A Scientific Approach Using Diagnostic Tools for the Pathogenesis Tailored Treatment of Parkinson’s Disease Volume 57- Issue 4

Dong Hwan Ho^1,2* and Ilhong Son^2,3*

• ¹Curahora Inc., Republic of Korea
• ²InAm Neuroscience Research Center, Sanbon Medical Center, Wonkwang University, Republic of Korea
• ³Department of Neurology, Sanbon Medical Center, College of Medicine, Wonkwang University, Republic of Korea

Received: July 10, 2024; Published: July 19, 2024

*Corresponding author: Dong Hwan Ho, Curahora Inc. #1002-43, 683, Gosan-ro, Gunpo-si, Gyeonggi-do, InAm Neuroscience Research Center, Sanbon Medical Center, Wonkwang University, 321, Sanbon-ro, Gunpo-si, Gyeonggi-do, Republic of Korea
Ilhong Son, InAm Neuroscience Research Center, Sanbon Medical Center, Wonkwang University, 321, Sanbon-ro, Gunpo-si, Gyeonggi-do, Department of Neurology, Sanbon Medical Center, College of Medicine, Wonkwang University, 321, Sanbon-ro, Gunpo-si, Gyeonggi-do, Republic of Korea

DOI: 10.26717/BJSTR.2024.57.009040

Abstract PDF

Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by motor dysfunction and various non-motor symptoms due to the loss of dopaminergic neurons. Traditional treatments like L-DOPA and deep brain stimulation manage symptoms but don’t address the root cause, leading to disease recurrence. Key factors in PD include genetic mutations in α-synuclein (α-syn) and leucine-rich repeat kinase 2 (LRRK2). α-syn aggregates and environmental toxins drive PD progression, with immunotherapy targeting α-syn showing promise. LRRK2 mutations increase kinase activity, linked to neuroinflammation, making LRRK2 inhibitors a potential treatment. Advancements in diagnostic technologies and biomarker research enhance PD diagnosis and enable tailored treatments. Combining these targeted approaches with traditional therapies aims to improve patient outcomes and quality of life by addressing the underlying causes of PD.

Abbreviations: CSF: Cerebrospinal Fluid; MPTP: 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine; LRRK2: Leucine-Rich Repeat Kinase 2; PD: Parkinson’s Disease ; α-syn: α-synuclein

Parkinson’s disease is the second most common neurodegenerative disease worldwide after Alzheimer’s disease. The main symptom of Parkinson’s disease is an impaired motor function, including tremors, rigidity, and bradykinesia. Other symptoms may include postural instability, anosmia, urinary incontinence, constipation, dysphagia, insomnia, depression, anxiety, and dementia [1]. As the world ages, the prevalence of Parkinson’s disease continues to increase, and has recently become higher than the prevalence of cancer in the elderly population [2]. Therefore, there is increasing interest in the diagnosis and treatment of Parkinson’s disease, and over the past decade, research on therapeutic targets, treatment drugs, and biomarkers has been actively conducted from academy to the industry.

The crucial pathology of PD is the loss of dopaminergic neurons in the substantia nigra pars compacta, and treatment has traditionally relied on providing additional dopamine through L-DOPA prescriptions [3]. Deep brain stimulation, which involves artificial electrical stimulation using a pacemaker, has also been employed as a treatment [4]. Recently, transplantation of tailored-dopaminergic neurons derived from stem cells has been applied to PD therapy [5]. However, these treatments do not eliminate the pathogens remaining in brain tissue, and because PD is likely to relapse without complete brain replacement, efforts are being made to develop treatments and diagnostic tools targeting these pathogens. The neurodegeneration of dopaminergic neurons is driven by genetic factors or environmental toxins, along with aging. Among genetic causes, α-synuclein (α-syn) is a notable factor in the pathogenesis of PD and is a major component of Lewy bodies and Lewy neurites [6]. The aggregation of α-syn is related to the progression of PD and is affected by environmental toxins such as rotenone, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 6-hydroxydopamine and paraquat. These toxins enhance oxidative stress in neurons, leading to the modification, interaction, and oligomerization of α-syn [7]. Therefore, many treatments have been studied to inhibit α-syn aggregation or boost the clearance of oligomeric α-syn. Immunization treatment using antibodies against α-syn oligomers is becoming more feasible as a treatment through clinical research [8].

Leucine-rich repeat kinase 2 (LRRK2) is another critical factor in PD and is considered a potential therapeutic target. Studies of genetic mutations in LRRK2 have demonstrated that upregulation of kinase activity is important for the pathogenesis of PD [9]. Increased LRRK2 kinase activity is also associated with oxidative stress and neuroinflammation [10,11], and idiopathic PD patients have shown increased LRRK2 kinase activity [12]. Therefore, drugs that specifically inhibit LRRK2 kinase activity are being studied as new PD therapies, with many researchers and industries around the world engaging in clinical research on LRRK2 inhibitors. The diagnosis of PD is still largely based on the judgment of medical experts using traditional methods. Recently, advancements in technology for live imaging of brain tissue and the application of artificial intelligence to improve image quality and resolution have supported more accurate diagnoses [13,14]. In addition to these technological advancements, research on diagnostic tools using PD biomarkers has also been conducted. Oligomeric α-syn and LRRK2 have been studied as representative biomarkers of PD. Biological fluids such as cerebrospinal fluid (CSF), serum, saliva, and urine have been used in diagnostic assay studies for α-syn oligomers and LRRK2 [15,16]. While it is important to uncover causal relationships with pathological causes through biomarker research using biological fluids, if PD pathogenesis can be diagnosed using these biomarkers, therapies can be tailored accordingly.

Diagnosing pathogens in PD patients using diagnostic tools is important to provide targeted therapeutic strategies to alleviate α-syn and LRRK2-driven pathology. α-syn aggregates and hyperactivated- LRRK2 will remain in brain tissue and continue to play a role in PD pathogenesis even after L-DOPA drug treatment or dopaminergic neuron transplantation. Evidence supporting this includes:

1. Studies suggesting that α-syn aggregates can transfer from existing host dopamine neurons to transplanted dopamine neurons, promoting disease progression [17-19].
2. The demonstrated transmission of α-syn via neuron-to-neuron or neuron-to-astroglia pathways [20-22] and
3. Reports elucidating that LRRK2 kinase activity is a key mediator of neuroinflammation in microglia and deficient neuroprotection in astrocytes [23-25].

For these reasons, unless the pathological causes are addressed, it is difficult to claim that PD has been completely cured simply by supplying dopamine through L-DOPA administration or transplanting dopamine neurons.It is presumed that tailored treatment according to the diagnosis of α-syn or LRRK2 pathogenesis can further increase therapeutic efficacy in the long term when combined with treatments that reinforce or regenerate the function of dopaminergic neurons. Therefore, pathological diagnosis will provide a sufficient basis for offering customized treatment to PD patients in the future, and such pathogenesis-tailored treatment will be able to provide patients with a satisfactory quality of life through synergistic effects when combined with other treatments.

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. Journal of neurology, neurosurgery, and psychiatry 79(4): 368-376.
2. Ou Z, Pan J, Tang S, Duan D, Yu D, et al. (2021) Global Trends in the Incidence, Prevalence, and Years Lived with Disability of Parkinson's Disease in 204 Countries/Territories From 1990 to 2019. Frontiers in public health 9: 776847.
3. Cacabelos R (2017) Parkinson's Disease: From Pathogenesis to Pharmacogenomics. International journal of molecular sciences 18(3).
4. Habets JGV, Heijmans M, Kuijf ML, Janssen MLF, Temel Y, et al. (2018) An update on adaptive deep brain stimulation in Parkinson's disease. Movement disorders: official journal of the Movement Disorder Society 33(12): 1834-1843.
5. Cha Y, Park TY, Leblanc P, Kim KS (2023) Current Status and Future Perspectives on Stem Cell-Based Therapies for Parkinson's Disease. Journal of movement disorders 16(1): 22-41.
6. Borghammer P, Okkels N, Weintraub D (2024) Parkinson's Disease and Dementia with Lewy Bodies: One and the Same. Journal of Parkinson's disease 14(3): 383-397.
7. Wen S, Aki T, Unuma K, Uemura K (2020) Chemically Induced Models of Parkinson’s Disease: History and Perspectives for the Involvement of Ferroptosis. Frontiers in Cellular Neuroscience, p. 14.
8. Vaikath NN, Hmila I, Gupta V, Erskine D, Ingelsson M, et al. (2019) Antibodies against alpha-synuclein: tools and therapies. Journal of neurochemistry 150(5): 612-625.
9. Kumar S, Behl T, Sehgal A, Chigurupati S, Singh S, et al. (2022) Exploring the focal role of LRRK2 kinase in Parkinson's disease. Environmental science and pollution research international 29(22): 32368-32382.
10. 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. Oxidative Medicine and Cellular Longevity 2021(1): 9969842.
11. Ho DH, Je AR, Lee H, Son I, Kweon HS, et al. (2018) LRRK2 Kinase Activity Induces Mitochondrial Fission in Microglia via Drp1 and Modulates Neuroinflammation. Exp Neurobiol 27(3): 171-180.
12. Rocha EM, Keeney MT, Di Maio R, De Miranda BR, Greenamyre JT (2022) LRRK2 and idiopathic Parkinson's disease. Trends in neurosciences 45(3): 224-236.
13. Dennis AP, Strafella AP (2024) The role of AI and machine learning in the diagnosis of Parkinson's disease and atypical parkinsonisms. Parkinsonism & related disorders, pp. 106986.
14. Peralta C, Biafore F, Depetris TS, Bastianello M (2019) Recent Advancement and Clinical Implications of 18FDG-PET in Parkinson's Disease, Atypical Parkinsonisms, and Other Movement Disorders. Current neurology and neuroscience reports 19(8): 56.
15. Magalhães P, Lashuel HA (2022) Opportunities and challenges of alpha-synuclein as a potential biomarker for Parkinson’s disease and other synucleinopathies. npj Parkinson's Disease 8(1): 93.
16. Kelly K, West AB (2020) Pharmacodynamic Biomarkers for Emerging LRRK2 Therapeutics. Frontiers in neuroscience 14: 807.
17. Li JY, Englund E, Holton JL, Soulet D, Hagell P, et al. (2008) Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation. Nature medicine 14(5): 501-503.
18. Li J Y, Englund E, Holton JL, Soulet D, Hagell P, et al. (2008) Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation. Nature medicine 14(5): 501-503.
19. Mendez I, Viñuela A, Astradsson A, Mukhida K, Hallett P, et al. (2008) Dopamine neurons implanted into people with Parkinson's disease survive without pathology for 14 years. Nature medicine 14(5): 507-509.
20. 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. The Journal of biological chemistry 285(12): 9262-9272.
21. Kim C, Ho DH, Suk JE, You S, Michael S, et al. (2013) Neuron-released oligomeric α-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia. Nature communications 4: 1562.
22. 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. Proceedings of the National Academy of Sciences of the United States of America 106(31): 13010-13015.
23. He KJ, Zhang JB, Liu JY, Zhao FL, Yao XY, et al. (2023) LRRK2 G2019S promotes astrocytic inflammation induced by oligomeric α-synuclein through NF-κB pathway. I Science 26(11): 108130.
24. 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).
25. 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.