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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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“By the time a clinical diagnosis is confirmed, a significant proportion of dopaminergic neurons have degenerated (1, 2).”
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Neuropsychological aspects of impulse control disorders in Parkinson’s disease
Scanferla, L., & Djamshidian, A. (2026) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2026.1768251 · Cited by 3
“The disease is more common in men and typically manifests in older adults, with a median age of onset at 60 years (Cheng et al., 2010; Dorsey et al., 2018). to frequency, assessing both presence and severity of ICDs and therefore increasing clinical utility (Weintraub et al., 2012).”
Swain, C. C., Prevoznik, S., Kalbus, J. A., Pokharel, D., Beligala, D. H., Jain, P., Reddy, M. V. S. R. R., Popovich, C., Russell, J. A., & Subramanian, T. (2026) · NeuroToxicology · doi:10.1016/j.neuro.2026.103433 · Cited by 3
Distinctive characteristics of dopamine neuron release mechanisms: Insights into Parkinson’s Disease
Martino, E. D., Maduro, S., Luchicchi, A., Wilhelmus, M. M. M., & Orefice, N. S. (2026) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2026.119534 · Cited by 3
Meng, Y., Zhang, J., Fan, R., Pang, W., Zeng, W., Guo, Q., Han, X., Liu, Y., & Luo, G. (2025) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2025.102506 · Cited by 3
Identification of a circRNA-miRNA-mRNA interactome associated with Parkinson's disease progression
Shrestha, L., & Leier, A. (2025) · Journal of Parkinson s Disease · doi:10.1177/1877718x251331930 · Cited by 4
“7 Moreover, it has been estimated that the onset of motor symptoms occurs with a loss of at least 30% of total dopaminergic neurons in the SN. 8 Approximately 90,000 people over the age of 65 are diagnosed annually, and with no cure identi fi ed, the annual economic burden of PD care is estimated at $52 billion in the…”
Bublíková, I., Mareček, S., Krajča, T., Malá, C., Dušek, P., & Krupička, R. (2025) · Applied Sciences · doi:10.3390/app15147902 · Cited by 3
Alae, A., Aouraghe, I., Khaissidi, G., Mrabti, M., Aboulem, G., & Belahsen, F. (2021) · Biomedical Signal Processing and Control · doi:10.1016/j.bspc.2021.102429 · Cited by 3
Müller, T. H. (2021) · Biologics · doi:10.2147/btt.s267281 · Cited by 4
Bose, S., Nag, T. C., Dey, S., Sundd, M., & Jain, S. (2022) · Annals of Neurosciences · doi:10.1177/09727531221117634 · Cited by 3
de Leeuw, V. C., van Oostrom, C. T. M., Zwart, E., Heusinkveld, H. J., & Hessel, E. V. S. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24043608 · Cited by 3
“Clinical features of PD are typically seen when 60–70% of dopaminergic neurons in the SNpc are lost [7,8].”
BackgroundAberrant somatic calcium channel function in cNurr1 and LRRK2-G2019S mice
Skiteva, O., Yao, N., Mantas, I., Zhang, X., Perlmann, T., Svenningsson, P., & Chergui, K. (2023) · npj Parkinson s Disease · doi:10.1038/s41531-023-00500-5 · Cited by 3
McDonald, K. O., Lyons, N. M. A., Gray, L. K. C., Xu, J. B., Schoderboeck, L., Hughes, S. M., & Basak, I. (2024) · Cells · doi:10.3390/cells13121016 · Cited by 3
“In Parkinson’s disease, a major limitation in finding a cure is that by the time of death of the patient, 60–80% of the dopaminergic neurons are dead [32].”
BackgroundSequestosome-1 (SQSTM1/p62) as a target in dopamine catabolite-mediated cellular dyshomeostasis
Masato, A., Andolfo, A., Favetta, G., Bellini, E. N., Cogo, S., Valle, L. D., Boassa, D., Greggio, E., Plotegher, N., & Bubacco, L. (2024) · Cell Death and Disease · doi:10.1038/s41419-024-06763-x · Cited by 6
“This is caused by the progressive loss of the nigrostriatal neurons in the central nervous system with more than 80% decrease in dopamine release within the striatum [3].”
BackgroundSchade, S., Ghosh, S., Garrido, A., Mahlknecht, P., Marques, T. M., Horlings, C. G. C., Jónsdóttir, S. R., Lang, E., Pauly, C., Rege, K., et al. (2025) · npj Parkinson s Disease · doi:10.1038/s41531-025-01008-w · Cited by 3
“…for the failure of putative neuroprotective strategies is that by the time PD is diagnosed through motor symptoms, a majority of dopaminergic neurons of the substantia nigra is already degenerated 2,3 and the disease is far too advanced to compensate for the progressing dopaminergic de fi cit.”
InfluentialYeo, S. S., & Seo, J. P. (2020) · The Journal of Korean Physical Therapy · doi:10.18857/jkpt.2020.32.6.388 · Cited by 3
Renko, J., Voutilainen, M. H., Visnapuu, T., Sidorova, Y. A., Saarma, M., & Tuominen, R. K. (2020) · PubMed · Cited by 3
A Repulsive Environment Induces Neurodegeneration of Midbrain Dopaminergic Neurons
Santiago-Lopez, A. J. (2018) · Journal of Neuroscience · doi:10.1523/jneurosci.3070-17.2017 · Cited by 3
“This loss precedes motor symptoms (Cheng et al., 2010; Dijkstra et al., 2015; Tagliaferro and Burke, 2016).”
Editorial: The synaptic basis of neuropathology
Nugent, F. S., Kirkwood, A., Lupica, C. R., & Sjöström, P. J. (2022) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2022.1043480 · Cited by 3
“Synaptic degeneration occurs early in many neurodegenerative pathologies such as Huntington’s and Parkinson’s diseases (Cheng et al., 2010; Milnerwood and Raymond, 2010), but the mechanisms of synaptic dysfunction and loss are not well-understood.”
BackgroundMcGregor, J. N., Farris, C. A., Ensley, S., Schneider, A. M., Wang, C., Liu, Y., Tu, J., Elmore, H., Ronayne, K. D., Weßel, R., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.09.01.555947 · Cited by 3
“Similarly, in Parkinson’s Disease, symptoms emerge only after significant cell death (Cheng et al., 2010).”
BackgroundSchuler, M., Gerwert, G., Mann, M., Woitzik, N., Langenhoff, L., Hubert, D., Duman, D., Höveler, A., Galkowski, S., Simon, J., et al. (2024) · medRxiv · doi:10.1101/2024.09.02.24312694 · Cited by 3
“4 Unlike Alzheimer's disease (AD), blood-based biomarkers and positron emission tomography (PET) for diagnosis are subject to ongoing research and have not yet been well established for αSyn.”
BackgroundSharma, C., Kim, S., Eo, H., & Kim, S. R. (2024) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-24-00724 · Cited by 2
Wu, Y., Guo, Q., Gan, J., Duan, L., Zhao, H., Tai, H., Yang, C., Li, Y., Xu, Z., Yao, Y., et al. (2025) · Brazilian Journal of Medical and Biological Research · doi:10.1590/1414-431x2025e14282 · Cited by 2
Targeting protein kinases in Parkinson’s disease: the emerging role of phytoconstituents
Joshi, D., Kulkarni, M., Parekh, P., Shah, S., Greig, N. H., & Acharya, S. P. (2025) · Nutritional Neuroscience · doi:10.1080/1028415x.2025.2531356 · Cited by 4
“In humans, motor symptoms, such as resting tremor, rigidity, and bradykinesia typically emerge after depletion of more than 30% of dopaminergic neurons in the SN and depletion of 70% dopamine terminals in the caudate [3 – 5].”
Bidirectional Relationship between the BDNF Gene and miRNA: Implications for PD Pathogenesis
Elangovan, A., Iyer, M., HariKrishnaReddy, D., Wander, A., Kinoshita, M., Krishnan, J., & Vellingiri, B. (2025) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.5c00173 · Cited by 4
Neuroprotective effects of chemical constituents from Nicotiana tabacum L. in Parkinson’s disease
Zang, H., Bai, X., Sui, X., Zhai, X.-R., Wang, Y., Yin, Q., Yin, Q.-Y., Hao, X., Wang, Y.-H., Liao, X., et al. (2025) · Natural Products and Bioprospecting · doi:10.1007/s13659-025-00541-8 · Cited by 2
Baruah, B., Kumar, A., & Halder, A. (2025) · Cognitive Computation · doi:10.1007/s12559-025-10515-0 · Cited by 2
“However, disease development is initiated long before the clinical symptoms are visible or suf-ficiently detectable [11, 12].”
Dopamine neurotransmission in Parkinson's disease
Cramb, K. M. L., Noor, H., Wade-Martins, R., & Cragg, S. J. (2025) · Handbook of behavioral neuroscience · doi:10.1016/b978-0-443-21992-4.00012-9 · Cited by 2
Intersectins as versatile scaffolds for membrane-associated processes
Hilse, A., & Maritzen, T. (2026) · Biological Chemistry · doi:10.1515/hsz-2025-0228 · Cited by 2
“In fact, PD is characterized by the degeneration of dopaminergic neurons leading to a decreased dopamine release in the striatum and subsequent alterations in neurotransmission (Cheng et al. 2010; Spargo et al. 2025).”
Feng, B.-D., Qin, J., Qin, Q.-Q., Xu, Z.-C., & Zhang, H. (2026) · Annals of Medicine · doi:10.1080/07853890.2026.2619216 · Cited by 2
“In animal models of PD, CBD reduces neuroinflammation by activating GPR3, thereby protecting dopaminergic neurons from damage [33,35], However, the mechanism of its therapeutic effect is still unclear.”
Approaches for the delivery of anti-parkinsonian therapeutic agents via the intranasal route
Banyyounes, J., & Obeid, M. A. (2026) · Discover Neuroscience · doi:10.1186/s13064-026-00258-5 · Cited by 2
From Stress to Neurodegeneration: A New Look at the Pathogenesis of Parkinson’s Disease
Kazanskaya, R. B., Tsytsarev, V., Volnova, A. B., Gainetdinov, R. R., & Lopachev, A. V. (2026) · Biomedicines · doi:10.3390/biomedicines14051130 · Cited by 2
“Parkinson’s disease is generally diagnosed only when around 30% of dopaminergic neurons in the substantia nigra have already been lost [6], and is characterized by an extensive prodromal stage that can last for decades [7].”
de Gomes, M. G., Goes, A. T. R., Fabbro, L. D., Souza, L. C., Ladd, A. A. B. L., Ladd, F. V. L., Boeira, S. P., & Jessé, C. R. (2022) · Learning and Motivation · doi:10.1016/j.lmot.2022.101847 · Cited by 2
Yaghoobi, A., Seyedmirzaei, H., & Ala, M. (2023) · Parkinson s Disease · doi:10.1155/2023/2893662 · Cited by 3
“Te diagnosis of PD is not usually made until at least 30% of dopaminergic neurons and 50–60% of their axon terminals in substantia nigra are lost [5].”
Background
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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