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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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InfluentialOral administration of Proteus mirabilis damages dopaminergic neurons and motor functions in mice
Choi, J. G., Kim, N., Ju, I. G., Eo, H., Lim, S.-M., Jang, S.-E., Kim, D.-H., & Oh, M. S. (2018) · Scientific Reports · doi:10.1038/s41598-018-19646-x · Cited by 170
Kadkhodaei, B., Alvarsson, A., Schintu, N., Ramsköld, D., Volakakis, N., Joodmardi, E., Yoshitake, T., Kehr, J., Decressac, M., Björklund, A., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1221077110 · Cited by 168
“Nurr1 ablation also results in a distinct fiber pathology that affects both dendrites and axons, which is interesting in light of PD studies identifying axon degeneration as an early event in disease progression (4).”
BackgroundInfluentialPham, A. H., Meng, S., Chu, Q. N., & Chan, D. C. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds311 · Cited by 170
“Cultures were fed three times a week using the Stoppini media (37).”
BackgroundMethodInfluentialmicroRNA Profiles in Parkinson's Disease Prefrontal Cortex
Hoss, A. G., Labadorf, A., Beach, T. G., Latourelle, J. C., & Myers, R. H. (2016) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2016.00036 · Cited by 168
Nandhagopal, R., Kuramoto, L., Schulzer, M., Mak, E., Cragg, J. J., McKenzie, J., McCormick, S., Ruth, T. J., Sossi, V., de la Fuente‐Fernández, R., et al. (2011) · Brain · doi:10.1093/brain/awr233 · Cited by 167
MR Biomarkers of Degenerative Brain Disorders Derived From Diffusion Imaging
Andica, C., Kamagata, K., Hatano, T., Saito, Y., Ogaki, K., Hattori, N., & Aoki, S. (2019) · Journal of Magnetic Resonance Imaging · doi:10.1002/jmri.27019 · Cited by 175
“Thus, DKI and NODDI appear to be more sensitive than the DTI parameters for the detection of GM abnormalities in PD.”
BackgroundInfluentialThe medical treatment of Parkinson disease from James Parkinson to George Cotzias
Fahn, S. (2014) · Movement Disorders · doi:10.1002/mds.26102 · Cited by 162
“(More recently, Burke and his colleagues, reviewing newer evidence from postmortem and PET studies, have concluded that the threshold of nigral neuron loss is only approximately 30% before parkinsonian symptoms are manifested.(95))”
BackgroundHaddad, D., & Nakamura, K. (2015) · FEBS Letters · doi:10.1016/j.febslet.2015.10.021 · Cited by 167
Ba, F., & Martin, W. R. W. (2014) · Parkinsonism & Related Disorders · doi:10.1016/j.parkreldis.2014.11.007 · Cited by 160
“There is a known gradient of dopaminergic dysfunction in PD, starting in the posterior putamen progressing anteriorly to caudate contralateral to the affected limbs, with later involvement of the putamen and caudate in the ipsilateral side as demonstrated by DAT imaging [16,17] and post-mortem pathological studies [18…”
A Cortical Pathogenic Theory of Parkinson’s Disease
Foffani, G., & Obeso, J. A. (2018) · Neuron · doi:10.1016/j.neuron.2018.07.028 · Cited by 167
Pathak, D., Berthet, A., & Nakamura, K. (2013) · Annals of Neurology · doi:10.1002/ana.24014 · Cited by 162
Nuber, S., Harmuth, F., Kohl, Z., Adame, A., Trejo, M., Schönig, K., Zimmermann, F., Bauer, C. C., Casadei, N., Giel, C., et al. (2013) · Brain · doi:10.1093/brain/aws358 · Cited by 161
Metformin rescues Parkinson’s disease phenotypes caused by hyperactive mitochondria
Mor, D. E., Sohrabi, S., Kaletsky, R. L., Keyes, W., Tartici, A., Kalia, V., Miller, G. W., & Murphy, C. T. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2009838117 · Cited by 155
Neuronal mitochondria transport Pink1 mRNA via synaptojanin 2 to support local mitophagy
Harbauer, A. B., Hees, J. T., Wanderoy, S., Segura, I., Gibbs, W., Cheng, Y., Ordonez, M., Cai, Z., Cartoni, R., Ashrafi, G., et al. (2022) · Neuron · doi:10.1016/j.neuron.2022.01.035 · Cited by 156
Rabie, H., Zhang, Y., Pasquale, N. J., Lagos, M. J., Batson, P. E., & Lee, K. (2019) · Advanced Materials · doi:10.1002/adma.201806991 · Cited by 155
Sundaram, S., Hughes, R. L., Peterson, E., Müller-Oehring, E. M., Brontë-Stewart, H. M., Poston, K. L., Faerman, A., Bhowmick, C., & Schulte, T. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.05.016 · Cited by 152
“While conservative estimates suggest the occurrence of motor symptoms after a 50-70% loss of dopaminergic neurons (Cheng et al., 2010), other recent studies have demonstrated that motor symptoms can become apparent with dopaminergic neuronal loss as low as 29% (Greffard et al., 2006).”
BackgroundVilaça-Faria, H., Salgado, A. J., & Teixeira, F. G. (2019) · Cells · doi:10.3390/cells8020118 · Cited by 154
“In fact, the literature shows that, at the time of the motor symptoms onset, 30% of the SNpc’ DAn are lost, while 50–60% of the axon terminals in the STR are already degenerated [26].”
BackgroundInterleukin-17A: The Key Cytokine in Neurodegenerative Diseases
Chen, J., Liu, X., & Zhong, Y. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.566922 · Cited by 157
“Before the onset of symptoms, there is a massive loss of dopamineproducing neurons in the substantia nigra (Cheng et al., 2010).”
BackgroundClinical and imaging evidence of brain-first and body-first Parkinson's disease
Horsager, J., Knudsen, K., & Sommerauer, M. (2022) · Neurobiology of Disease · doi:10.1016/j.nbd.2022.105626 · Cited by 164
Regulation of motor proteins, axonal transport deficits and adult-onset neurodegenerative diseases
Brady, S. T., & Morfini, G. A. (2017) · Neurobiology of Disease · doi:10.1016/j.nbd.2017.04.010 · Cited by 150
Narbute, K., Piļipenko, V., Pupure, J., Dzirkale, Z., Jonavičė, U., Tunaitis, V., Kriaučiūnaitė, K., Jarmalavičiūtė, A., Jansone, B., Kluša, V., et al. (2019) · Stem Cells Translational Medicine · doi:10.1002/sctm.18-0162 · Cited by 150
Neuronal autophagy and mitophagy in Parkinson's disease
Lizama, B. N., & Chu, C. T. (2021) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2021.100972 · Cited by 152
Decressac, M., Mattsson, B., & Björklund, A. (2012) · Experimental Neurology · doi:10.1016/j.expneurol.2012.02.012 · Cited by 158
“ex classically described as a neurodegenerative disease clinically diagnosed by the cardinal motor symptoms when about 30–50% of the nigral DA neurons and 60–70% of the striatal terminals are lost, as assessed by post-mortem analyses and imaging techniques (Cheng et al., 2010).”
Nuber, S., Rajsombath, M. M., Minakaki, G., Winkler, J., Müller, C. P., Ericsson, M., Caldarone, B. J., Dettmer, U., & Selkoe, D. J. (2018) · Neuron · doi:10.1016/j.neuron.2018.09.014 · Cited by 153
Dopaminergic pathway reconstruction by Akt/Rheb‐induced axon regeneration
Kim, S. R., Chen, X. M., Oo, T. F., Kareva, T., Yarygina, O., Wang, C., During, M. J., Kholodilov, N. G., & Burke, R. E. (2011) · Annals of Neurology · doi:10.1002/ana.22383 · Cited by 144
“However, even if these findings are confined to the dopaminergic nigrostriatal projection, they nevertheless have implications for the treatment of Parkinson’s disease, which has been proposed to initially involve axons, and in which even partial reinnervation may be sufficient to restore normal motor function.(34) Bo…”
BackgroundSelf-citationStrategies for the Treatment of Parkinson’s Disease: Beyond Dopamine
Iarkov, A., Barreto, G. E., Grizzell, J. A., & Echeverrı́a, V. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.00004 · Cited by 146
“Given that PD genesis is multifactorial and depends mainly on the age of disease onset (Marsden, 1990; Cheng et al., 2010; Okun, 2017), the prognosis is highly variable, and personalized treatment regimens are theoretically possible.”
BackgroundSynapses: The Brain’s Energy-Demanding Sites
Faria‐Pereira, A., & Morais, V. A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23073627 · Cited by 152
“On the other hand, the onset of neurodegenerative disorders (NDs) is associated with synaptic energy deficits, mitochondrial dysfunction and, ultimately, synaptic degeneration, which precedes neuronal loss [166,167], reviewed in [7–9].”
BackgroundNLRP3 inflammasome in neurodegenerative disease
Anderson, F. L., Biggs, K. E., Rankin, B. E., & Havrda, M. C. (2022) · Translational research · doi:10.1016/j.trsl.2022.08.006 · Cited by 154
McKinley, J. W., Shi, Z., Kawikova, I., Hur, M., Bamford, I. J., Sudarsana Devi, S. P., Vahedipour, A., Darvas, M., & Bamford, N. S. (2019) · Neuron · doi:10.1016/j.neuron.2019.06.013 · Cited by 130
“While no available model fulfils criteria for PD (Burke, 2004), L-dopa-responsive Slc6a3DTR/+ mice emulate human PD, where a ~30% loss in DA is expected at the onset of motor symptoms and a 60% to 80% loss is present at the time of death (Cheng et al., 2010).”
BackgroundAkt Suppresses Retrograde Degeneration of Dopaminergic Axons by Inhibition of Macroautophagy
Cheng, H.-C., Kim, S. R., Oo, T. F., Kareva, T., Yarygina, O., Rzhetskaya, M., Wang, C., During, M. J., Tallóczy, Z., Tanaka, K., et al. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.5519-10.2011 · Cited by 138
“Indeed, for both of these disorders some have proposed that axons and their synaptic terminals are the initial locus of the disease process and that it is this pathology, not the loss of neurons, that results in the first manifestations and clinical progression of disease (Hornykiewicz, 1998; Selkoe, 2002; Cheng et al…”
BackgroundSelf-citationMagnetothermal nanoparticle technology alleviates parkinsonian-like symptoms in mice
Hescham, S., Chiang, P., Gregureć, D., Moon, J., Christiansen, M. G., Jahanshahi, A., Liu, H., Rosenfeld, D., Pralle, A., Anikeeva, P., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-25837-4 · Cited by 137
Spatiotemporal changes in substantia nigra neuromelanin content in Parkinson’s disease
Biondetti, E., Gaurav, R., Yahia‐Cherif, L., Mangone, G., Pyatigorskaya, N., Valabrègue, R., Ewenczyk, C., Hutchison, M., François, C., Arnulf, I., et al. (2020) · Brain · doi:10.1093/brain/awaa216 · Cited by 134
“Here, the measured loss in SN at diagnosis was lower than the 30– 50% calculated using histology-based neuronal counts (Fearnley and Lees, 1991; Greffard et al., 2006; Cheng et al., 2010) and slightly lower than the 30–34% reported by measuring striatal presynaptic dopamine function in patients with approximately the…”
BackgroundResultIn vivo imaging of neuromelanin in Parkinson’s disease using18F-AV-1451 PET
Hansen, A. K., Knudsen, K., Lillethorup, T. P., Landau, A. M., Parbo, P., Fedorova, T., Audrain, H., Bender, D., Østergaard, K., Brooks, D. J., et al. (2016) · Brain · doi:10.1093/brain/aww098 · Cited by 128
Grosch, J., Winkler, J., & Kohl, Z. (2016) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2016.00293 · Cited by 132
“At present, neuro-pathological and -imaging findings suggest that at the onset of motor symptoms in PD the loss of striatal or putaminal dopaminergic projections largely exceeds that of dopaminergic SN neurons, again supporting the hypothesis of a “dying back” of axons to their dopaminergic perikarya in PD (Cheng et a…”
BackgroundResultParkinson's disease: convergence on synaptic homeostasis
Soukup, S., Vanhauwaert, R., & Verstreken, P. (2018) · The EMBO Journal · doi:10.15252/embj.201898960 · Cited by 131
“…accumulate at presynaptic terminals (Kramer & Schulz-Schaeffer, 2007) and additional neuroanatomical studies of post-mortem patient brain samples from familial PD cases support the idea that synaptic decay precedes neuronal death (Hornykiewicz, 1998; Cheng et al, 2010; Burke & O’Malley, 2013).”
BackgroundInfectious Etiologies of Parkinsonism: Pathomechanisms and Clinical Implications
Limphaibool, N., Iwanowski, P. S., Holstad, M. J. V., Kobylarek, D., & Kozubski, W. P. (2019) · Frontiers in Neurology · doi:10.3389/fneur.2019.00652 · Cited by 131
The necroptosis machinery mediates axonal degeneration in a model of Parkinson disease
Oñate, M., Catenaccio, A., Salvadores, N., Saquel, C., Martinez, A. N., Moreno‐González, I., Gamez, N., Rudolffi-Soto, P., Soto, C. A., Hetz, C. A., et al. (2019) · Cell Death and Differentiation · doi:10.1038/s41418-019-0408-4 · Cited by 133
Neuroimaging and fluid biomarkers in Parkinson’s disease in an era of targeted interventions
Zarkali, A., Thomas, G. E. C., Zetterberg, H., & Weil, R. S. (2024) · Nature Communications · doi:10.1038/s41467-024-49949-9 · Cited by 131
“By the time motor symptoms present in PD, extensive loss of dopaminergic neurons in the substantia nigra (SN) has already occured 39 .”
BackgroundPatricio, F., Morales-Andrade, A. A., Patricio-Martínez, A., & Limón, I. D. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.595635 · Cited by 129
“This finding is important for understanding the modulatory role of CBD in PD, as 90% of dopaminergic neuronal death occurs in PD (Cheng et al., 2010), FIGURE 4 | The basal ganglia network and its wide expression of receptors in presynaptic neurons.”
BackgroundFarrand, A. Q., Helke, K. L., Gregory, R. A., Gooz, M. B., Hinson, V. K., & Boger, H. A. (2017) · Brain stimulation · doi:10.1016/j.brs.2017.08.008 · Cited by 130
Neuropathology of incidental Lewy body & prodromal Parkinson’s disease
Koeglsperger, T., Rumpf, S.-L., Schließer, P., Struebing, F. L., Brendel, M., Levin, J., Trenkwalder, C., Höglinger, G. U., & Herms, J. W. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00622-7 · Cited by 145
“Moreover, neuroanatomical studies of post mortem brain samples from familial PD cases support the idea that synaptic decay precedes neuronal death [131, 132].”
Result
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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