Perspective: cell death mechanisms and early diagnosis as precondition for disease modification in Parkinson’s disease: are we on the right track?

References

• Armstrong MJ, Okun MS. Diagnosis and Treatment of Parkinson Disease: a Review. JAMA. 2020;323(6):548–560.
   PubMed Web of Science ®Google Scholar
• Ahmed H, Abushouk AI, Gabr M, et al. Parkinson’s disease and pesticides: a meta-analysis of disease connection and genetic alterations. Biomed Pharmacother. 2017;90:638–649.
   PubMed Web of Science ®Google Scholar
• Liu X, Ma T, Qu B, et al. Pesticide-induced gene mutations and Parkinson disease risk: a meta-analysis. Genet Test Mol Biomarkers. 2013;17:826–832.
   PubMed Web of Science ®Google Scholar
• Onaolapo A, Onaolapo O. COVID-19, the Brain, and the Future: is Infection by the Novel Coronavirus a Harbinger of Neurodegeneration? CNS Neurol Disord Drug Targets. 2021. doi:https://doi.org/10.2174/1871527321666211222162811.
   Google Scholar
• Salari M, Zaker HB, Etemadifar M, et al. Movement Disorders Associated with COVID-19. Parkinsons Dis. 2021;3227753. https://doi.org/10.1155/2021/3227753.
   Google Scholar
• Semerdzhiev SA, Fakhree MAA, Segers-Nolten I, et al. Interactions between SARS-CoV-2 N-Protein and alpha-Synuclein Accelerate Amyloid Formation. ACS Chem Neurosci. 2021;13 ;143–150.
   PubMed Web of Science ®Google Scholar
• Riederer P, Ter M,V. Coronaviruses: a challenge of today and a call for extended human postmortem brain analyses. J Neural Transm (Vienna). 2020;127:1217–1228.
   PubMed Web of Science ®Google Scholar
• Murphy MP, LeVine H III. Alzheimer’s disease and the amyloid-beta peptide. J Alzheimers Dis. 2010;19:311–323.
   PubMed Web of Science ®Google Scholar
• Surguchov A. Intracellular Dynamics of Synucleins: “Here, There and Everywhere.” Int Rev Cell Mol Biol. 2015;320:103–169.
   PubMed Web of Science ®Google Scholar
• Prasad A, Bharathi V, Sivalingam V, et al. Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis. Front Mol Neurosci. 2019;12:25. eCollection 2019.
   PubMed Web of Science ®Google Scholar
• Angelini DF, De AF, Vacca V, et al. Very Early Involvement of Innate Immunity in Peripheral Nerve Degeneration in SOD1-G93A Mice. Front Immunol. 2020;11:575792. eCollection 2020.
   PubMed Web of Science ®Google Scholar
• Chaplot K, Jarvela TS, Lindberg I. Secreted Chaperones in Neurodegeneration. Front Aging Neurosci. 2020;12:268. eCollection 2020.
   PubMed Web of Science ®Google Scholar
• Gracia P, Camino JD, Volpicelli-Daley L, et al. Multiplicity of α-Synuclein Aggregated Species and Their Possible Roles in Disease. Int J Mol Sci. 2020;21(21):8043.
   Web of Science ®Google Scholar
• Riederer P, Berg D, Casadei N, et al., α-Synuclein in Parkinson’s disease: causal or bystander? J Neural Transm (Vienna). 126(7): 815–840. 2019.
   PubMed Web of Science ®Google Scholar
• Müller T, Woitalla D. Quality of life, caregiver burden and insurance in patients with Parkinson’s disease in Germany. Eur J Neurol. 2010;17(11):1365–1369.
   PubMed Web of Science ®Google Scholar
• Müller T, Muhlack S, Woitalla D. Pain perception, pain drug therapy and health status in patients with Parkinson’s disease. Neuroepidemiology. 2011;37(3–4):183–187.
   PubMed Web of Science ®Google Scholar
• Zella MAS, May C, Müller T, et al. Landscape of pain in Parkinson’s disease: impact of gender differences. Neurol Res. 2019;41(1):87–97.
   PubMed Web of Science ®Google Scholar
• Chen YI, Brownell A-L, Galpern W, et al. Detection of dopaminergic cell loss and neural transplantation using pharmacological MRI, PET and behavioral assessment. Neuroreport. 1999;10(14):2881–2886.
   PubMed Web of Science ®Google Scholar
• Chen JJ. Parkinson’s disease: health-related quality of life, economic cost, and implications of early treatment. Am J Manag Care. 2010;16 Suppl Implications:S87–S93. Suppl Implications.
   Web of Science ®Google Scholar
• Cilia R, Cereda E, Akpalu A, et al. Natural history of motor symptoms in Parkinson’s disease and the long-duration response to levodopa. Brain. 2020;143:2490–2501.
   PubMed Web of Science ®Google Scholar
• Gelb DJ, Oliver E, Gilman S. Diagnostic criteria for Parkinson disease. Arch Neurol. 1999;56:33–39.
   PubMed Web of Science ®Google Scholar
• Covell DJ, Robinson JL, Akhtar RS, et al. Novel conformation-selective alpha-synuclein antibodies raised against different in vitro fibril forms show distinct patterns of Lewy pathology in Parkinson’s disease. Neuropathol Appl Neurobiol. 2017;43:604–620.
   PubMed Web of Science ®Google Scholar
• Killinger BA, Kordower JH. Spreading of alpha-synuclein - relevant or epiphenomenon? J Neurochem. 2019;150:605–611.
   PubMed Web of Science ®Google Scholar
• Uchihara T. An order in Lewy body disorders: retrograde degeneration in hyperbranching axons as a fundamental structural template accounting for focal/multifocal Lewy body disease. Neuropathology. 2017;37:129–149.
   PubMed Web of Science ®Google Scholar
• Kingsbury AE, Bandopadhyay R, Silveira-Moriyama L, et al. Brain stem pathology in Parkinson’s disease: an evaluation of the Braak staging model. Mov Disord. 2010;25:2508–2515.
   PubMedGoogle Scholar
• Przuntek H, Müller T, Riederer P. Diagnostic staging of Parkinson’s disease: conceptual aspects. J Neural Transm (Vienna). 2004;111:201–216. ** excellent review on the symptoms of Parkinson’s disease in the light of the Braak hypothesis.
   PubMed Web of Science ®Google Scholar
• Barasa A, Wang J, Dewey RB Jr. Probable REM Sleep Behavior Disorder Is a Risk Factor for Symptom Progression in Parkinson Disease. Front Neurol. 2021;12:651157.
   PubMed Web of Science ®Google Scholar
• Berg D, Borghammer P, Fereshtehnejad SM, et al. Prodromal Parkinson disease subtypes - key to understanding heterogeneity. Nat Rev Neurol. 2021;17:349–361.
   PubMed Web of Science ®Google Scholar
• Chen YC, Chen RS, Weng YH, et al. The severity progression of non-motor symptoms in Parkinson’s disease: a 6-year longitudinal study in Taiwanese patients. Sci Rep. 2021;11:14781.
   PubMed Web of Science ®Google Scholar
• Di V I, Cirillo G, Tessitore A, et al. Fatigue in hypokinetic, hyperkinetic, and functional movement disorders. Parkinsonism Relat Disord. 2021;86:114–123.
   PubMed Web of Science ®Google Scholar
• Forbes EJ, Byrne GJ, O’Sullivan JD, et al. Defining Atypical Anxiety in Parkinson’s Disease. Mov Disord Clin Pract. 2021;8:571–581.
   PubMed Web of Science ®Google Scholar
• Hughes KC, Gao X, Baker JM, et al. Non-Motor Features of Parkinson’s Disease in Women. J Parkinsons Dis. 2021;11:1237–1246.
   PubMedGoogle Scholar
• Berg D, Godau J, Seppi K, et al. The PRIPS study: screening battery for subjects at risk for Parkinson’s disease. Eur J Neurol. 2013;20:102–108.
   PubMed Web of Science ®Google Scholar
• Weiner WJ. There is no Parkinson disease. Arch Neurol. 2008;65:705–708. * a wake up call on Parkinsons’s disease as a disease entity.
   PubMed Web of Science ®Google Scholar
• Wersinger C, Sidhu A. Attenuation of dopamine transporter activity by alpha-synuclein. Neurosci Lett. 2003;340:189–192.
   PubMed Web of Science ®Google Scholar
• Balestrino R, Tunesi S, Tesei S, et al. Penetrance of Glucocerebrosidase (GBA) Mutations in Parkinson’s Disease: a Kin Cohort Study. Mov Disord. 2020;35:2111–2114.
   PubMed Web of Science ®Google Scholar
• Greuel A, Trezzi JP, Glaab E, et al. GBA Variants in Parkinson’s Disease: clinical, Metabolomic, and Multimodal Neuroimaging Phenotypes. Mov Disord. 2020;35:2201–2210.
   PubMed Web of Science ®Google Scholar
• Mullin S, Stokholm MG, Hughes D, et al. Brain Microglial Activation Increased in Glucocerebrosidase (GBA) Mutation Carriers without Parkinson’s disease. Mov Disord. 2021;36:774–779.
   PubMed Web of Science ®Google Scholar
• Straniero L, Asselta R, Bonvegna S, et al. The SPID-GBA study: sex distribution, Penetrance, Incidence, and Dementia in GBA-PD. Neurol Genet. 2020;6:e523.
   PubMed Web of Science ®Google Scholar
• Thaler A, Shenhar-Tsarfaty S, Shaked Y, et al. Metabolic syndrome does not influence the phenotype of LRRK2 and GBA related Parkinson’s disease. Sci Rep. 2020;10:9329.
   PubMed Web of Science ®Google Scholar
• Emamzadeh FN, Surguchov A. Parkinson’s Disease: biomarkers, Treatment, and Risk Factors. Front Neurosci. 2018;12:612.
   PubMed Web of Science ®Google Scholar
• Kim C, Beilina A, Smith N, et al. LRRK2 mediates microglial neurotoxicity via NFATc2 in rodent models of synucleinopathies. Sci Transl Med. 2020;12:eaay0399.
   PubMed Web of Science ®Google Scholar
• Panagiotakopoulou V, Ivanyuk D, De CS, et al. Interferon-gamma signaling synergizes with LRRK2 in neurons and microglia derived from human induced pluripotent stem cells. Nat Commun. 2020;11:5163.
   PubMed Web of Science ®Google Scholar
• Zhang Q, Cheng X, Wu W, et al. Age-related LRRK2 G2019S Mutation Impacts Microglial Dopaminergic Fiber Refinement and Synaptic Pruning Involved in Abnormal Behaviors. J Mol Neurosci. 2022;72:527–543.
   PubMed Web of Science ®Google Scholar
• Tiwari PC, Pal R. The potential role of neuroinflammation and transcription factors in Parkinson disease. Dialogues Clin Neurosci. 2017;19:71–80.
   PubMed Web of Science ®Google Scholar
• Lashgari NA, Roudsari NM, Momtaz S, et al. The involvement of JAK/STAT signaling pathway in the treatment of Parkinson’s disease. J Neuroimmunol. 2021;361:577758.
   PubMed Web of Science ®Google Scholar
• Mayfield RD, Zhu L, Smith TA, et al. The SMYD1 and skNAC transcription factors contribute to neurodegenerative diseases. Brain Behav Immun Health. 2020;9. 100129.
   Google Scholar
• Wang Y, Gao L, Chen J, et al. Pharmacological Modulation of Nrf2/HO-1 Signaling Pathway as a Therapeutic Target of Parkinson’s Disease. Front Pharmacol. 2021;12:757161.
   PubMed Web of Science ®Google Scholar
• Willems S, Zaienne D, Merk D. Targeting Nuclear Receptors in Neurodegeneration and Neuroinflammation. J Med Chem. 2021;64:9592–9638.
   PubMed Web of Science ®Google Scholar
• Zgorzynska E, Dziedzic B, Walczewska A. An Overview of the Nrf2/ARE Pathway and Its Role in Neurodegenerative Diseases. Int J Mol Sci. 2021;22:9592.
   PubMed Web of Science ®Google Scholar
• Müller T, Mueller BK, Riederer P. Perspective: treatment for Disease Modification in Chronic Neurodegeneration. Cells. 2021;10:873. ** review on failures on disease modification in neurodegeneration
   PubMed Web of Science ®Google Scholar
• Sian-Hulsmann J, Mandel S, Youdim MB, et al. The relevance of iron in the pathogenesis of Parkinson’s disease. J Neurochem. 2011;118:939–957.
   PubMed Web of Science ®Google Scholar
• Tan EK, Chan DK, Ng PW, et al. Effect of MDR1 haplotype on risk of Parkinson disease. Arch Neurol. 2005;62:460–464.
   PubMed Web of Science ®Google Scholar
• Tanner CM, Ross GW, Jewell SA, et al. Occupation and risk of parkinsonism: a multicenter case-control study. Arch Neurol. 2009;66:1106–1113.
   PubMed Web of Science ®Google Scholar
• Tanner CM, Goldman SM, Ross GW, et al. The disease intersection of susceptibility and exposure: chemical exposures and neurodegenerative disease risk. Alzheimers Dement. 2014;10:S213–S225.
   PubMed Web of Science ®Google Scholar
• Przuntek H, Conrad B, Dichgans J, et al. SELEDO: a 5-year long-term trial on the effect of selegiline in early Parkinsonian patients treated with levodopa. Eur J Neurol. 1999;6:141–150.
   PubMed Web of Science ®Google Scholar
• Espay AJ. Movement disorders research in 2021: cracking the paradigm. Lancet Neurol. 2022;21:10–11.
   PubMed Web of Science ®Google Scholar
• Sian-Hulsmann J, Monoranu C, Strobel S, et al. Lewy Bodies: a Spectator or Salient Killer? CNS Neurol Disord Drug Targets. 2015;14:947–955.
   PubMed Web of Science ®Google Scholar
• Weinreb O, Drigues N, Sagi Y, et al. The application of proteomics and genomics to the study of age-related neurodegeneration and neuroprotection. Antioxid Redox Signal. 2007;9:169–179.
   PubMed Web of Science ®Google Scholar
• Kumar P, Jha NK, Jha SK, et al. Tau Phosphorylation, Molecular Chaperones, and Ubiquitin E3 Ligase: clinical Relevance in Alzheimer’s Disease. J Alzheimers Dis. 2015;43:341–361.
   PubMed Web of Science ®Google Scholar
• Witjas T, Kaphan E, Azulay JP, et al. Nonmotor fluctuations in Parkinson’s disease: frequent and disabling. Neurology. 2002;59:408–413.
   PubMed Web of Science ®Google Scholar
• Baglio F, Pirastru A, Bergsland N, et al. Neuroplasticity mediated by motor rehabilitation in Parkinson’s disease: a systematic review on structural and functional MRI markers. Rev Neurosci. 202133(2):213–226 .
   PubMed Web of Science ®Google Scholar
• Soman SK, Dagda RK. Role of Cleaved PINK1 in Neuronal Development, Synaptogenesis, and Plasticity: implications for Parkinson’s Disease. Front Neurosci. 2021;15:769331.
   PubMed Web of Science ®Google Scholar
• Sujkowski A, Hong L, Wessells RJ, et al. The protective role of exercise against age-related neurodegeneration. Ageing Res Rev. 2021;74:101543.
   PubMedGoogle Scholar
• Müller T. Investigational agents for the management of Huntington’s disease. Expert Opin Investig Drugs. 2017;26:175–185.
   PubMed Web of Science ®Google Scholar
• Surguchov A. Biomarkers in Parkinson’s Disease. 2022. https://doi.org/10.1007/978-1-0716-1712-0_7.
   Google Scholar
• Joling M, Vriend C, van den Heuvel OA, et al. Analysis of Extrastriatal (123)I-FP-CIT Binding Contributes to the Differential Diagnosis of Parkinsonian Diseases. J Nucl Med. 2017;58:1117–1123.
   PubMed Web of Science ®Google Scholar
• Lewitt PA, Taylor DC. Protection against Parkinson’s disease progression: clinical experience. Neurotherapeutics. 2008;5:210–225.
   PubMed Web of Science ®Google Scholar
• Schapira AH, Olanow CW. Neuroprotection in Parkinson disease: mysteries, myths, and misconceptions. JAMA. 2004;291:358–364.
   PubMed Web of Science ®Google Scholar
• Giordano S, Rley-usmar V, Zhang J. Autophagy as an essential cellular antioxidant pathway in neurodegenerative disease. Redox Biol. 2014;2:82–90.
   PubMed Web of Science ®Google Scholar
• Beal MF, Oakes D, Shoulson I, et al. A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease: no evidence of benefit. JAMA Neurol. 2014;71:543–552.
   PubMed Web of Science ®Google Scholar
• Yoritaka A, Kawajiri S, Yamamoto Y, et al. Randomized, double-blind, placebo-controlled pilot trial of reduced coenzyme Q10 for Parkinson’s disease. Parkinsonism Relat Disord. 2015;21:911–916.
   PubMed Web of Science ®Google Scholar
• Fortuny A, Polo SE. The response to DNA damage in heterochromatin domains. Chromosoma. 2018;127:291–300.
   PubMed Web of Science ®Google Scholar
• Korecka JA, Moloney EB, Eggers R, et al. Repulsive Guidance Molecule a (RGMa) Induces Neuropathological and Behavioral Changes That Closely Resemble Parkinson’s Disease. J Neurosci. 2017;37:9361–9379.
   PubMed Web of Science ®Google Scholar
• Bezard E. How Lazy Reading and Semantic Sloppiness May Harm Progress in Synucleinopathy Research. Biomolecules. 2022;12(2): 228. Epub.
   PubMed Web of Science ®Google Scholar
• Müller T. What are the main considerations when prescribing pharmacotherapy for Parkinson’s disease? Expert Opin Pharmacother. 2022Feb;25:1–6.
   Google Scholar
• Kubo T, Tokita S, Yamashita T. Repulsive guidance molecule-a and demyelination: implications for multiple sclerosis. J Neuroimmune Pharmacol. 2012;7:524–528.
   PubMed Web of Science ®Google Scholar
• Mothe AJ, Tassew NG, Shabanzadeh AP, et al. RGMa inhibition with human monoclonal antibodies promotes regeneration, plasticity and repair, and attenuates neuropathic pain after spinal cord injury. Sci Rep. 2017;7:10529.
   PubMed Web of Science ®Google Scholar
• Mothe AJ, Coelho M, Huang L, et al. Delayed administration of the human anti-RGMa monoclonal antibody elezanumab promotes functional recovery including spontaneous voiding after spinal cord injury in rats. Neurobiol Dis. 2020;143:104995.
   PubMed Web of Science ®Google Scholar
• Oda W, Fujita Y, Baba K, et al. Inhibition of repulsive guidance molecule-a protects dopaminergic neurons in a mouse model of Parkinson’s disease. Cell Death Dis. 2021;12:181.
   PubMed Web of Science ®Google Scholar
• Chen J, Shifman MI. Inhibition of neogenin promotes neuronal survival and improved behavior recovery after spinal cord injury. Neuroscience. 2019;408:430–447.
   PubMed Web of Science ®Google Scholar
• Müller T, Barghorn S, Lutge S, et al. Decreased levels of repulsive guidance molecule A in association with beneficial effects of repeated intrathecal triamcinolone acetonide application in progressive multiple sclerosis patients. J Neural Transm (Vienna). 2015;122:841–848.
   PubMed Web of Science ®Google Scholar
• Nakagawa H, Ninomiya T, Yamashita T, et al. Treatment With the Neutralizing Antibody Against Repulsive Guidance Molecule-a Promotes Recovery From Impaired Manual Dexterity in a Primate Model of Spinal Cord Injury. Cereb Cortex. 2019;29:561–572.
   PubMed Web of Science ®Google Scholar
• Yang W, Sun P. Promoting functions of microRNA-29a/199B in neurological recovery in rats with spinal cord injury through inhibition of the RGMA/STAT3 axis. J Orthop Surg Res. 2020;15:427.
   PubMed Web of Science ®Google Scholar
• Korner A, Schlegel M, Kaussen T, et al. Sympathetic nervous system controls resolution of inflammation via regulation of repulsive guidance molecule A. Nat Commun. 2019;10:633.
   PubMed Web of Science ®Google Scholar
• Ngollo M, Lebert A, Dagdemir A, et al. The association between histone 3 lysine 27 trimethylation (H3K27me3) and prostate cancer: relationship with clinicopathological parameters. BMC Cancer. 2014;14:994.
   PubMed Web of Science ®Google Scholar
• Xiao B, Zhang W, Chen L, et al. Analysis of the miRNA-mRNA-lncRNA network in human estrogen receptor-positive and estrogen receptor-negative breast cancer based on TCGA data. Gene. 2018;658:28–35.
   PubMed Web of Science ®Google Scholar
• Müller T, Trommer I, Muhlack S, et al. Levodopa increases oxidative stress and repulsive guidance molecule A levels: a pilot study in patients with Parkinson’s disease. J Neural Transm (Vienna). 2016;123:401–406.
   PubMed Web of Science ®Google Scholar
• Kim M, Park YK, Kang TW, et al. Dynamic changes in DNA methylation and hydroxymethylation when hES cells undergo differentiation toward a neuronal lineage. Hum Mol Genet. 2014;23:657–667.
   PubMed Web of Science ®Google Scholar
• Li VS, Yuen ST, Chan TL, et al. Frequent inactivation of axon guidance molecule RGMA in human colon cancer through genetic and epigenetic mechanisms. Gastroenterology. 2009;137:176–187.
   PubMed Web of Science ®Google Scholar
• Li Y, Liu HT, Chen X, et al. Aberrant promoter hypermethylation inhibits RGMA expression and contributes to tumor progression in breast cancer. Oncogene. 2022;41(3):361- 371.
   PubMed Web of Science ®Google Scholar
• Müller T. Pharmacokinetics and pharmacodynamics of levodopa/carbidopa cotherapies for Parkinson’s disease. Expert Opin Drug Metab Toxicol. 2020;16:403–414. ** excellent review on levodopa cotherapies in Parkinson’s disease.
   PubMed Web of Science ®Google Scholar
• Zhao ZW, Lian WJ, Chen GQ, et al. Decreased expression of repulsive guidance molecule member A by DNA methylation in colorectal cancer is related to tumor progression. Oncol Rep. 2012;27:1653–1659.
   PubMed Web of Science ®Google Scholar
• Verschuur CVM, Suwijn SR, Boel JA, et al. Randomized Delayed-Start Trial of Levodopa in Parkinson’s Disease. N Engl J Med. 2019;380:315–324.
   PubMed Web of Science ®Google Scholar
• Espay AJ. The Final Nail in the Coffin of Disease Modification for Dopaminergic Therapies: the LEAP Trial. JAMA Neurol. 2019;76:747–748.
   PubMed Web of Science ®Google Scholar
• Leal RM, Rascol O, Ferreira JJ. The “long and winding road” of the disease-modifying effects of levodopa has not ended yet. Mov Disord. 2020;35:397–399.
   PubMed Web of Science ®Google Scholar
• Müller T, van Lt, Cornblath DR, et al. Peripheral neuropathy in Parkinson’s disease: levodopa exposure and implications for duodenal delivery. Parkinsonism Relat Disord. 2013;19:501–507.
   PubMed Web of Science ®Google Scholar