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Parkinson’s Disease Pathway

Parkinson’s disease (PD) is a devastating disorder of the nervous system. It is typically characterized by motor deficits that are closely associated with progressive degeneration and loss of dopaminergic neurons in the substantia nigra and pars compacta, as well as subsequent reduction of dopamine levels in striatum. Additionally, executive dysfunction such as impulsivity and deficits in attention, short-term working memory, and speed of mental processing. With a global prevalence in millions, has been regarded as the second most common neurodegenerative disorder behind Alzheimer’s disease. However, no cure for PD is currently available, as the most commonly used therapies neither restore the lost or degenerated dopaminergic neurons, nor stop or delay the disease progression.

PD is a multifactorial disorder, where both genetic and non-genetic, such as toxin exposure and environmental factors, are involved. There are quite a few theories as to the cellular and molecular mechanisms of PD initiation and progression, including mitochondrial damage, oxidative stress, excitotoxicity, protein misfolding and aggregation, failure of protein clearance pathways, neuroinflammation and cell-autonomous mechanisms.

Schematic diagram showing the involvement of different factors and signaling pathways for degeneration of DA-neurons in PD

Figure 1. Schematic diagram showing the involvement of different factors and signaling pathways for degeneration of DA-neurons in PD. (Panchanan Maiti, et.al., 2017)

Genetics

Several gene mutations have been found to associate with the pathogenesis of PD, including genes coding for α-synuclein, parkin, PINK1 (PTEN Induced Putative Kinase 1), LRRK2 (Leucine rich repeat kinase 2), and DJ-1. Loss of function mutations and recessive inheritance of parkin, DJ-1 and PINK1 lead to mitochondrial dysfunction and reactive oxygen species (ROS) the accumulation of ROS, while missense mutation and dominant inheritance of α-synuclein and LRRK2 may affect protein degradation pathways, leading to protein aggregation and accumulation of Lewy bodies. Mitochondrial dysfunction and protein aggregation in dopaminergic neurons may be responsible for premature neuronal degeneration. Another common feature of α-synuclein, parkin, DJ-1, PINK1 and LRRK2 mutations is dopamine release and impaired dopaminergic neurotransmission, which may be a precursor to early pathological changes that precede the necrosis of dopaminergic neurons.

Mitochondrial Damage & Oxidative Stress

Oxidative stress plays a key role in PD pathology. Oxidative stress occurs when the amount of ROS exceeds a certain threshold, which affects the normal function of neurons. Evidence from clinical studies revealed that dopaminergic neurons in PD patients are particularly susceptible to high levels of ROS. The loss of dopamine, which generally acts as antioxidant, contributes to the formation of ROS. In addition, oxidative stress potentially links many other theories involved, predominantly the mitochondrial dysfunction. Mitochondria are the main producer of ROS in the brain. The abnormal activity of mitochondria complex-I in the brain and other tissues has been observed in PD models, which directly interferes with cellular ATP production, leading to cell death.

Mitochondrial dysfunction affects diverse cellular processes that can culminate in cell death

Figure 2. Mitochondrial dysfunction affects diverse cellular processes that can culminate in cell death. (Claire Henchcliffe, et al. 2008)

Protein Misfolding & Aggregation

The Ubiquitin-Proteasome System (UPS) is the most efficient disposal mechanism responsible for degradation of unwanted proteins and proteinaceous material in normal cells, such as misfolded or damaged proteins in the cytosol, nucleus, or endoplasmic reticulum. The impairment or even failure of UPS is expected to cause toxic levels of its substrate protein α-synuclein as it may lead to the intracellular accumulation of Lewy bodies in dopaminergic neurons. Lewy bodies contain misfolded aggregates of SNCA and other associated proteins, and have been regarded as one of the hallmark pathologies of PD.

Neuroinflammation

Enhanced inflammation and glial cells activity may also play a role in PD mechanisms by acting as mediators of programmed cell death of dopaminergic neurons. Such neuroinflammation processes in PD involved in a cascade of events, including the activation of microglia and increased secretion of pro-inflammatory cytokines, which is strongly linked to the degeneration of dopaminergic neurons. Microglial activation leads to apoptosis through the JNK pathway and blocks the Akt signaling pathway through REDD1. In addition, mitochondrial dysfunction, oxidative stress, protein products from genetic loci (e.g. parkin, α-synuclein, and DJ1) linked to familial PD and dopamine itself are also likely to potentiate neuroinflammation even if not the primary process.

References:

1. Maiti P, Manna J, et al. Current understanding of the molecular mechanisms in Parkinson's disease: Targets for potential treatments. Translational neurodegeneration. 2017, 6(1): 28.
2. Dauer W, Przedborski S. Parkinson's disease: mechanisms and models. Neuron. 2003, 39(6): 889-909.
3. Subramaniam S R, Chesselet M F. Mitochondrial dysfunction and oxidative stress in Parkinson's disease. Progress in neurobiology. 2013, 106: 17-32.

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