Etiology and Pathogenesis of Parkinson Disease
Section snippets
Genetic factors
Several recent case control studies have confirmed that PD is more common in relatives of PD cases compared with matched controls.10, 11, 12, 13 Overall, the relative risk in first-degree relatives of PD cases has increased approximately 2 to 3-fold.14 A large PD twin study showed no significant concordance for PD among monozygotic twins, suggesting no significant genetic contribution to PD.15 However, for those with onset before age 50 years, the concordance rate was significant, implying that
Environmental factors
The traditional view has been that the environment must play a significant role in the etiology of PD. This has been supported over the years with the description of cases of parkinsonism in response to certain dopaminergic nigral toxins such as MPTP. The role of the environment was reenforced by the failure of twin studies to unequivocally demonstrate significant concordance, particularly in late-onset cases. However, the discovery of single gene mutations as causes of familial PD has led to a
Pathogenesis of Parkinson disease
Even before the discovery of the first gene mutation for PD, biochemical analyses of postmortem brains had established mitochondrial dysfunction and oxidative stress as major participants in the pathogenesis of PD. Their role has only been reinforced by the discovery of several genetic causes for PD and an understanding of their mechanism of action.
Defects of the mitochondrial respiratory chain and, in particular, complex I deficiency were traditionally associated with mitochondrial myopathies.
Autophagy
Intracellular protein degradation is achieved through a combination of the UPS and autophagic pathways. However, the role of the UPS in alpha-synuclein metabolism remains unclear. Attention has recently focused on the potential contribution of autophagy to the pathogenesis of neurodegenerative diseases.173, 174, 175 Autophagy comprises 3 separate pathways: macroautophagy (MA), microautophagy, and chaperone-mediated autophagy (CMA). MA involves the formation of double-membraned autophagosomes,
Summary
The last few years have witnessed important advances in our understanding of the etiology and pathogenesis of PD. Several features have become self-evident. The first is that there are multiple causes of the clinical phenotype that we currently recognize as PD, and these same causes can result in a spectrum of phenotypes. Thus, there is some disconnect between genotype and phenotype. Secondly, there is variation in the pathology that may be induced by the specific gene mutations, a further
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Cited by (92)
Human gingival mesenchymal stem cells improve movement disorders and tyrosine hydroxylase neuronal damage in Parkinson disease rats
2022, CytotherapyCitation Excerpt :Parkinson disease (PD) is the second most common neurodegenerative disorder behind Alzheimer disease and is characterized by tremor, rigidity, postural instability and bradykinesia [6]. The apparent loss of dopaminergic neurons (DA neurons) in the substantia nigra is a pathological hallmark observed in the brains of PD patients [7–9]. The endogenous niche cells of DA neurons play an important role in maintaining the normality of the neural network, the loss of which is related to neuronal damage and loss in PD patients [10].
Identification of bioactive metabolites in human iPSC-derived dopaminergic neurons with PARK2 mutation: Altered mitochondrial and energy metabolism
2021, Stem Cell ReportsCitation Excerpt :Although the multifactorial etiology of PD and the pathological mechanisms underlying the neuronal degeneration remain largely undetermined, various PD-related genetic-environmental interactions are thought to contribute to the pathogenesis of the disease. Mitochondrial dysfunction associated with oxidative stress and energy failure is increasingly thought to be implicated in PD (Dias et al., 2013; Schapira, 2009). Mutations in a number of genes have been found to cause monogenic forms of PD with both recessive (e.g., PARK2, PINK1, DJ-1) and autosomal dominant transmission (e.g., LRRK2, SNCA) (Bonifati et al., 2003; Lucking et al., 2000).
Inhibitory potential of plant secondary metabolites on anti-Parkinsonian drug targets: Relevance to pathophysiology, and motor and non-motor behavioural abnormalities
2020, Medical HypothesesCitation Excerpt :Although no cure is available, treatment of PD is focused on two strategies: (1) oral DA replenishment therapy using precursor of DA, L-3,4-dihydroxyphenylalanine (levodopa or L-DOPA), and (2) oral administration of inhibitors of DA catabolizing enzymes. Ever since its introduction in 1967 [19], L-DOPA remains a therapeutic gold-standard in amelioration of the motor symptoms of PD [20] by replenishing the levels of DA in the striatum [20–22]. However, studies in animal models revealed that L-DOPA therapy is associated with oxidative stress, and generation of toxic metabolites [23–-25].
Farrerol protects dopaminergic neurons in a rat model of lipopolysaccharide-induced Parkinson's disease by suppressing the activation of the AKT and NF-κB signaling pathways
2019, International ImmunopharmacologyCitation Excerpt :The main feature of Parkinson's disease (PD), the second most common neurodegenerative disease in the world, is the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) of the midbrain [1].
Garcinol, a multifaceted sword for the treatment of Parkinson's disease
2019, Neurochemistry InternationalCitation Excerpt :Thus, it is suggested that the hyperacetylation of histones, as evident in PD patients and animal models of the disease, can be regulated and effectively controlled by garcinol, and therefore confer neuroprotection to dopaminergic neurons (Fig. 3). Oxidative stress is one of the major contributors to dopaminergic neurodegeneration in PD (Beal, 2005; Leszek et al., 2016; Jenner, 2003; Chinta et al., 2007; Dexter and Jenner, 2013; Quinn, 1997, Schapira, 2009), and several antioxidants have been reported to confer significant neuroprotection in animal models of the disease (Borah and Mohanakumar 2009, 2010(a,b); Fujisawa et al., 2004; Grunstein, 1997; Tapias et al., 2009; Yuan et al., 2010). Garcinol causes a favorable downshift in reactive oxygen species (ROS) by quenching hydroxyl as well as methyl radicals, and preventing their interruption in normal functioning of cellular biomolecules at an inhibitory concentration of 0.32 μM (Padhye et al., 2009; Liu et al., 2015; Yamaguchi et al., 2000b) (Table 1).