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Clinical progression in Parkinson disease and the neurobiology of axons
Open accessAbstract
Despite tremendous growth in recent years in our knowledge of the molecular basis of Parkinson disease (PD) and the molecular pathways of cell injury and death, we remain without therapies that forestall disease progression. Although there are many possible explanations for this lack of success, one is that experimental therapeutics to date have not adequately focused on an important component of the disease process, that of axon degeneration. It remains unknown what neuronal compartment, either the soma or the axon, is involved at disease onset, although some have proposed that it is the axons and their terminals that take the initial brunt of injury. Nevertheless, this concept has not been formally incorporated into many of the current theories of disease pathogenesis, and it has not achieved a wide consensus. More importantly, in view of growing evidence that the molecular mechanisms of axon degeneration are separate and distinct from the canonical pathways of programmed cell death that mediate soma destruction, the possibility of early involvement of axons in PD has not been adequately emphasized as a rationale to explore the neurobiology of axons for novel therapeutic targets. We propose that ongoing degeneration of axons, not cell bodies, is the primary determinant of clinically apparent progression of disease, and that future experimental therapeutics intended to forestall disease progression will benefit from a new focus on the distinct mechanisms of axon degeneration.
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“The diagnosis of PD is reliant on clinical motor symptoms and neuroimaging; however, by the onset of symptoms, it is estimated that 50–70% of substantia nigra pars compacta dopaminergic neurons have already been lost [247, 248].”
From Extracellular vesicles as nanotheranostic platforms for targeted neurological disorder interventions (2024) · cites this paper as [247]
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“Interestingly, it has been speculated that prevention of axonal degeneration may prevent somal demise in the clinical progression of Parkinson’s disease (Cheng et al. 2010).”
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Bicknell, B. T., Liebert, A. D., & Herkes, G. (2024) · Journal of Personalized Medicine · doi:10.3390/jpm14010112 · Cited by 41
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BackgroundRegion-Specific Defects of Respiratory Capacities in the Ndufs4(KO) Mouse Brain
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“In contrast, dopaminergic fiber loss may actually precede cell death and there may be already 50% fiber loss in the putamen at the onset of motor signs (Cheng et al., 2010).”
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“…importance of axonal degradation over programmed cell death in early PD pathology may explain the failure of anti-apoptotic kinase inhibitors to prevent disease progression, as these neuroprotective agents do not confer any sort of axonal protection or regenerative influence (Cheng et al., 2010).”
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“The advanced stage of the disease involves characteristic brain pathology and motor impairment and at this stage a significant proportion of the dopaminergic neurons in the cells involved in motor control (substantia nigra) have degenerated axons or have been lost (Cheng et al., 2010).”
BackgroundMorpho‐Functional Changes of Nigral Dopamine Neurons in an α‐Synuclein Model of Parkinson's Disease
Ledonne, A., Cenere, M. M., Paldino, E., D’Angelo, V., D’Addario, S. L., Casadei, N., Nobili, A., Berretta, N., Fusco, F. R., Ventura, R., et al. (2022) · Movement Disorders · doi:10.1002/mds.29269 · Cited by 32
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“The current view is that the slow and progressive death of SNpc mDA neurons remains asymptomatic until 30% of mDA neuron cell bodies and 50–60% of axonal terminals are lost [6].”
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“death within the substantia nigra [105], as assessed by brain MRI voxel-based morphometry examination on HC, early PD, and advanced PD patients.”
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“In Parkinson’s patients, initial signs of motor impairment appear when 50%–70% of nigrostriatal dopaminergic neurons have been lost [22,23].”
BackgroundLeão, A. H. F. F., Meurer, Y. D. S. R., Silva, A. F., Medeiros, A. M., Campêlo, C. L. D. C., Abílio, V. C., Engelberth, R. C. G. J., Cavalcante, J. S., Izídio, G. S., Ribeiro, A. M., et al. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00078 · Cited by 32
Oh, S. H., Lee, S. C., Kim, D. Y., Kim, H., Shin, J. Y., Ye, B. S., & Lee, P. H. (2017) · Stem Cells · doi:10.1002/stem.2650 · Cited by 32
Characterization of a Parkinson’s disease rat model using an upgraded paraquat exposure paradigm
Cristóvão, A. C., Campos, F. L., Je, G., Esteves, M., Guhathakurta, S., Yang, L., Beal, M. F., Fonseca, B. M., Salgado, A. J., Queiroz, J. A., et al. (2020) · European Journal of Neuroscience · doi:10.1111/ejn.14683 · Cited by 33
Neuroprotective mechanisms of red clover and soy isoflavones in Parkinson's disease models
Jacquet, A. D. R., Ambaw, A., Tambe, M. A., Ma, S. Y., Timmers, M. A., Grace, M. H., Wu, Q., Simon, J. E., McCabe, G. P., Lila, M. A., et al. (2021) · Food & Function · doi:10.1039/d1fo00007a · Cited by 32
Kalyn, M., & Ekker, M. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.718244 · Cited by 34
Naughton, C., O’Toole, D. P., Kirik, D., & Dowd, E. (2016) · Behavioural Brain Research · doi:10.1016/j.bbr.2016.08.056 · Cited by 32
“retrograde die-back disease with the pathology starting in the xonal terminals in the striatum and progressing to the cell bodies n the substantia nigra [3], we wanted to assess the effect of termial rotenone exposure on -synuclein compromised nigrostriatal erminals.”
Zhang, C., Hou, L., Yang, J., Che, Y., Sun, F., Li, H., & Wang, Q. (2018) · Cell Death and Disease · doi:10.1038/s41419-017-0091-7 · Cited by 32
“The salient features of our study are: (1) n-hexane exposure resulted in loss of dopaminergic neurons in rats; (2) microglial activation preceded dopaminergic neurodegeneration and depletion of microglia reduced HDinduced dopaminergic neurotoxicity; (3) HD exposure stimulated activation of NOX2 by inducing membrane tr…”
BackgroundAdvances in NURR1-Regulated Neuroinflammation Associated with Parkinson’s Disease
Al‐Nusaif, M., Lin, Y., Li, T., Cheng, C., & Le, W. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232416184 · Cited by 32
“Although neurodegeneration is not restricted to nigral dopaminergic neurons, it also affects cells in other areas of the neural network [5,6].”
BackgroundMarine-Derived Components: Can They Be a Potential Therapeutic Approach to Parkinson’s Disease?
Silva, J., Alves, C., Soledade, F., Martins, A., Pintéus, S., Gaspar, H., Alfonso, A., & Pedrosa, R. (2023) · Marine Drugs · doi:10.3390/md21080451 · Cited by 35
“It is estimated that at the onset of PD symptoms, approximately 50–60% of dopa inergic neurons in the SNpc are lost, and at the sa e time, there is a 70–80% loss of i e in the striatum [12].”
BackgroundWakita, S., Izumi, Y., Nakai, T., Adachi, K., Takada‐Takatori, Y., Kume, T., & Akaike, A. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.09.012 · Cited by 32
“In fact, at the onset of symptoms, the striatal dopamine content decreases to only 20%, but 50e70% of the dopaminergic cell bodies in the substantia nigra still remain (Bernheimer et al., 1973; Cheng et al., 2010; Chu et al., 2012).”
Kalyanaraman, B. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101665 · Cited by 31
“As reported, it is likely that nearly 70% or more of dopaminergic neurons were damaged in these patients [57].”
BackgroundThe Nigral Coup in Parkinson’s Disease by α-Synuclein and Its Associated Rebels
Sian‐Hülsmann, J., & Riederer, P. F. (2021) · Cells · doi:10.3390/cells10030598 · Cited by 30
“Indeed, early symptoms are evident in around 50–60% of nigro-striatal axon terminal degeneration; in contrast, there is only about 30% loss of neuromelanin (NM) containing dopaminergic neurons in the SN [6,7].”
BackgroundGenetic diversity of axon degenerative mechanisms in models of Parkinson's disease
Peters, O. M., Weiss, A., Metterville, J., Song, L., Logan, R. A., Smith, G. A., Schwarzschild, M. A., Mueller, C., Brown, R. H., & Freeman, M. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2021.105368 · Cited by 32
Carola, G., Malagarriga, D., Calatayud, C., Pons‐Espinal, M., Blasco-Agell, L., Richaud‐Patín, Y., Fernández‐Carasa, I., Baruffi, V., Beltramone, S., Molina, E., et al. (2021) · npj Parkinson s Disease · doi:10.1038/s41531-021-00198-3 · Cited by 31
Trease, A. J., George, J. W., Roland, N. J., Lichter, E. Z., Emanuel, K. M., Totusek, S., Fox, H. S., & Stauch, K. L. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.852368 · Cited by 31
“Additionally, bioenergetic deficits are common to several neurological disorders including AD (Lin and Beal, 2006; Parihar and Brewer, 2007; Rhein et al., 2009; Cheng et al., 2010; Harris et al., 2012; Pathak et al., 2013).”
BackgroundLi, L., & Zhou, F. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2012.12.065 · Cited by 32
“Therefore, it is likely that while the PD motor symptoms are treated with L-dopa, the residual DA neurons continue to degenerate (Morrish et al., 1996; Lee et al. 2004; Hilker et al., 2005; Cheng et al., 2010).”
BackgroundBäck, S., Raki, M., Tuominen, R. K., Raasmaja, A., Bergström, K., & Männistö, P. T. (2013) · EJNMMI Research · doi:10.1186/2191-219x-3-46 · Cited by 31
Nigral dopaminergic PAK4 prevents neurodegeneration in rat models of Parkinson’s disease
Won, S.-Y., Park, M.-H., You, S.-T., Choi, S.-W., Kim, H. K., McLean, C., Bae, S., Kim, S. R., Jin, B. K., Lee, K. H., et al. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aaf1629 · Cited by 31
“At the onset of symptoms in human PD, about 50% of DA neurons have already died (3, 4), suggesting that the midbrain would not provide a proliferative environment.”
BackgroundAn optimized method for counting dopaminergic neurons in zebrafish
Matsui, H., & Sugie, A. (2017) · PLoS ONE · doi:10.1371/journal.pone.0184363 · Cited by 31
Moráles, I., Sabaté, M., & Rodrı́guez, M. (2013) · European Journal of Neuroscience · doi:10.1111/ejn.12205 · Cited by 30
“…DA cells to striatal glutamate Despite increasing evidence suggesting that the DA-cell degeneration starts in their synaptic terminals at the striatum and progresses retrogradely to the substantia nigra (Cheng et al., 2010), the striatal toxicity of GLU in PD is still practically unexplored.”
BackgroundMolecular Imaging of the Dopaminergic System in Idiopathic Parkinson's Disease.
de Natale, E. D., Niccolini, F., Wilson, H., & Politis, M. (2018) · International review of neurobiology · doi:10.1016/bs.irn.2018.08.003 · Cited by 21
Howson, P. A., Johnston, T. H., Ravenscroft, P., Hill, M. P., Su, J. Y., Brotchie, J. M., & Koprich, J. B. (2019) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.118.255695 · Cited by 30
“This model does not alter overall motor activity of the macaques; however, this is not surprising since people with PDdo not exhibitmotor symptoms until striatal dopamine loss is ∼60% (Cheng et al., 2010).”
BackgroundMolecular Connections Between Circadian Clocks and Mood-related Behaviors
Albrecht, U. (2019) · Journal of Molecular Biology · doi:10.1016/j.jmb.2019.11.021 · Cited by 29
“Abnormalities in the mesolimbic pathway are associated with addiction, affective disorders, schizophrenia, and attentiondeficit hyperactivity disorder [35e37], while the degeneration of the nigrostriatal pathway can induce Parkinson's disease [38], which may be associated with some degree of depression [39,40].”
BackgroundJones-Tabah, J., Mohammad, H., Hadj-Youssef, S., Kim, L., Martin, R., Benaliouad, F., Tanny, J. C., Clarke, P. B. S., & Hébert, T. E. (2020) · Scientific Reports · doi:10.1038/s41598-020-71121-8 · Cited by 31
Neuropathology of Parkinson’s Disease
Jellinger, K. A. (2014) · Springer eBooks · doi:10.1007/978-3-319-08046-8_2 · Cited by 31
“Of note, the previous concept that PD motor symptoms fi rst appear which more than 50 % of dopaminergic SN neurons are lost [ 65 ] has recently been changed by the fi nding that at the time of fi rst diagnosis of PD, only around 30 % of dopaminergic SN neurons, but 50–60 % of their axon terminals have been lost [ 84 ].”
BackgroundAshfaque Mostafa, T., Soltaninejad, S., McIsaac, T. L., & Cheng, I. (2021) · Sensors · doi:10.3390/s21196446 · Cited by 32
“It is difficult to diagnose PD without the manifestation of motor symptoms, which are often unlikely to appear before 50% to 70% of the neurons have been damaged [8], making it difficult to administer any kind of preventive measures.”
BackgroundMediterranean Diet Adherence, Gut Microbiota and Parkinson’s Disease: A Systematic Review
Seelarbokus, B. A., Menozzi, E., Schapira, A. H. V., Kalea, A. Z., & Macnaughtan, J. (2024) · Nutrients · doi:10.3390/nu16142181 · Cited by 36
“[11,12].”
BackgroundHegarty, S. V., Sullivan, A. M., & O’Keeffe, G. W. (2018) · Neuronal Signaling · doi:10.1042/ns20170181 · Cited by 29
“In recent years, it is increasingly recognized that mDA axonal degeneration may be central to the progression of the early stages of PD [4,5].”
Glucocerebrosidase as a therapeutic target for Parkinson’s disease
Chen, Y., Sam, R., Sharma, P., Chen, L., Do, J., & Sidransky, E. (2020) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2020.1733970 · Cited by 30
Modern Brainstem MRI Techniques for the Diagnosis of Parkinson's Disease and Parkinsonisms
Arribarat, G., Barros, A. D., & Péran, P. (2020) · Frontiers in Neurology · doi:10.3389/fneur.2020.00791 · Cited by 29
“The SNc plays a pivotal role, with classic PD motor symptoms occurring when 30% or more of its dopaminergic neurons have disappeared (2).”
BackgroundERRγ ligand HPB2 upregulates BDNF-TrkB and enhances dopaminergic neuronal phenotype
Kim, H. I., Lee, S., Lim, J., Chung, S.-K., Koo, T., Ji, Y.-G., Suh, Y., Son, W. S., Kim, S., & Choi, H. J. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2021.105423 · Cited by 29
Seger, A., Ophey, A., Heitzmann, W., Doppler, C. E. J., Lindner, M., Brune, C., Kickartz, J., Dafsari, H. S., Oertel, W. H., Fink, G. R., et al. (2023) · Movement Disorders · doi:10.1002/mds.29389 · Cited by 30
“In a stage where moderate motor symptoms of PD are present, large parts of the dopaminergic neurons and their terminals are already irreversibly degenerated.(30,31) iRBD represents an early stage of α-synucleinopathy where dopaminergic and cerebral neurodegeneration has not yet progressed as far as in overt PD patient…”
BackgroundWldS but not Nmnat1 protects dopaminergic neurites from MPP+ neurotoxicity
Antenor‐Dorsey, J. A. V., & O’Malley, K. L. (2012) · Molecular Neurodegeneration · doi:10.1186/1750-1326-7-5 · Cited by 29
“Symptoms appear after 50-70% [5,6] of striatal dopamine has been depleted and 30-50% [7,8] of the nigral dopaminergic cells have died.”
Compartmentalized Platforms for Neuro-Pharmacological Research
Jadhav, A., Li, W., & Shi, P. (2015) · Current Neuropharmacology · doi:10.2174/1570159x13666150516000957 · Cited by 33
“Extensive studies focused on Parkinson’s disease, Alzheimer’s disease have suggested the involvement of axonal transport and degeneration on disease onset as well as progression [39, 40].”
BackgroundEvaluation of the Parkinson’s KinetiGraph in monitoring and managing Parkinson’s disease
Farzanehfar, P., & Horne, M. K. (2017) · Expert Review of Medical Devices · doi:10.1080/17434440.2017.1349608 · Cited by 29
“Loss of terminals impairs the capacity to synthesize and store DA [4,6,8,9].”
Gaurav, R., Valabrègue, R., Yahia‐Cherif, L., Mangone, G., Narayanan, S., Arnulf, I., Vidailhet, M., Corvol, J., & Lehéricy, S. (2022) · NeuroImage Clinical · doi:10.1016/j.nicl.2022.103250 · Cited by 29
“The motor symptoms start to show up when the dopaminergic (DA) neuronal loss reaches a threshold of 30 % to 60 % (Cheng et al., 2010; Fearnley and Lees, 1991; Greffard et al., 2006; Hornykiewicz, 1998; Kish et al., 1988).”
Belur, N. R., Bustos, B. I., Lubbe, S. J., & Mazzulli, J. R. (2024) · Neuron · doi:10.1016/j.neuron.2024.05.003 · Cited by 28
Ranasinghe, T., Seo, Y., Park, H., Choe, S., & Cha, S. (2024) · Journal of Hazardous Materials · doi:10.1016/j.jhazmat.2024.136215 · Cited by 27
Synaptic sabotage: How Tau and α-Synuclein undermine synaptic health
Uytterhoeven, V., Verstreken, P., & Nachman, E. (2024) · The Journal of Cell Biology · doi:10.1083/jcb.202409104 · Cited by 29
Alieva, A. K., Rudenok, M. M., Filatova, E. V., Karabanov, A. V., Doronina, O. B., Doronina, K. S., Kolacheva, A. A., Ugrumov, M. V., Illarioshkin, S. N., Slominsky, P. A., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-57938-3 · Cited by 27
Metadata
- Authors
- Cheng, H., Ulane, C. M., & Burke, R. E.
- Affiliations
- Columbia University Irving Medical Center (US)
- Corresponding author
- Burke, Robert E.
- ORCID
- Burke, Robert E.
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2010-05-26
- Volume
- 67
- Issue
- 6
- Pages
- 715-725
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- PMC
- PMC2918373
- OpenAlex
- W1967659552
- Cited by
- 1,012
- References
- 77
- Citations by year
- 2026: 56 · 2025: 74 · 2024: 101 · 2023: 92 · 2022: 108 · 2021: 109 · 2020: 100 · 2019: 82 · 2018: 67 · 2017: 59 · 2016: 35 · 2015: 36 · 2014: 24 · 2013: 22 · 2012: 23
- FWCI
- 12.98
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (NS26836, P50NS038370, R56NS026836, NS38370, R01NS026836)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Keywords
- Parkinson's disease, axonal degeneration, disease progression, axonal injury, programmed cell death, therapeutic target, pathogenesis, axon terminals
- MeSH terms
- Axons, Humans, Neurobiology, Neurons, Parkinson Disease, Disease Progression
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