autere et al.
Mitochondrial complex I has come under particular scrutiny.
Deficiencies have been noted in this complex in brain and other tissues in post-mortem PD studies Schapira and Jenner, Most intriguing, the toxin MPTP which provides us with many of our PD animal models creates parkinsonism through interaction with mitochondrial complex I Schapira et al. Iron deposition is common in a variety of movement disorders Dusek et al.
It is not clear if it is pathogenic in PD. However, other studies have not shown this increase in iron in early PD Galazka-Friedman, ; Uitti et al. Iron is potentially destructive because it is actively involved in chemical reactions that produce free radicals, including the catabolism of dopamine itself Mochizuki and Yasuda, Dopaminergic cells appear to be selectively damaged and susceptible to excessive iron but other nervous tissue is also affected Mochizuki and Yasuda, Neuromelanin is thought to act as a reservoir for excessive iron and to bind free radicals.
If neuromelanin becomes saturated, free radical formation may cause greater cellular toxicity Mochizuki and Yasuda, Ubiquitin- Proteasome System.
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The ubiquitin-proteasome system UPS is the main system through which the body degrades and removes unwanted proteins and proteinaceous material Olanow and McNaught, When unwanted proteins reach a critical mass, the cell has difficulty functioning and is said to be under proteolytic stress Grune et al. Logically, failure of the UPS could be expected to lead to toxic levels of this protein. In addition, the UPS is the primary means by which defective oxidative radical producing mitochondria are removed as well Brunk and Terman, McNaught et al.
There is a corresponding increase in proteasome function across other areas of the brain, potentially as a compensatory mechanism Olanow and McNaught, ; McNaught et al. These changes in function have been seen in very early PD as well as later stages Tofaris et al. Enhanced inflammation and activated glial cells may play a role in PD mechanisms by becoming mediators of programmed dopaminergic cell death.
However, whether this is a primary degenerative process or a response to other activities has not been determined Graeber et al. Certainly, astrocytosis and lymphocytosis have been found in the SNpc of PD patients in postmortem studies Hirsch and Hunot, ; Przedborski, Some animal studies suggest a more primary mechanism of action with microglial activation in toxin-induced PD models and less pronounced neuron degeneration in models where glial cell function is suppressed Hirsch et al.
Other processes mentioned seem to potentiate neuroinflammation even if not the primary process. Mitochondrial dysfunction and oxidative stress can initiate an inflammatory response Witte et al. Environment, especially certain toxins and trauma, has long been thought to play a pathogenic role in PD but finding proof has been difficult. Herbicide and pesticide contribution continues to be debated. Although Hubble et al. Studies attempting to link pesticides to PD have been hampered by several issues, including the long latency between the exposure and the development of clinical disease.
For a putative toxin to cause cerebral neurodegeneration consistent with PD, it must not cause death to the person or preferential damage to peripheral nerves, yet still trigger a cascade of processes resulting in ongoing damage to the basal ganglia over other areas of the brain. To date, no pesticide has been shown to produce the full clinical picture of PD. Because parkinsonism can be seen with rather non-specific brain injuries such as hypoxemia, pesticide exposure might be seen in closer association with some of the features of PD without actually meeting the formal diagnostic criteria.
In this situation, it would be difficult to distinguish the cause between hypoxemia versus the toxin, or even other intervening factors. PD motor symptoms can all be seen following brain injury from many sources, including trauma Jankovic, However, these conditions generally do not progress in the same manner as PD, and there are qualitative differences in the presentation. For example, the tremor associated with TBI is typically present in both rest and action.
Role of Autophagy in Parkinson’s Disease
Large epidemiological studies do not support trauma as an etiology for PD. In a case-control study of reported head injury, Williams et al. In a recent hospitalization study, Fang et al.
While doubted for many years, it has become increasingly clear that genetics plays a role in PD. The proven mutations all affect the cellular mechanisms mentioned above and lead to similar phenotypic presentations that closely mimic that seen with idiopathic PD. LRRK2 is a tyrosine kinase -like protein which is the rate limiting enzyme in the formation of dopamine Mata et al.
Mutations in LRRK2 may put dopaminergic neurons at increased risk of other stressors due to an importance of the protein in regulating cellular dynamics during mitochondrial inhibition Saha et al. LRRK2 has furthermore been found to interact with microglia and increase dopaminergic cell death Hirsch and Hunot, Finally, Lin et al.
Molecular-genetic features of parkinson’s disease
ATP13A2 proteins are present on the lysosome membrane, and defects appear to affect function of this organelle Ramirez et al. Widespread genetic analysis in idiopathic PD continues. Large case-control studies, most notably by Sidransky et al. MAPT is involved with the cytoskeleton and affects tau protein formation, and has also been shown in large case control studies to be associated with increased risk of idiopathic PD Bekris et al.
Thus, there are many theories as to why PD occurs at the cellular level and what processes may incite these changes environment, toxin exposure, genetic predisposition , etc. We have only briefly touched on the more common suggested mechanisms. Increasingly, it seems PD is a syndrome with potentially multiple interrelated causes all leading to a similar phenotypic presentation. This disease may be a complex, heterogeneous disorder with multiple overlapping subtypes, which have yet to be established. This has made it difficult for physicians and scientists to determine the etiology, and ultimately, to construct a neuroprotective or curative therapy.
Christopher M. Tolleson, M.
Hum Genet , J Geriatr Psychiatry Neurol , Neurobiol Aging , Brunk UT, Terman A. The mitochondrial-lysosomal axis theory of aging: accumulation of damaged mitochondria as a result of imperfect autophagocytosis. Eur J Biochem , Nat Rev Neurosci 12 6 , Accelerated in vitro fibril formation by mutant alpha-synuclein linked to early-onset Parkinson disease Nat Med , Dauer W, Przedborski S. Neuron , Del Tredici K, Braak H. Mov Disord 27 5 , Mapping of the inducible IkappaB phosphorylation sites that signal its ubiquitination and degradation. Mol Cell Biol , Influence of neuromelanin on oxidative pathways within the human substantia nigra.
Neurotoxicol Teratol , Dumont M, Beal MF. Free Radic Biol Med 51 5 , Iron dysregulation in movement disorders. Neurobiol Dis 46 1 , Fahn S, Przedborski S. Mov Disord 27 13 , Farrer MJ. Genetics of Parkinson disease: paradigm shifts and future prospects. Nat Rev Gent 7 4 , Freire C, Koifman S. Neurotoxicology 33 5 , Cells overexpressing PD-associated variants of mortalin showed increased ROS levels after proteolytic stress compared to cells expressing wild-type mortalin.
Moreover, mitochondrial dysfunction induced by knock-down of mortalin could only be rescued by wild-type mortalin but not by PD-associated variants Burbulla et al. Some of these variants were mimicked in yeast, thus unraveling the presence of a wide range of mitochondrial alterations and further reinforcing mortalin involvement as a susceptibility factor for PD Goswami et al.
Mortalin has been found to interact with several proteins linked to genetic PD, such as DJ-1 Jin et al. Interestingly, PINK1 or Parkin overexpression in mortalin-knock down cells rescued the mitochondrial phenotype, thus suggesting that mortalin might also participate in the PINK1-Parkin pathway Yang et al.
However, in recent years, mortalin's role in the pathogenesis of PD has been questioned. In the screening of a cohort of early-onset PD patients, only one missense change in the PD group and another in the control group were found, suggesting that mortalin variants may not be a major determinant of early-onset PD Freimann et al. The authors revealed that PINK1 overexpression protects cells against oxidative stress-induced apoptosis by suppressing mitochondrial cytochrome c release; this protective action depends on the PINK1-dependent phosphorylation of TRAP1 Pridgeon et al. The protease LONP1 is responsible for the degradation of oxidized proteins.
MPTP-intoxicated mice displayed increase expression of LONP1 in the ventral mesencephalon concomitantly with the presence of oxidized proteins and dopaminergic cell loss. These mutations do not affect the localization of the protein, but instead affect its proteolytic activity, resulting in increased mitochondrial susceptibility Strauss et al.
Mice lacking HTRA2 expression develop a specific neurodegeneration of striatal neurons together with a parkinsonian phenotype akinetic and rigid syndrome, showing a lack of coordination, decreased mobility and tremor leading to early death, thus challenging the notion that HTRA2 is a major regulator of apoptotic cell death Martins et al.
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HTRA2 phosphorylation increases its proteolytic activity in a PINK1-dependent manner, suggesting that these proteins might be part of the same stress-sensing pathway Plun-Favreau et al.
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