Geon 16. The Roles of GSK-3β and LRRK2 in Parkinson's Disease MT

 

As presented in Chapter 15, there is compelling evidence indicating that microtubule dysfunction plays a critical role in Parkinson's disease (PD). The mechanism of microtubule dysfunction was not discussed. This chapter will show that, in PD, microtubule dysfunction could be caused primarily by hyperactive glycogen synthase kinase-3 beta (GSK-3β).

Implication of GSK-3β in PD

  1. GSK-3β has been demonstrated to phosphorylate α-synuclein - a major component in the pathological inclusion bodies (called "Lewy bodies") of PD. Approximately 90% of α-synuclein found in Lewy bodies are phosphorylated at serine-129 (S129) (Sato et al., 2011; Oueslati, 2016). Strikingly, S129 of α-synuclein is the phosphorylation site of GSK-3β (Credle et al., 2015).
  2. In PD, GSK-3β activity is elevated (Cartelli et al., 2012).
  3. GSK-3β activation mediates the cytotoxicity induced by rotenone, which is known to increase PD risk (Hongo et al., 2012).
  4. MPTP, which is commonly used in the animal model of PD, causes a rapid activation of GSK-3β (Wang et al., 2007).
  5. Another neurotoxin commonly used to induce PD in animal models, 6-hydroxydopamine (6-OHDA), can also activate GSK-3β by significantly inhibiting phosphorylation of GSK-3β at Ser9, and inducing hyperphosphorylation of Tyr216 (Chen et al., 2004).

GSK-3β May Decrease Transportable Microtubules by Targeting α-Synuclein

α-Synuclein plays a crucial role in the assembly of short, stable and mobile microtubules called "transportable microtubules" (tMTs). The tMTs at the axon initial segment (AIS) are required for long-range electromagnetic coupling which underlies the generation of brain waves. Hence, dysfunctional α-synuclein may alter the power of brain waves (see this article). The mutation S129E, which mimics S129 phosphorylation, has been demonstrated to abolish the normal function of α-synuclein (Toba et al., 2017). Furthermore, the S129-phosphorylated α-synuclein is targeted for degradation (Oueslati, 2016; Arawaka et al., 2017), consequently reducing the number of tMTs.

GSK-3β May Impair Axonal Transport by Targeting Tau Protein

Tau protein is a microtubule-associated protein which plays a role in stabilizing microtubules. GSK-3β may phosphorylate Tau at multiple sites, thus disrupting the Tau-microtubule binding. This could impair microtubule-based axonal transport (Zhang et al., 2018).

GSK-3β May Impede Neurite Outgrowth by Targeting CRMP2

Collapsin response mediator protein-2 (CRMP2) is a microtubule-associated protein, responsible for the growth of neurites (axon and dendrites). GSK-3β may phosphorylate CRMP2 and inhibit its function. In the animal model of PD induced by MPTP (which is metabolized into MPP+ inside the brain), the axon degeneration was shown to depend on the Akt/GSK-3β/CRMP2 pathway (Fang et al., 2015). Genetic suppression of CRMP2 phosphorylation prevents axon degeneration induced by MPTP (Togashi et al., 2019).

LRRK2 Increases GSK-3β Activity

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of late-onset PD. It has been found that LRRK2 can enhance GSK-3β activity by direct interaction (Kawakami et al., 2014). The pathogenic mutations of LRRK2 can increase GSK-3β activity even higher (Berwick et al., 2017). Therefore, LRRK2 mutations may alter the functions of α-synuclein, Tau protein and CRMP2 via hyperactive GSK-3β, in accordance with the following findings:

  1. LRRK2 mutations exacerbate α-synuclein pathology (Hyun et al., 2013; Bieri et al., 2019).
  2. LRRK2 mutations increase Tau phosphorylation (Melrose et al., 2010).
  3. One of the most consistently observed effects of LRRK2 mutations is impaired neurite outgrowth (Pellegrini et al., 2017).

Summary

The roles of LRRK2 and GSK-3β in Parkinson's disease are summarized in the following figure.

Image

Figure 1. A model for the roles of LRRK2 and GSK-3β in Parkinson's Disease. tMT: transportable microtubules.

 

Author: Frank Lee
First published: May 29, 2019