Parkinson’s Disease, a Noxious Concerto by Two Villains: α -Synuclein and Leucine-Rich Repeat Kinase 2

Parkinson’s disease (PD) is the second most common neurodegenerative disease, and the loss of motor skills is the primary symptom of PD, and the death of dopamine neurons is the primary pathological cause of PD [1]. Although, the mechanism underlying the pathway in dopaminergic neuronal degeneration is not completely understood, dopamine neuronal death is caused not only by physiological degeneration within the neuron, but also by effects on surrounding brain cells [2]. Alpha-synuclein (αSyn) is a primary pathological factor of PD. Oligomeric αSyn is formed by the accumulation via an aberrant protein quality control and promotes oxidative stress, mitochondrial dysfunction, and neuroinflammation in the substantia nigra [3]. The propagation of αSyn is a critical factor in the progression of PD, particularly in the context of aging [4].

Leucine-rich repeat kinase 2 (LRRK2) is important in the pathogenesis of PD, and increased kinase activity of LRRK2 is involved in several pathological mechanisms, including mitochondrial dysfunction, impaired endoplasmic reticulum trafficking, cellular senescence, abnormal autophagy-lysosomal pathways, and neuroinflammation [5]. Therefore, in this study, we aim to describe the progression of PD induced by αSyn oligomers and LRRK2 kinase activity and how they crosstalk.

α-Synuclein

αSyn is a major component of Lewy bodies (LB), which are known to be a pathogenic marker of PD [6]. The accumulation of αSyn is caused by dysfunction of the protein degradation machinery, including the ubiquitin-proteasome system [7], chaperonemediated autophagy [8], and lysosomal activity [9]. Misfolded or chemically modified αSyn would be resistant to degradation and is responsible for the generation of oligomeric αSyn in the cytosol or vesicles such as late endosome, autophagosome or lysosome [10]. The degradation of αSyn is a potential therapeutic target, as a cleaner of accumulated αSyn [11]. The accumulated αSyn oligomers is shown to demolish the membrane potential of mitochondria within dopaminergic neurons, resulting in degeneration of dopaminergic neurons [12]. And αSyn oligomers disrupt the homeostasis of intracellular calcium ion regulation and stimulate various cell death signaling [13]. Recently, αSyn oligomers have been known to accelerate the progression of PD by the transmission of neuronto- neuron [14], and αSyn oligomers released from neurons have been found to stimulate microglia or astrocytes, thereby promoting neuroinflammation [15,16].

LRRK2

LRRK2 contains GTPase and kinase domain and their respective enzymatic activities are altered in pathogenic mutations. The G2019S LRRK2 mutation is the most common and studied mutation and its kinase activity is increased. LRRK2 interacts with and phosphorylates several substrates that regulate biological signaling and cell survival [17]. The tumor suppressor p53 is an important transcription factor, and phosphorylation of p53 is a very important process that regulates its activation state [18]. Activated p53 is known to induce the transcription of genes involved in apoptosis and cell cycle arrest [19]. Several studies have shown that p53 activation is associated with neurodegenerative diseases [20]. PD, which is caused by LRRK2, is known to be a late-onset disease, and PD is also an age-related disease [21]. In particular, the p53-p21 intracellular signaling pathway is the most common pathway for cellular senescence. Our findings are that cellular senescence is the result of p53 phosphorylation by LRRK2 [22]. In addition, p53 promotes the expression of cytokines in inflammatory responses, and it was also shown that LRRK2 involvement induces phosphorylation of p53, resulting in neuroinflammation [23,24].

The crosstalk between αSyn and LRRK2 in PD

Recent studies have reported that αSyn oligomers released from neurons act as ligands for toll-like receptors in microglia [25], where the neuroinflammatory response in microglia is activated by LRRK2 kinase, leading to the release of inflammatory cytokines [26], which ultimately results in the death of surrounding dopaminergic neurons [27]. Interestingly, it has been reported that LRRK2-induced cellular senescence is associated with increased accumulation of αSyn due to a disruption of autophagy-lysosomal degradation or an inability to degrade already formed oligomeric αSyn, which further exacerbate αSyn aggregates [28,29]. Recently, we found that neurotrophic factors are reduced in astrocytes expressing G2019S mutations that increase the LRRK2 kinase, thereby reducing the expression of factors involved in dopamine production in dopaminergic neurons [30]. Presumably, when alphasynuclein reactivates astrocytes, the phosphorylation of LRRK2 increases, which may result in a decrease in dopamine production due to a decrease in neurotrophic factors.

The interaction of LRRK2 and alpha-synuclein with neurons, microglia, and astrocytes facilitates the progression of PD via various signaling pathways. LRRK2-mediated cellular senescence exacerbates the aggregation of alpha-synuclein, resulting in increased release of alpha-synuclein oligomers from neurons. This, in turn, stimulates microglia and astrocytes to increase LRRK2- mediated neuroinflammation. In Parkinson’s disease, which is particularly age-related, this vicious cycle accumulates over time, making dopaminergic neurons increasingly vulnerable.

I appreciate to the member of InAm Neuroscience Research Center.

The authors declare no competing financial interests.

1. Jankovic J (2008) Parkinson's disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry, 79(4): 368-376.
2. Mochizuki H (2024) Pathological mechanisms and treatment of sporadic Parkinson's disease: past, present, and future. J Neural Transm (Vienna) 131(6): 597-607.
3. Negi S, Khurana N, Duggal N (2024) The misfolding mystery: α-synuclein and the pathogenesis of Parkinson's disease. Neurochem Int 177: 105760.
4. Neupane S, De Cecco E, Aguzzi A (2023) The Hidden Cell-to-Cell Trail of α-Synuclein Aggregates.
   J Mol Biol 435(12): 167930.
5. Sosero YL, Gan-Or Z (2023) LRRK2 and Parkinson's disease: from genetics to targeted therapy. Ann Clin Transl Neurol 10(6): 850-864.
6. Sommer B, Barbieri S, Hofele K, Wiederhold K, et al. (2000) Mouse models of alpha-synucleinopathy and Lewy pathology. Exp Gerontol 35(9-10): 1389-1403.
7. McNaught KS, Mytilineou C, Jnobaptiste R, Yabut J, Shashidharan P, et al. (2002) Impairment of the ubiquitin-proteasome system causes dopaminergic cell death and inclusion body formation in ventral mesencephalic cultures. J Neurochem 81(2): 301-306.
8. Alvarez-Erviti L, Rodriguez-Oroz MC, Cooper JM, Caballero C, Ferrer I, et al. (2010) Chaperone-mediated autophagy markers in Parkinson disease brains. Arch Neurol 67(12): 1464-1472.
9. Mak SK, McCormack AL, Manning-Bog AB, Cuervo AM, Di Monte DA (2010) Lysosomal degradation of alpha-synuclein in vivo. J Biol Chem 285(18): 13621-13629.
10. Smith JK, Mellick GD, Sykes AM (2022) The role of the endolysosomal pathway in α-synuclein pathogenesis in Parkinson's disease. Front Cell Neurosci 16: 1081426.
11. Masliah E, Rockenstein E, Adame A, Alford M, Crews L, et al. (2005) Effects of alpha-synuclein immunization in a mouse model of Parkinson's disease. Neuron 46(6): 857-868.
12. Wu F, Poon WS, Lu G, Wang A, Meng H, et al. (2009) Alpha-synuclein knockdown attenuates MPP+ induced mitochondrial dysfunction of SH-SY5Y cells. Brain research 1292: 173-179.
13. Ying Z, Lin F, Gu W, Su Y, Arshad A, et al. (2011) α-Synuclein increases U251 cells vulnerability to hydrogen peroxide by disrupting calcium homeostasis. J Neural Transm (Vienna) 118(8): 1165-1172.
14. Desplats P, Lee HJ, Bae EJ, Patrick C, Rockenstein E, et al. (2009) Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc Natl Acad Sci USA 106(31): 13010-13015.
15. Refolo V, Stefanova N (2019) Neuroinflammation and Glial Phenotypic Changes in Alpha-Synucleinopathies.
    Front Cell Neurosci 13: 263.
16. Lee HJ, Suk JE, Patrick C, Bae EJ, Cho JH, et al. (2010) Direct transfer of alpha-synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies. J Biol Chem 285(12): 9262-9272.
17. Cookson MR (2015) LRRK2 Pathways Leading to Neurodegeneration. Curr Neurol Neurosci Rep 15(7): 42.
18. Blattner C, Tobiasch E, Litfen M, Rahmsdorf HJ, Herrlich P (1999) DNA damage induced p53 stabilization: no indication for an involvement of p53 phosphorylation. Oncogene 18(9): 1723-1732.
19. Indeglia A, Murphy ME (2024) Elucidating the chain of command: our current understanding of critical target genes for p53-mediated tumor suppression. Crit Rev Biochem Mol Biol 59(1-2): 128-138.
20. Checler F, Alves da Costa C (2014) p53 in neurodegenerative diseases and brain cancers. Pharmacol Ther 142(1): 99-113.
21. Hur EM, Lee BD (2021) LRRK2 at the Crossroad of Aging and Parkinson's Disease. Genes 12(4): 505.
22. Ho DH, Kim H, Kim J, Sim H, Ahn H, et al. (2015) Leucine-Rich Repeat Kinase 2 (LRRK2) phosphorylates p53 and induces p21(WAF1/CIP1) expression. Molecular brain 8: 54.
23. Pandya P, Kublo L, Stewart-Ornstein J (2022) p53 Promotes Cytokine Expression in Melanoma to Regulate Drug Resistance and Migration. Cells 11(3): 405.
24. Ho DH, Seol W, Eun JH, Son IH (2017) Phosphorylation of p53 by LRRK2 induces microglial tumor necrosis factor α-mediated neurotoxicity. Biochem Biophys Res Commun 482(4): 1088-1094.
25. Kouli A, Horne CB, Williams-Gray CH (2019) Toll-like receptors and their therapeutic potential in Parkinson's disease and α-synucleinopathies. Brain Behav Immun 81: 41-51.
26. Kim C, Beilina A, Smith N, Li Y, Kim M, et al. (2020) LRRK2 mediates microglial neurotoxicity via NFATc2 in rodent models of synucleinopathies. Sci Transl Med 12(565): eaay0399.
27. Ho DH, Nam D, Seo M, Park SW, Seol W, et al. (2022) LRRK2 Inhibition Mitigates the Neuroinflammation Caused by TLR2-Specific α-Synuclein and Alleviates Neuroinflammation-Derived Dopaminergic Neuronal Loss. Cells 11(5): 861.
28. Ho DH, Nam D, Seo MK, Park SW, Seol W, et al. (2021) LRRK2 Kinase Inhibitor Rejuvenates Oxidative Stress-Induced Cellular Senescence in Neuronal Cells. Oxid Med Cell Longev 2021: 9969842.
29. Ho DH, Seol W, Son I (2019) Upregulation of the p53-p21 pathway by G2019S LRRK2 contributes to the cellular senescence and accumulation of α-synuclein. Cell cycle 18(4): 467-475.
30. Ho DH, Kim H, Nam D, Seo MK, Park SW, et al. (2024) Expression of G2019S LRRK2 in Rat Primary Astrocytes Mediates Neurotoxicity and Alters the Dopamine Synthesis Pathway in N27 Cells via Astrocytic Proinflammatory Cytokines and Neurotrophic Factors. Current issues in molecular biology 46(5): 4324-4336.