15. Parkinson’s Disease Related Signalling Pathways

 

15.1. Dopaminergic Neurodegeneration Facilitated Through G2019S LRRK2 Is Relied on Kinase or Action by GTPase 

 

According to Nguyen A P T et al., 2020  “A low number of Parkinson’s disease (PD) cases, as a neurodegenerative disease, are inherited and related to mutations in no less than 14 various genes such as mutations in the leucine-rich repeat kinase 2 (LRRK2)” (Hernandez D G et al., 2016) (Nguyen A P T et al., 2020).

 

Also as Nguyen A P T et al., 2020 suggested “LRRK2 consists of two dominant enzymatic regions, Roc (Ras of Complex) GTPase domain and a tyrosine kinase like kinase domain, connected by COR (C-terminal of Roc) domain and bordered by four protein interface repeat domains” (Islam M S and Moore D J., 2017) (Nguyen A P T et al., 2020). 

 

Essential roles for enzymatic functions in the pathophysiology of PD were demonstrated by familial PD-related mutations group within the (i) Roc-COR tandem (N1437H, R1441C/G/H, R1628P and Y1699C) and (ii) kinase (I2012T, G2019S, and I2020T) domains of LRRK2 (Nguyen A P T et al., 2020).

 

The functionality of kinase domain in LRRK2 is dependent on GTP binding. This is the result of the ability of LRRK2 to act as both GTPase and Kinase in vitro and in cells per an integral GTPase domain (Biosa A et al., 2013) (Ito G et al., 2007 as cited in Nguyen A P T et al., 2020) (Nguyen A P and Moore D J., 2017) (Taymans J M et al., 2011) (Nguyen A P T et al., 2020).

 

Substrate phosphorylation (a subset of Rab GTPases) and autophosphorylation (at Ser 1292) take place as a result of a rise in kinase activity of the LRRK2 in different capacities in mammalian cells after being mutated in familial PD (Sheng Z et al., 2012 as cited in Nguyen A P T et al., 2020) (Steger M et al., 2016) (West A B et al., 2005) (Nguyen A P T et al., 2020). 

 

The outcome of kinase functionality, for common G2019S mutation, which is placed within kinase activation loop, is direct. However, diminished GTP hydrolysis action and consequent extending the GTP bound “on” state of LRRK2, caused by secondary mutations in Roc-COR domain (Nguyen A P et al., 2017) (Daniëls V et al., 2011) 

(Lewis P A et al., 2007) (Li X et al., 2007) (Xiong Y et al., 2010) (Liao J et al., 2014) (Nguyen A P T et al., 2020).  

 

Furthermore, according to Nguyen A P T et al., 2020 “G2019S LRRK2, through a cell autonomous mechanism, is capable to promote dopaminergic neuronal defect, however, a non-cell-autonomous activity of LRRK2 in astrocyte and/or microglia is not rejected” (Nguyen A P T et al., 2020). 

 

Therefore, neurotoxic influences of LRRK2 mutations can be diminished by therapeutic interventions targeting kinase inhibition, rise in GTP hydrolysis and GTP binding inhibition. Consequently, the neurodegenerative influences of the G2019S LRRK2 in vivo are essentially arbitrated by the activity of both GTPase and kinase (Nguyen A P T et al., 2020).

 

Dopaminergic Neurodegeneration Facilitated Through G2019S LRRK2 Is Relied on Kinase or Action by GTPase References

 

1.        Biosa, A. et al. GTPase activity regulates kinase activity and cellular phenotypes of Parkinson’s disease-associated LRRK2. Hum. Mol. Genet. 22, 1140–1156 (2013).

2.        Daniëls, V. et al. Insight into the mode of action of the LRRK2 Y1699C pathogenic mutant. J. Neurochem. 116, 304–315 (2011).

3.        Hernandez, D. G., Reed, X. & Singleton, A. B. Genetics in Parkinson disease: Mendelian versus non-Mendelian inheritance. J. Neurochem. 139, 59–74 (2016).

4.        Islam, M. S. & Moore, D. J. Mechanisms of LRRK2-dependent neurodegeneration: role of enzymatic activity and protein aggregation. Biochem. Soc. Trans. 45, 163–172 (2017).

5.        Ito, G. et al. GTP Binding Is Essential to the Protein Kinase Activity of LRRK2, a Causative Gene Product for Familial Parkinson’s Disease. Biochemistry 46, 1380–1388 (2007).

6.        Lewis, P. A. et al. The R1441C mutation of LRRK2 disrupts GTP hydrolysis. Biochem. Biophys. Res. Commun.357, 668–671 (2007).

7.        Li, X. et al. Leucine-rich repeat kinase 2 (LRRK2)/PARK8 possesses GTPase activity that is altered in familial Parkinson?s disease R1441C/G mutants. J. Neurochem. 0, 070710052154004-??? (2007).

8.        Liao, J. et al. Parkinson disease-associated mutation R1441H in LRRK2 prolongs the “active state” of its GTPase domain. Proc. Natl. Acad. Sci. 111, 4055–4060 (2014).

9.        Nguyen, A. P. T. & Moore, D. J. Understanding the GTPase Activity of LRRK2: Regulation, Function, and Neurotoxicity. in 71–88 (2017). doi:10.1007/978-3-319-49969-7_4

10.     Nguyen, A. P. T. et al. Dopaminergic neurodegeneration induced by Parkinson’s disease-linked G2019S LRRK2 is dependent on kinase and GTPase activity. Proc. Natl. Acad. Sci. 117, 17296–17307 (2020).

11.     Sheng, Z. et al. Ser 1292 Autophosphorylation Is an Indicator of LRRK2 Kinase Activity and Contributes to the Cellular Effects of PD Mutations. Sci. Transl. Med. 4, (2012).

12.     Steger, M. et al. Phosphoproteomics reveals that Parkinson’s disease kinase LRRK2 regulates a subset of Rab GTPases. Elife 5, (2016).

13.     Taymans, J.-M. et al. LRRK2 Kinase Activity Is Dependent on LRRK2 GTP Binding Capacity but Independent of LRRK2 GTP Binding. PLoS One 6, e23207 (2011).

14.     West, A. B. et al. Parkinson’s disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc. Natl. Acad. Sci. 102, 16842–16847 (2005).

15.     Xiong, Y. et al. GTPase Activity Plays a Key Role in the Pathobiology of LRRK2. PLoS Genet. 6, e1000902 (2010).

 

15.2. Dopaminergic Neurons and ERK Signalling

 

According to Volpicelli F et al., 2020 “Issues that contribute to the death of mDA (Midbrain Dopaminergic) such as ROS, 6-OHDA (6-hydroxydopamine), Ca+2 and mitochondrial dysfunction, can control, or be controlled by, ERK (the Extracellular signal Regulated kinases ½ ), also recognized as p42/p44 MAPK (extracellular Mitogen Activated protein Kinases)” (Volpicelli F et al., 2020).

 

Pathophysiology of the number of neurodegenerative diseases is associated with modification of ERK signalling (Colucci-D’ Amato L et al., 2003) (Fusco F R et al., 2012 as cited in Volpicelli F et al., 2020) (Volpicelli F et al., 2020). Furthermore, in mDA neurons’ cytoplasm and mitochondria of the patients with PD (Parkinson’s Disease) and dementia with Lewy bodies, Phosphorylated ERK is augmented (Zhu J H et al., 2002) (Volpicelli F et al., 2020).

 

Also, ERK plays a critical role in arbitrating the toxic influences of the number of pro-cell death incentives such as 6-OHDA, MPTP/MPP+ (1-metil 4-fenil 1,2,3,6-tetraidro-piridine), rotenone and high doses of dopamine, which was demonstrated in the studies, involving chemical and genetic models of PD and/or neurotoxicity (Volpicelli F et al., 2020). Additionally, ROS incorporating H2O2 and superoxide with noxious effects on mDA neurons, can be produced by 6-OHDA (Volpicelli F et al., 2020). According to some studies, ROS stimulates the ERK activation, facilitating mechanisms of cell death, thus MEK inhibitors which obstruct ERK, can promote cell survival (Kulich S M and Chu C T., 2001) (Volpicelli F et al., 2020).

 

It is known that coherent translocation of ERK into the nucleus with consequent cell death occurs as a result of continuous induction of ERK. However, shielding influence of ERK takes place when ERK is rapidly induced and localized in cytoplasm (Wainstein E and Seger R., 2016 as cited in Volpicelli F et al., 2020) (Volpicelli F et al., 2020).

 

Furthermore, Physiological progression of neurogenesis and mDA neural progenitors growth is facilitated through ERK signaling (Yoo D Y et al., 2011 as cited in Volpicelli F et al., 2020) (Volpicelli F et al., 2020).

 

Conversely, IL10, which controls the induction of ERK and STAT3 in nestin+ neural progenitors, is critical to promote neurogenesis in the adult SVZ (Subventricular Zone), one of two neurogenic regions and it is known that ERK obstruction hinders neurogenesis in SVZ (Colucci-D’ Amato L and di Porzio U., 2008) (Pereira L et al., 2015 as cited in Volpicelli F et al., 2020) (Volpicelli F et al., 2020).

 

Finally, an elegant study inD2R -/- mice demonstrated that Wnt5a via ERK induction regulates the quantity of TH (Tyrosine Hydroxylase) neurons in addition to their morphogenic characteristics like their neutrite length, in midbrain neural cultures (Yoo D Y et al., 2011) (Volpicelli F et al., 2020).

 

Dopaminergic Neurons and ERK Signalling References

 

1.        Colucci-D’Amato, L. & di Porzio, U. Neurogenesis in adult CNS: From denial to opportunities and challenges for therapy. BioEssays 30, 135–145 (2008).

2.        Colucci-D’Amato, L., Perrone-Capano, C. & di Porzio, U. Chronic activation of ERK and neurodegenerative diseases. BioEssays 25, 1085–1095 (2003).

3.        Fusco, F. R. et al. Changes in the expression of extracellular regulated kinase (ERK 1/2) in the R6/2 mouse model of Huntington’s disease after phosphodiesterase IV inhibition. Neurobiol. Dis. 46, 225–233 (2012).

4.        Kulich, S. M. & Chu, C. T. Sustained extracellular signal-regulated kinase activation by 6-hydroxydopamine: implications for Parkinson’s disease. J. Neurochem. 77, 1058–1066 (2001).

5.        Pereira, L. et al. IL-10 regulates adult neurogenesis by modulating ERK and STAT3 activity. Front. Cell. Neurosci. 9, (2015).

6.        Volpicelli, F., Perrone-Capano, C., Bellenchi, G. C., Colucci-D’Amato, L. & di Porzio, U. Molecular Regulation in Dopaminergic Neuron Development. Cues to Unveil Molecular Pathogenesis and Pharmacological Targets of Neurodegeneration. Int. J. Mol. Sci. 21, 3995 (2020).

7.        Wainstein, E. & Seger, R. The dynamic subcellular localization of ERK: mechanisms of translocation and role in various organelles. Curr. Opin. Cell Biol. 39, 15–20 (2016).

8.        Yoo, D. Y. et al. Synergistic Effects of Sodium Butyrate, a Histone Deacetylase Inhibitor, on Increase of Neurogenesis Induced by Pyridoxine and Increase of Neural Proliferation in the Mouse Dentate Gyrus. Neurochem. Res. 36, 1850–1857 (2011).

9.        Zhu, J.-H., Kulich, S. M., Oury, T. D. & Chu, C. T. Cytoplasmic Aggregates of Phosphorylated Extracellular Signal-Regulated Protein Kinases in Lewy Body Diseases. Am. J. Pathol. 161, 2087–2098 (2002).