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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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“Available evidence based on neuropathological and imaging studies indicates that this neuronal loss begins years before motor manifestations of PD are fully manifest.(26) As in other studies,(1,23,27,28) olfactory dysfunction was greater in those who received an aSN diagnosis, and orthostatic hypotension more prevalen…”
BackgroundMelatonin as a Chronobiotic and Cytoprotective Agent in Parkinson’s Disease
Perez‐Lloret, S., & Cardinali, D. P. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.650597 · Cited by 66
“Since a loss of 50–80% of dopaminergic neurons in the substantia nigra pars compacta is needed for the first motor signs occur (Cheng et al., 2010), Edited by:”
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“However, it is estimated that motor symptoms begin to appear when > 30% of dopaminergic neurons have been degenerated [6].”
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BackgroundInfluentialSex is a defining feature of neuroimaging phenotypes in major brain disorders
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The astrocytic response to the dopaminergic denervation of the striatum
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Oligomeric α-Synuclein Is Increased in Basal Tears of Parkinson’S Patients
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Parkinson's disease – genetic cause
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Glucocerebrosidase modulates cognitive and motor activities in murine models of Parkinson’s disease
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“PD is characterized by progressive degeneration of the dopaminergic terminals, which precedes the neuronal cell loss (49).”
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Cilento, E. M., Jin, L., Stewart, T., Shi, M., Sheng, L., & Zhang, J. (2019) · Journal of Neurochemistry · doi:10.1111/jnc.14635 · Cited by 60
Serotonin 1A Receptors on Astrocytes as a Potential Target for the Treatment of Parkinson’s Disease
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“…in mouse models of PD and is observed in brains of PD patients, where the loss of dopamine is significantly greater in the striatum than in the substantia nigra and DA axons and their terminals appear to be the earliest and principal site of PD pathology (Cheng et al., 2010; Hornykiewicz, 1966).”
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Airavaara, M., Parkkinen, I., Konovalova, J., Albert, K., Chmielarz, P., & Domanskyi, A. (2020) · Current Protocols in Neuroscience · doi:10.1002/cpns.88 · Cited by 61
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“SN changes are considered an important landmark in the progression of PD because progressive dopaminergic neuron loss (up to 70% of dopamine neurons have been lost by the time of the first diagnosis) in this area leads to the motor symptoms of PD (Cheng et al., 2010).”
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“The brain has a remarkable ability to compensate for the loss of nigrostriatal fibers: It is estimated that up to 50–80% of dopaminergic cells in the nigrostriatal system can be lost before motor symptoms manifest [9–11].”
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“degeneration in PD occurs at the level of the striatal terminals, followed subsequently by cell loss in the SN (34,35).”
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“Degeneration of dopaminergic neurons in the substantia nigra pars compacta, as observed here, is typically considered to be the hallmark neuropathological feature of Parkinson’s disease [80], but multiple lines of evidence from anatomical and imaging studies indicate that cell loss or cell dysfunction in other brain r…”
BackgroundParkinson's disease: connecting mitochondria to inflammasomes
Lawrence, G. M. E. P., Holley, C. L., & Schroder, K. (2022) · Trends in Immunology · doi:10.1016/j.it.2022.09.010 · Cited by 57
Mitochondrial dysfunction induces dendritic loss via eIF2α phosphorylation
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“Mitochondrial dysfunction in these diseases and their models results in a variety of neuropathological events, including neuronal loss, axonal degeneration, and dendritic pathology (Patt et al., 1991; Cheng et al., 2010).”
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“Motor deficits are a salient feature of PD and become apparent in patients with ongoing DA neurodegeneration after an approximate 80% loss of striatal dopamine content (Cheng et al., 2010).”
Tapias, V., McCoy, J. L., & Greenamyre, J. T. (2019) · Redox Biology · doi:10.1016/j.redox.2019.101164 · Cited by 57
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“In contrast, targeted attention to such early neurite pathology prior to alterations in cell soma(33,64) may pave the way to detect earlier and more clinically relevant manifestations of various neurological diseases for early therapeutic intervention.(23,84) Such attention to neurite pathology, called “nexopathy”,(85…”
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Is Cell Death Primary or Secondary in the Pathophysiology of Idiopathic Parkinson’s Disease?
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“degeneration exceeds the nigral neuron loss by 100% [81].”
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“A recent assessment of available data further supports the idea that the loss of striatal dopaminergic axon terminals can indeed be an early and dominant feature of PD, as the extent of loss of striatal dopaminergic markers largely exceeds that of SNpc mDA neuron loss at the time of motor symptom onset [24,77,78].”
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“However, it is well established that the overwhelming majority of dopamine (DA) neurons of the substantia nigra pars compacta (SNpc) and dopaminergic (DAergic) innervation to the putamen already have succumbed to degeneration at later stages of the disease (Cheng et al., 2010; Kordower et al., 2013).”
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BackgroundInfluentialNeuroprotection of Exendin-4 by Enhanced Autophagy in a Parkinsonian Rat Model of α-Synucleinopathy
Bu, L.-L., Liu, Y., Shen, Y., Fan, Y., Yu, W., Jiang, D., Tang, Y., Yang, Y., Wu, P., Zuo, C., et al. (2021) · Neurotherapeutics · doi:10.1007/s13311-021-01018-5 · Cited by 54
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“1988; Hornykiewicz 1966), although more recent studies suggest that only ∼30% of substantia nigra DA neurons and around 50–60% of their axon terminals have been lost when motor signs first appear (Cheng et al. 2010).”
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Loss of nigral excitation of cholinergic interneurons contributes to parkinsonian motor impairments
Cai, Y., Nielsen, B. E., Boxer, E. E., Aoto, J. N., & Ford, C. (2021) · Neuron · doi:10.1016/j.neuron.2021.01.028 · Cited by 55
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“In late-stage PD, as much as 95% of these neurons may be lost (Burke and O’Malley, 2013; Cheng et al., 2010).”
BackgroundExtracellular Vesicles for the Diagnosis of Parkinson's Disease: Systematic Review and Meta‐Analysis
Xylaki, M., Chopra, A., Weber, S., Bartl, M., Outeiro, T. F., & Mollenhauer, B. (2023) · Movement Disorders · doi:10.1002/mds.29497 · Cited by 53
“irreversible loss of the majority of central dopaminergic neurons.(1) Thus far, clinical trials of potentially neuro-”
BackgroundCharacterization of a new low‐dose 6‐hydroxydopamine model of Parkinson's disease in rat
Penttinen, A., Suleymanova, I., Albert, K., Anttila, J. E., Voutilainen, M. H., & Airavaara, M. (2016) · Journal of Neuroscience Research · doi:10.1002/jnr.23708 · Cited by 49
“The literature suggests that the degeneration of striatal axons and terminals outweighs cell loss in the SN not only at the onset of motor symptoms but also in the later stage of the disease (Kish et al., 1988; Fearnley and Lees, 1991; Cheng et al., 2010; Burke and O’Malley, 2013).”
BackgroundSingh, B., Pandey, S., Rumman, M., Kumar, S., Kushwaha, P. P., Verma, R., & Mahdi, A. A. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.616413 · Cited by 49
“Moreover, PD also affects cognition,mental state, sleep, personality, and behavior leading to depression and anxiety (Cheng et al., 2010).”
BackgroundA microdevice platform for visualizing mitochondrial transport in aligned dopaminergic axons
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“The loss of striatal terminals is suggested to precede dopaminergic cell loss in PD [61]; therefore, striatal degeneration in Thy1-aSyn mice together with the behavioral readouts provides a platform to test drugs which modify the underlying pathogenic processes.”
BackgroundChoi, W., Kim, H.-W., Tronche, F., Palmiter, R. D., Storm, D. R., & Xia, Z. (2017) · Scientific Reports · doi:10.1038/srep44989 · Cited by 49
Neuropathology of Nonmotor Symptoms of Parkinson's Disease
Jellinger, K. A. (2017) · International review of neurobiology · doi:10.1016/bs.irn.2017.05.005 · Cited by 50
Development and Differentiation of Midbrain Dopaminergic Neuron: From Bench to Bedside
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“The loss of dopaminergic neurons in the SNc of nearly 30% with a 50–60% decrease of dopamine secretion in the corpus striatum is common in the majority of PD patients with the onset of motor dysfunctions [5,6], suggesting high severity of disease progression even at the first initial diagnosis.”
BackgroundAcylated Ghrelin as a Multi-Targeted Therapy for Alzheimer's and Parkinson's Disease
Reich, N., & Hölscher, C. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.614828 · Cited by 48
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“This lack of reliable diagnostic tools also obstructs efforts to assess disease-modifying treatments during the prodromal stages, a critical period where majority of neuronal death occurs [6].”
Clinical and diagnostic implications of Alzheimer's disease copathology in Lewy body disease
Barba, L., Abu‐Rumeileh, S., Barthel, H., Massa, F., Foschi, M., Bellomo, G., Gaetani, L., Thal, D. R., Parnetti, L., & Otto, M. (2024) · Brain · doi:10.1093/brain/awae203 · Cited by 52
Neuroplasticity in Parkinson’s disease
Popescu, B. O., Batzu, L., Ruiz, P., Tulbă, D., Moro, E., & Santens, P. (2024) · Journal of Neural Transmission · doi:10.1007/s00702-024-02813-y · Cited by 57
“The onset of motor symptoms occurs after a loss of some 50–60% of nigrostriatal afferents, which corresponds to a loss of 30% of dopaminergic neurons in substantia nigra (Cheng et al. 2010).”
Guatteo, E., Rizzo, F. R., Federici, M., Cordella, A., Ledonne, A., Latini, L., Nobili, A., Viscomi, M. T., Biamonte, F., Landrock, K. K., et al. (2016) · Experimental Neurology · doi:10.1016/j.expneurol.2016.10.009 · Cited by 46
Johnson, M., Salvatore, M. F., Maiolo, S., & Bobrovskaya, L. (2018) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2018.01.002 · Cited by 49
Combination of acamprosate and baclofen as a promising therapeutic approach for Parkinson’s disease
Hajj, R., Milet, A., Toulorge, D., Cholet, N., Laffaire, J., Foucquier, J., Robelet, S., Mitry, R., Guedj, M., Nabirotchkin, S., et al. (2015) · Scientific Reports · doi:10.1038/srep16084 · Cited by 46
Watanabe, H., Dijkstra, J. M., & Nagatsu, T. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25042009 · Cited by 48
“At both PD motor symptom onset and death, the loss of striatal DA markers exceeds that of SNc DA neurons [36].”
The Physiology of Homeoprotein Transduction
Nardo, A. A. D., Fuchs, J., Joshi, R. L., Moya, K. L., & Prochiantz, A. (2018) · Physiological Reviews · doi:10.1152/physrev.00018.2017 · Cited by 52
Hamm‐Alvarez, S. F., Janga, S. R., Edman, M. C., Feigenbaum, D., Freire, D., Mack, W. J., Okamoto, C. T., & Lew, M. (2019) · Biomarkers in Medicine · doi:10.2217/bmm-2019-0315 · Cited by 46
von Linstow, C. U., Gan‐Or, Z., & Brundin, P. (2020) · Translational Neurodegeneration · doi:10.1186/s40035-020-00218-x · Cited by 45
Orr, A. L., Rutaganira, F. U., de Roulet, D., Huang, E. J., Hertz, N. T., Shokat, K. M., & Nakamura, K. (2017) · Neurochemistry International · doi:10.1016/j.neuint.2017.04.006 · Cited by 47
“…and loss of DA axons consistently precedes loss of cell bodies in the SNc in other pharmacologic and genetic mitochondrial-based models of DA neuron degeneration (Berthet et al., 2014; Pickrell et al., 2011; Pham et al., 2012; Betarbet et al., 2000) and in PD (Cheng et al., 2010; Chu et al., 2012).”
DNAJC6 Mutations Disrupt Dopamine Homeostasis in Juvenile Parkinsonism‐Dystonia
Ng, J., Cortès‐Saladelafont, E., Abela, L., Termsarasab, P., Mankad, K., Sudhakar, S. V., Gorman, K. M., Heales, S., Pope, S. A. S., Biassoni, L., et al. (2020) · Movement Disorders · doi:10.1002/mds.28063 · Cited by 46
“Postmortem studies have confirmed striatal dopamine deficiency in patients with parkinsonism.(22,23) Together, these observations suggest a neurodegenerative process in DNAJC6 patients.”
BackgroundSlézia, A., Hegedüs, P., Rusina, E., Lengyel, K., Solari, N., Kaszás, A., Balázsfi, D., Botzanowski, B., Acerbo, E., Missey, F., et al. (2023) · Scientific Reports · doi:10.1038/s41598-023-46576-0 · Cited by 48
“In addition, axonal degeneration may precede cell loss in PD patients 96 .”
Darvas, M., Henschen, C. W., & Palmiter, R. D. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.01.017 · Cited by 45
Martella, G., Madeo, G., Maltese, M., Vanni, V., Puglisi, F., Ferraro, E., Schirinzi, T., Valente, E. M., Bonanni, L., Shen, J., et al. (2016) · Neurobiology of Disease · doi:10.1016/j.nbd.2015.12.020 · Cited by 46
“Moreover, findings from PD patients clearly reported a more profound DAergic alteration in the striatum than in the SN (Cheng et al., 2010; Kordower et al., 2013; Kish et al., 1988; Bellinger et al., 2011; Galvin et al., 1999; Burke and O'Malley, 2013).”
BackgroundVriend, C. (2018) · Cell and Tissue Research · doi:10.1007/s00441-017-2771-0 · Cited by 49
“nigrostriatal dopamine projections are degenerated (Cheng et al. 2010; Fearnley and Lees 1991).”
A Novel NAD Signaling Mechanism in Axon Degeneration and its Relationship to Innate Immunity
Hopkins, E. L., Gu, W., Kobe, B., & Coleman, M. P. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.703532 · Cited by 48
Antioxidative role of Traditional Chinese Medicine in Parkinson's disease
Muhammad, F., Liu, Y., Zhou, Y., Yang, H., & Li, H. (2021) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2021.114821 · Cited by 47
Dysfunction of Synaptic Vesicle Endocytosis in Parkinson’s Disease
Zou, L., Tian, Y., & Zhang, Z. (2021) · Frontiers in Integrative Neuroscience · doi:10.3389/fnint.2021.619160 · Cited by 44
“be the earliest feature of the disease (Lee et al., 2000; Serra et al., 2002; Dauer and Przedborski, 2003; Shin et al., 2008; Li L.H. et al., 2009; Qing et al., 2009; Cheng et al., 2010; Kagi et al., 2010; Schulz-Schaeffer, 2010; Peelaerts et al., 2015).”
BackgroundLRRK 2 R1441G mice are more liable to dopamine depletion and locomotor inactivity
Liu, H., Song, L., Ho, P. W., Tse, H., Pang, S. Y., Kung, M. H.-W., Ho, J. W.-M., Ramsden, D. B., Zhou, Z., & Ho, S. (2014) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.45 · Cited by 43
Herzog, C. D., Brown, L., Kruegel, B. R., Wilson, A., Tansey, M. G., Gage, F. H., Johnson, E. M., & Bartus, R. T. (2013) · Neurobiology of Disease · doi:10.1016/j.nbd.2013.04.011 · Cited by 48
“Significant evidence demonstrates that, like many neurodegenerative diseases, Parkinson's disease (PD) progresses as an axonopathy (Burke, 2010; Cheng et al., 2010; Hilliard, 2009) and that deficits in axonal transport occur as important and relatively early pathologic events (Chu et al., 2012; De…”
BackgroundMotor speech and non-motor language endophenotypes of Parkinson’s disease
Magee, M., Copland, D. A., & Vogel, A. P. (2019) · Expert Review of Neurotherapeutics · doi:10.1080/14737175.2019.1649142 · Cited by 44
“Idiopathic Parkinson’s Disease (PD) is a chronic neurodegenerative disorder characterized by the progressive death of dopaminergic neurons in the substantia nigra pars compacta and accumulation of α-synuclein [1,2].”
BackgroundPradhan, S., & Andreasson, K. I. (2012) · Experimental Neurology · doi:10.1016/j.expneurol.2012.12.008 · Cited by 43
Zeiss, C. J., Allore, H. G., & Beck, A. P. (2017) · PLoS ONE · doi:10.1371/journal.pone.0171790 · Cited by 46
Struzyna, L. A., Adewole, D. O., Gordián‐Vélez, W. J., Grovola, M. R., Burrell, J. C., Katiyar, K. S., Petrov, D., Harris, J. P., & Cullen, D. K. (2017) · Journal of Visualized Experiments · doi:10.3791/55609 · Cited by 43
“Micro-TENN development can be summarized by three steps: (1) the fabrication of the hollow hydrogel tube, (2) the addition of ECM solution to the lumen of the tube, and (3) the seeding of aggregates of isolated neurons into the ends of the tube.”
BackgroundBittencourt, A., Brum, P. O., Ribeiro, C. T., Gasparotto, J., Bortolin, R. C., de Vargas, A. R., Heimfarth, L., de Almeida, R. F., Moreira, J. C. F., de Oliveira, J., et al. (2020) · Nutritional Neuroscience · doi:10.1080/1028415x.2020.1831261 · Cited by 43
An early axonopathy in a hLRRK2(R1441G) transgenic model of Parkinson disease
Tagliaferro, P. A., Kareva, T., Oo, T. F., Yarygina, O., Kholodilov, N. G., & Burke, R. E. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2015.07.009 · Cited by 43
Self-citationImaging of Substantia Nigra in Parkinson’s Disease: A Narrative Review
Feraco, P., Gagliardo, C., Tona, G. L., Bruno, E., D’Angelo, C., Marrale, M., Poggio, A. D., Malaguti, M. C., Geraci, L., Baschi, R., et al. (2021) · Brain Sciences · doi:10.3390/brainsci11060769 · Cited by 42
“The SNc, which is subdivided into nigrosomes and the nigral matrix, plays an essential role in regulating movements, with classic PD motor symptoms appearing when 30% or more of its dopaminergic neurons have vanished [13,14].”
BackgroundReich, N., & Hölscher, C. (2024) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2024.101122 · Cited by 43
“Up to ~30 % of dopaminergic SNpc neurons, ~60 % of their striatal processes and ~70 % of dopamine release in the dorsal striatum are lost when PD motor symptoms emerge (Cheng et al., 2010).”
GBA1-Associated Parkinson’s Disease Is a Distinct Entity
Skrahin, A., Horowitz, M., Istaiti, M., Skrahina, V., Lukáš, J., Yahalom, G., Cohen, M. E., Revel‐Vilk, S., Göker-Alpan, Ö., Becker‐Cohen, M., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25137102 · Cited by 44
“Pathological studies estimate a 40–60% loss of dopaminergic cells and a significant reduction in synaptic function before the appearance of motor symptoms meets the current PD diagnostic criteria [4,5].”
BackgroundThe degeneration and replacement of dopamine cells in Parkinson’s disease: the role of aging
Rodrı́guez, M., Moráles, I., Rodriguez‐Sabate, C., Sánchez, A., Castro, R., Armas, J. M. B., & Sabaté, M. (2014) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2014.00080 · Cited by 45
Can Growth Factors Cure Parkinson’s Disease?
Sidorova, Y. A., & Saarma, M. (2020) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2020.09.010 · Cited by 42
“This can be explained by the progressive nature of PD and low number of DNs and their fibers which GFs are expected to support and restore in late-stage patients [1].”
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“axon terminals [14].”
Weil, R. S., Lashley, T., Brás, J., Schrag, A. E., & Schott, J. M. (2017) · F1000Research · doi:10.12688/f1000research.11725.1 · Cited by 41
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Focused ultrasound in Parkinson's disease: A twofold path toward disease modification
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Han, Y., Wang, T., Li, C., Wang, Z., Zhao, Y., He, J., Fu, L., & Han, B. (2021) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2021.174413 · Cited by 41
Motor Progression and Nigrostriatal Neurodegeneration in Parkinson Disease
Furukawa, K., Shima, A., Kambe, D., Nishida, A., Wada, I., Sakamaki‐Tsukita, H., Yoshimura, K., Terada, Y., Sakato, Y., Mitsuhashi, M., et al. (2022) · Annals of Neurology · doi:10.1002/ana.26373 · Cited by 41
“This hypothesis is in line with postmortem data showing that, at the time of motor symptom onset, dopaminergic terminal capacity in the striatum decreased to <50% of baseline values, whereas NM in SN was reduced by approximately 70% of control values.(46) Additionally, the experimental data from a mouse transgenic mod…”
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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