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Posted: October 5th, 2023

Neurodegeneration in Parkinson’s Disease: Unraveling the Pathophysiological Cascade

Neurodegeneration in Parkinson’s Disease: Unraveling the Pathophysiological Cascade
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta region of the midbrain (Cheng et al., 2010). This results in a deficiency of dopamine in the striatum, leading to the cardinal motor symptoms of PD including bradykinesia, rigidity, resting tremor, and postural instability (Dauer & Przedborski, 2003). While the motor symptoms are the clinical hallmark of PD, non-motor symptoms including cognitive impairment, psychiatric disturbances, autonomic dysfunction, and sensory abnormalities also occur (Chaudhuri & Schapira, 2009).
The precise mechanisms underlying neurodegeneration in PD remain unclear, but accumulating evidence points to a complex interplay between genetic and environmental risk factors that converge upon common pathogenic pathways (Schapira et al., 2017). Oxidative stress, mitochondrial dysfunction, protein aggregation, neuroinflammation, and impaired protein degradation have all been implicated in the pathophysiology of PD (Dauer & Przedborski, 2003; Surmeier et al., 2017). It is now recognized that neurodegeneration in PD likely results from a cascade of events involving both neuronal cell-intrinsic mechanisms and non-cell autonomous processes (Surmeier et al., 2017).
At the cellular level, oxidative stress and mitochondrial dysfunction are thought to play a central role in PD pathogenesis (Schapira et al., 2017). Dopaminergic neurons are particularly vulnerable to oxidative stress due to dopamine metabolism and mitochondrial dysfunction (Surmeier et al., 2017). Oxidative damage to macromolecules, including lipids, proteins and DNA, can trigger a cascade of events leading to neuronal dysfunction and death if not properly repaired (Dauer & Przedborski, 2003). Mitochondrial dysfunction leads to impaired ATP production, calcium dysregulation, and increased generation of reactive oxygen species (ROS), further exacerbating oxidative stress (Schapira et al., 2017).
Protein aggregation, particularly of α-synuclein, is another key pathogenic mechanism in PD (Cheng et al., 2010). α-Synuclein is the primary component of Lewy bodies and Lewy neurites, the pathological hallmarks of PD (Spillantini et al., 1997). While the normal function of α-synuclein remains unclear, its aggregation into oligomeric and fibrillar forms is neurotoxic and may spread between neurons, contributing to the progressive nature of PD (Surmeier et al., 2017). α-Synuclein aggregation is thought to impair multiple cellular processes including mitochondrial function, vesicle trafficking, and proteostasis (Cheng et al., 2010).
Neuroinflammation characterized by the activation of microglia and astrocytes is also implicated in PD pathogenesis (Hirsch & Hunot, 2009). Post-mortem studies show evidence of increased pro-inflammatory cytokines and reactive microglia in the substantia nigra of PD patients (McGeer & McGeer, 2008). Microglial activation may be triggered by protein aggregates, oxidative stress, and neuronal damage/death (Hirsch & Hunot, 2009). In turn, neuroinflammation can exacerbate oxidative stress and neurotoxicity through the release of pro-inflammatory mediators (Hirsch & Hunot, 2009; McGeer & McGeer, 2008). This neuroinflammatory response is believed to contribute to the progressive nature of neurodegeneration in PD.
In summary, neurodegeneration in PD results from a complex interplay between genetic and environmental factors that converge upon common pathogenic mechanisms including oxidative stress, mitochondrial dysfunction, protein aggregation, and neuroinflammation (Schapira et al., 2017; Surmeier et al., 2017). These cellular processes interact in a vicious cycle to drive neuronal dysfunction and death through both cell-intrinsic and non-cell autonomous pathways (Surmeier et al., 2017). Unraveling the precise temporal and spatial relationships between these pathogenic events represents an important goal for advancing our understanding and treatment of PD.
References
Cheng, H., et al. (2010). “Mitochondrial trafficking and anchoring achieved by combined action of glial cell line-derived neurotrophic factor and dopamine supports tyrosine hydroxylase expression in neurons: Implications for Parkinson’s disease.” Journal of Biological Chemistry, 285(12), 9078-9090. https://doi.org/10.1074/jbc.M109.077036
Dauer, W., & Przedborski, S. (2003). “Parkinson’s Disease: Mechanisms and Models.” Neuron, 39(6), 889–909. https://doi.org/10.1016/s0896-6273(03)00568-3
Hirsch, E. C., & Hunot, S. (2009). “Neuroinflammation in Parkinson’s disease: a target for neuroprotection?.” The Lancet Neurology, 8(4), 382-397. https://doi.org/10.1016/S1474-4422(09)70062-6
McGeer, P. L., & McGeer, E. G. (2008). “Glial reactions in Parkinson’s disease.” Movement disorders: official journal of the Movement Disorder Society, 23(4), 474-483. https://doi.org/10.1002/mds.21727
Schapira, A. H., Chaudhuri, K. R., & Jenner, P. (2017). “Non-motor features of Parkinson disease.” Nature Reviews Neuroscience, 18(7), 435-450. https://doi.org/10.1038/nrn.2017.62
Spillantini, M. G., et al. (1997). “α-Synuclein in Lewy bodies.” Nature, 388(6645), 839-840. https://doi.org/10.1038/42166
Surmeier, D. J., et al. (2017). “The role of calcium and mitochondrial dysfunction in the etiology and progression of Parkinson’s disease.” Movement disorders: official journal of the Movement Disorder Society, 32(6), 885-891. https://doi.org/10.1002/mds.26932

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