Alzheimer  >   C. The Pathogenesis of Parkinson's Disease

Parkinson's disease (PD) is a neurodegenerative disorder that affects dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc). Its symptoms include tremor, rigidity and other forms of motor dysfunction. PD is characterized by the build-up of pathological inclusion bodies called "Lewy bodies", composed mainly the α-synuclein which is a small protein with 140 amino acids. The Lewy bodies are also a hallmark of the disorder, Dementia with Lewy Bodies (DLB), that affects the neocortex and limbic system involved in cognition (thinking, remembering, and reasoning) (Outeiro et al., 2019). For PD, the Lewy bodies appear first in subcortical areas such as olfactory bulb or medulla oblongata (Braak et al., 2003). These areas are enriched with α-synuclein (Taguchi et al., 2019). Pathological α-synuclein can propagate from cell to cell. Hence, PD patients in the advanced stages also exhibit dementia (loss of cognitive functioning) as the α-synuclein pathology spreads to the neocortex and/or limbic system.

Initiation of α-Synuclein Pathology

The level of α-synuclein should be maintained in a normal range. If too low, the amount of transportable microtubules could decrease, thereby impairing long-range synchronization of neural oscillations and consequently altering beta rhythms responsible for motor function or other brain waves involved in cognition (see Article 1). If too high, α-synuclein could aggregate to form oligomers which are toxic to the cell by interfering with mitochondrial functions (Faustini et al., 2017) or enhancing the activity of glycogen synthase kinase-3β (GSK-3β).

During oxidative stress, α-synuclein is upregulated (Quilty et al., 2006). This reaction is neuroprotective because monomeric α-synuclein can reduce apoptosis under oxidative stress (Menges et al., 2017). However, overwhelming oxidative stress may produce large amount of α-synuclein, predisposing to the formation of α-synuclein oligomers which have detrimental effects.

The upregulation of α-synuclein during oxidative stress may enhance the activity of GSK-3β (Duka et al., 2009; Kawakami et al., 2011; Haggerty et al., 2011). This reaction can provide a negative feedback to downregulate α-synuclein as GSK-3β has been demonstrated to phosphorylate α-synuclein at serine-129 (S129) (Credle et al., 2015). The S129-phosphorylated α-synuclein is targeted for degradation (Oueslati, 2016; Arawaka et al., 2017). However, hyperactive GSK-3β may impair axonal transport, neurite outgrowth, and long-range coupling as discussed in Article 3. It can also cause neuronal hyperexcitability, resulting in excitotoxicity. This view is supported by the reports that potassium channels are implicated in PD (Chen et al., 2018).

The above mechanism explains why oxidative stress is a major risk factor for PD. Oxidative stress, in turn, results from traumatic brain injury (Khatri et al., 2018) or exposure to neurotoxins. Stroke and concussion are two examples of traumatic brain injury. Neurotoxins, such as MPTP, 6-hydroxydopamine (6-OHDA) and rotenone, have been widely used in animal models to induce PD. They have been shown to trigger oxidative stress (Sriram et al., 1997; Smith and Cass, 2007; Testa et al., 2005) and increase GSK-3β activity (Wang et al., 2007; Chen et al., 2004; Hongo et al., 2012).

In addition to oxidative stress, inflammation has been demonstrated to play a key role in PD (Caggiu et al., 2019). Consistently, GSK-3 is at the heart of inflammation. During infections, toll-like receptor-4 (TLR4) can be activated by lipopolysaccharide (LPS), thereby enhancing the activity of GSK-3 to trigger inflammatory response (Jope et al., 2017). Death of dopaminergic neurons has been observed both in vitro and in vivo after stimulation of microglia with LPS (Caggiu et al., 2019). The expression of TLR4 is highest within human substantia nigra. Picomolar concentrations of oligomeric alpha-synuclein is sufficient to induce TLR4-dependent inflammation (Hughes et al., 2019).

These findings suggest a pathogenic cascade as depicted in Figure C-1.


Figure C-1. A model for the pathogenic cascade of Parkinson's disease. Note that various risk factors converge to hyperactive GSK-3β.

BDNF/GSK-3β vs. BDNF/4R-Tau Pathway

Aging is associated with decreased level of brain-derived neurotrophic factor (BDNF) (Li et al., 2009). As with other neurodegenerative disorders, the BDNF levels in PD patients are significantly lower than healthy controls (Jiang et al., 2019). Therefore, in addition to oxidative stress, BDNF deficiency can also contribute to PD. Consistent with the critical role of GSK-3β in PD, low level of BDNF can lead to hyperactive GSK-3β via a well-established BDNF/TrkB signaling pathway. Binding between BDNF and TrkB triggers a series of signaling cascade that activates Akt, which in turn inactivates GSK-3β by phosphorylating serine-9 (Article 2). Hence, BDNF deficiency can augment GSK-3β activity.

On the other hand, BDNF deficiency may lead to elevated total and 4-repeat (4R) Tau protein (Chapter 11). Depending on sites of onset, the BDNF/4R-Tau pathway may cause different tauopathies: Alzheimer's disease originates in lateral entorhinal cortex (LEC), FTLD-Tau begins in frontal-temporal cortex; progressive supranuclear palsy (PSP) starts from basal ganglia (Figure C-2). FTLD refers to frontotemporal lobar degeneration, which is the pathological term for frontotemporal dementia (FTD). FTLD may be either Tau-positive (FTLD-Tau) or Tau-negative (FTLD-U), with roughly equal prevalence (Goedert et al., 2012).

The BDNF/GSK-3β pathway may cause synucleinopathy by phosphorylating α-synuclein at S129. PD begins in basal ganglia whereas DLB starts from the frontal-temporal cortex.


Figure C-2. Contribution of BDNF deficiency to neurodegenerative disorders depends on affected areas and signaling pathways.

Spreading of α-Synuclein Pathology

There is compelling evidence that α-synuclein can be secreted from cells to the extracellular space via exosomes (Emmanouilidou et al., 2010), which are 50–100 nm vesicles capable of transporting protein and RNA. It was thought that spreading of the α-synuclein pathology requires the extracellular α-synuclein enter the target cells. However, the uptake mechanism remains largely unknown. Although a few possible mechanisms, such as endocytosis, have been proposed (Valdinocci et al., 2017), direct evidence is still lacking.

Recently, it has been shown that the extracellular α-synuclein has the capacity to induce damages within target cells through receptor-mediated mechanism, independent of endocytosis or pore formation (Ferreira et al., 2017). Specifically, extracellular α-synuclein oligomers can form a complex with the prion protein to activate non-receptor tyrosine kinase (Src or Fyn) via metabotropic glutamate receptors 5 (mGluR5). The tyrosine kinase can augment GSK-3β activity by phosphorylating it at tyrosine 216 (Goc et al., 2014; Lesort et al., 1999). This mechanism is corroborated by the finding that extracellular α-synuclein leads to microtubule destabilization through GSK-3β-dependent Tau phosphorylation (Gąssowska et al., 2014). Therefore, the spreading of α-synuclein pathology could essentially be the transfer of hyperactive GSK-3β from one cell to another.

Motor symptoms do not appear before the α-synuclein pathology spreads to basal ganglia, which comprises SNc, subthalamic nucleus (STN), striatum and others (Article 5, Figure 2). The site of onset within basal ganglia is not clear. However, hyperactive GSK-3β will cause hyperexcitability whereas PD is characterized by reduced dopamine release from SNc DA neurons. Hence, during the natural progression of PD, SNc is unlikely to be the site of onset within basal ganglia. Substantial evidence indicates that the loss of DA neurons in SNc arises from glutamate-mediated excitotoxicity (Blandini et al., 1996; Ambrosi et al., 2014). STN provides major glutamatergic inputs to SNc (Rodriguez et al., 1998). In PD, STN is hyperactive (Hilker et al., 2005; Jahanshahi et al., 2015). Therefore, STN could be the site of onset for motor dysfunction in PD.

The following scenario is now emerging. As α-synuclein oligomers reach STN, they may bind prion protein on the surface of glutamatergic neurons to activate Src via mGluR5. Src then activate GSK-3β, resulting in hyperactive glutamatergic neurons within STN which, in turn, leads to excitotoxicity (including oxidative stress) in DA neurons of SNc. The oxidative stress upregulates α-synuclein, thereby inducing TLR4-dependent inflammation, which is accompanied by hyperactive GSK-3β that may eventually kill SNc DA neurons and reduce the dopamine level.

Related Articles

1. A Novel Function of α-Synuclein at the Axon Initial Segment

2. Glycogen Synthase Kinase-3 (GSK-3)

3. The Roles of GSK-3β and LRRK2 in Parkinson's Disease

4. The Role of Parkin in Parkinson's Disease

5. Global Synchronization of Beta Rhythms


Author: Frank Lee
First published: June 11, 2019
Last updated: June 1, 2021