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 Parkinson's disease is reliant on clinical motor symptoms and neuroimaging; by symptom onset, an estimated 50-70% of substantia nigra pars compacta dopaminergic neurons have already been lost.
“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]
In “Estimates of SN Neuron Loss at Disease Onset” (page unavailable), the paper acknowledges that reviews cite 50–70% loss, but concludes that the available data consistently indicate about 30% loss when motor signs appear. Its discussion of imaging concerns estimates of striatal terminal loss, not a requirement for diagnosis. (LLM, conf=0.88)
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1 retracted
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BackgroundMutant LRRK2R1441G BAC transgenic mice recapitulate cardinal features of Parkinson's disease
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Self-citationRole of autophagy in G2019S‐LRRK2‐associated neurite shortening in differentiated SH‐SY5Y cells
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Self-citationIn situ immunodetection of activated caspase-3 in apoptotic neurons in the developing nervous system
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BackgroundResultCytochrome c Release and Caspase Activation in Traumatic Axonal Injury
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Parkinsonian signs and substantia nigra neuron density in decendents elders without PD
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BackgroundResultA critical evaluation of current staging of α-synuclein pathology in Lewy body disorders
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“This discordance has been observed with a variety of antiapoptotic approaches in a variety of neurotoxin models of parkinsonism in adult rodents and in a genetic model of motor neuron disease.(73) Recent work from our laboratory provides a particularly striking example of this discordance.”
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“(C) A similar estimate can be derived from the data of Ma and colleagues, based on their dissector counts of pigmented SN neurons.(24) A linear regression analysis of their data with extrapolation to time of disease onset yields an estimate of about a 30% loss.”
BackgroundMethodWldS requires Nmnat1 enzymatic activity and N16–VCP interactions to suppress Wallerian degeneration
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“These proteins have been implicated in the regulation of neurite outgrowth.(48) The ability of LRRK2 to regulate the phosphorylation status of these proteins, and the closely correlated degree of neurite growth, has been observed in primary cultures.”
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Caspases 3 and 9 Send a Pro-Apoptotic Signal from Synapse to Cell Body in Olfactory Receptor Neurons
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Reduced striatal tyrosine hydroxylase in incidental Lewy body disease
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“In an assessment of ILB brains, Beach and colleagues determined that the putamen had a 50% reduction in tyrosine hydroxylase (TH) protein.(30) Although counts of remaining neurons in the SN are not likely to be altered by factors affecting the quality of postmortem tissue preservation, biochemical assess-”
BackgroundResultInfluentialWldS protein requires Nmnat activity and a short N-terminal sequence to protect axons in mice
Conforti, L., Wilbrey, A. L., Morreale, G., Janečková, L., Beirowski, B., Adalbert, R., Mazzola, F., Stefano, M. D., Hartley, R., Babetto, E., et al. (2009) · Journal of Cell Biology · doi:10.1083/jcb.200807175 · Cited by 125 · see citing works
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Self-citationExperimental Therapeutics of Neurodegenerative Disorders: Unmet Needs
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“Toward the close of the Decade of the Brain (1990–2000), hope was expressed that an ability to forestall the progression of these devastating diseases was not far off.(3) Yet 10 years later, we seem no closer to our goal, despite a multitude of important advances in our understanding of the molecular and genetic basis…”
BackgroundRies, V., Silva, R. M., Oo, T. F., Cheng, H., Rzhetskaya, M., Kholodilov, N. G., Flavell, R. A., Kuan, C.-Y., RAKIC, P. T., & Burke, R. E. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05713.x · Cited by 81 · cited 2× · see citing works
“Although there are of course many possible reasons why the trial failed, as previously reviewed,(77) an important possibility is that although blockade of MAPK signaling blocks apoptosis, it does not protect axons in the mature brain.(9,10) A new emphasis on protecting axons may provide new therapeutic approaches.”
BackgroundSelf-citationNeuroprotection trials in Parkinson's disease: Systematic review
Hart, R. G., Pearce, L. A., Ravina, B. M., Yaltho, T. C., & Marler, J. R. (2008) · Movement Disorders · doi:10.1002/mds.22432 · Cited by 78 · see citing works
Invited Article: Functional imaging in Parkinson disease
Nandhagopal, R., McKeown, M. J., & Stoessl, A. J. (2008) · Neurology · doi:10.1212/01.wnl.0000310432.92489.90 · Cited by 77 · see citing works
WldS mice are protected against the Parkinsonian mimetic MPTP
HASBANI, D., & O’Malley, K. L. (2006) · Experimental Neurology · doi:10.1016/j.expneurol.2006.05.017 · Cited by 73 · cited 1× · see citing works
“In neurotoxin models of parkinsonism, the Wld mutation protects dopaminergic axons, but not cell bodies, from medial forebrain bundle injection of 6-hydroxydopamine (6OHDA)(58) (see Fig 4B) and injection of methyl-phenyl-tetrahydropyridine.(59) These observations suggest that with a deeper understanding of the mechani…”
BackgroundLees, A. J. (2009) · Neurology · doi:10.1212/wnl.0b013e318198daec · Cited by 71 · see citing works
Chen, X., Rzhetskaya, M., Kareva, T., Bland, R., During, M. J., Tank, A. W., Kholodilov, N., & Burke, R. E. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.2132-07.2008 · Cited by 62 · see citing works
Self-citationEl‐Khodor, B. F., & Burke, R. E. (2002) · The Journal of Comparative Neurology · doi:10.1002/cne.10367 · Cited by 49 · see citing works
Self-citationProgrammed cell death and new discoveries in the genetics of parkinsonism
Burke, R. E. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.05106.x · Cited by 32 · see citing works
Self-citation
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Cryan, J. F., O'Riordan, K. J., Cowan, C. S. M., Sandhu, K. V., Bastiaanssen, T. F. S., Boehme, M., Codagnone, M. G., Cussotto, S., Fulling, C., Golubeva, A. V., et al. (2019) · Physiological Reviews · doi:10.1152/physrev.00018.2018 · Cited by 5,286 · see citing works
Hallmarks of neurodegenerative diseases
Wilson, D. M., Cookson, M. R., Van Den Bosch, L., Zetterberg, H., Holtzman, D. M., & Dewachter, I. (2023) · Cell · doi:10.1016/j.cell.2022.12.032 · Cited by 1,789 · see citing works
Dopamine: Functions, Signaling, and Association with Neurological Diseases
Klein, M. O., Battagello, D. S., Cardoso, A. R., Hauser, D. N., Bittencourt, J. C., & Correa, R. G. (2019) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-018-0632-3 · Cited by 1,073 · see citing works
Brain-first versus body-first Parkinson’s disease: a multimodal imaging case-control study
Horsager, J., Andersen, K. B., Knudsen, K., Skjærbæk, C., Fedorova, T. D., Okkels, N., Schaeffer, E., Bonkat, S. K., Geday, J., Otto, M., et al. (2020) · Brain · doi:10.1093/brain/awaa238 · Cited by 782 · see citing works
Oxidative stress in the aging substantia nigra and the etiology of Parkinson's disease
Trist, B. G., Hare, D. J., & Double, K. L. (2019) · Aging Cell · doi:10.1111/acel.13031 · Cited by 778 · see citing works
Human iPSC-based modeling of late-onset disease via progerin-induced aging
Miller, J. D., Ganat, Y. M., Kishinevsky, S., Bowman, R. L., Liu, B., Tu, E. Y., Mandal, P. K., Vera, E., Shim, J.-W., Kriks, S., et al. (2013) · Cell stem cell · doi:10.1016/j.stem.2013.11.006 · Cited by 777 · see citing works
Brain-Derived Neurotrophic Factor in Brain Disorders: Focus on Neuroinflammation
Lima Giacobbo, B., Doorduin, J., Klein, H. C., Dierckx, R. A. J. O., Bromberg, E., & de Vries, E. F. J. (2019) · Molecular Neurobiology · doi:10.1007/s12035-018-1283-6 · Cited by 750 · see citing works
Mitochondria at the neuronal presynapse in health and disease
Devine, M. J., & Kittler, J. T. (2018) · Nature reviews. Neuroscience · doi:10.1038/nrn.2017.170 · Cited by 615 · see citing works
The Synucleinopathies: Twenty Years On
Goedert, M., Jakes, R., & Spillantini, M. G. (2017) · Journal of Parkinson s Disease · doi:10.3233/jpd-179005 · Cited by 566 · see citing works
“At the time of clinical diagnosis, around 30% of the dopaminergic neurons of the substantia nigra and 50–60% of their axon terminals have been lost [81], consistent with a centripetal mechanism of aggregate formation and neurodegeneration.”
BackgroundParkinson’s Disease: Etiology, Neuropathology, and Pathogenesis
Kouli, A., Torsney, K., & Kuan, W. (2018) · Codon Publications eBooks · doi:10.15586/codonpublications.parkinsonsdisease.2018.ch1 · Cited by 556 · see citing works
Berg, D., Postuma, R. B., Bloem, B. R., Chan, P., Dubois, B., Gasser, T., Goetz, C. G., Halliday, G. M., Hardy, J., Lang, A. E., et al. (2014) · Movement Disorders · doi:10.1002/mds.25844 · Cited by 502 · see citing works
Axon degeneration in Parkinson's disease
Burke, R. E., & O’Malley, K. L. (2012) · Experimental Neurology · doi:10.1016/j.expneurol.2012.01.011 · Cited by 494 · see citing works
“(Figure modified from (Cheng et al., 2010)).”
BackgroundSelf-citationNeuropathology of sporadic Parkinson's disease: Evaluation and changes of concepts
Jellinger, K. A. (2011) · Movement Disorders · doi:10.1002/mds.23795 · Cited by 448 · see citing works
“Furthermore, it will discuss the interaction between aSyn and other pathological proteins, recent changes in the conception of neuropathology with regard to clinical manifestation, various subtypes of the disorder, and the neuropathological substrate of cognitive impairment in PD.”
BackgroundInfluentialEnvironmental risk factors and Parkinson's disease: An umbrella review of meta-analyses
Bellou, V., Belbasis, L., Tzoulaki, I., Εvangelou, Ε., & Ioannidis, J. P. A. (2015) · Parkinsonism & Related Disorders · doi:10.1016/j.parkreldis.2015.12.008 · Cited by 429 · see citing works
On Cell Loss and Selective Vulnerability of Neuronal Populations in Parkinson's Disease
Giguère, N., Burke, S., & Trudeau, L. (2018) · Frontiers in Neurology · doi:10.3389/fneur.2018.00455 · Cited by 415 · see citing works
“At clinical presentation, it has been estimated that 40–60% of SNc DA neurons have already degenerated (2, 3).”
BackgroundProdromal Parkinson disease subtypes — key to understanding heterogeneity
Berg, D., Borghammer, P., Fereshtehnejad, S.-M., Heinzel, S., Horsager, J., Schaeffer, E., & Postuma, R. B. (2021) · Nature Reviews Neurology · doi:10.1038/s41582-021-00486-9 · Cited by 409 · see citing works
Mechanisms of α-Synuclein Induced Synaptopathy in Parkinson's Disease
Bridi, J. C., & Hirth, F. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00080 · Cited by 381 · see citing works
“Loss of DA neurons in the SN leads to marked decrease of dopamine levels in synaptic terminals of the dorsal striatum (Figures 1A,B), ultimately leading to a loss of the nigrostriatal pathway (Cheng et al., 2010).”
BackgroundGenetics of Parkinson's disease
Lill, C. M. (2016) · Molecular and Cellular Probes · doi:10.1016/j.mcp.2016.11.001 · Cited by 362 · see citing works
“Therapy is initiated after the clinical onset of disease at which point in time more than 50% of dopaminergic neurons have typically already been lost (14).”
BackgroundImmune Signaling in Neurodegeneration
Hammond, T. R., Marsh, S. E., & Stevens, B. (2019) · Immunity · doi:10.1016/j.immuni.2019.03.016 · Cited by 336 · see citing works
“The onset of symptoms follows significant loss of dopamine-producing neurons in the substantia nigra that appears to accelerate exponentially as the disease progresses (Cheng et al., 2010; Greffard et al., 2006).”
BackgroundA Progressive Mouse Model of Parkinson’s Disease: The Thy1-aSyn (“Line 61”) Mice
Chesselet, M.-F., Richter, F., Zhu, C., Magen, I., Watson, M. B., & Subramaniam, S. R. (2012) · Neurotherapeutics · doi:10.1007/s13311-012-0104-2 · Cited by 346 · see citing works
“Evidence from brain imaging studies suggests that axonal pathology precedes dopaminergic cell loss in PD [35].”
BackgroundJohnson, M., & Bobrovskaya, L. (2014) · NeuroToxicology · doi:10.1016/j.neuro.2014.12.002 · Cited by 335 · see citing works
“Degeneration induced in the rodent rotenone model reproduces the degeneration in clinical PD (Cheng et al., 2010), with damage occurring in the dopaminergic nerve terminals of the striatum and cell bodies in the SN (Betarbet et al.”
BackgroundLong Road to Ruin: Noradrenergic Dysfunction in Neurodegenerative Disease
Weinshenker, D. (2018) · Trends in Neurosciences · doi:10.1016/j.tins.2018.01.010 · Cited by 323 · see citing works
“This pattern is consistent with dopaminergic degeneration in clinical and experimental PD, where imaging studies reveal DA axon loss prior to cell body degeneration [57], striatal DA loss ( 80%) is greater than death of DA neurons in the substantia nigra ( 50%) [58], and Thy1-Syn transgenicmice show progressive reduct…”
Programmed axon degeneration: from mouse to mechanism to medicine
Coleman, M. P., & Höke, A. (2020) · Nature reviews. Neuroscience · doi:10.1038/s41583-020-0269-3 · Cited by 320 · see citing works
The Role of Mitochondrially Derived ATP in Synaptic Vesicle Recycling
Pathak, D., Shields, L. Y., Mendelsohn, B. A., Haddad, D., Lin, W., Gerencser, A. A., Kim, H., Brand, M. D., Edwards, R. H., & Nakamura, K. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.656405 · Cited by 311 · see citing works
“Energy status at the synapse may be particularly important because in most neurons most mitochondria likely reside in axons (56), and degeneration begins in this compartment (4, 5).”
BackgroundMitochondrial Biology and Parkinson's DiseasePreprint
Perier, C., & Vila, M. (2011) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a009332 · Cited by 304 · see citing works
“These observations may explain, at least in part, the apparent increased susceptibility of striatal dopaminergic terminals, compared to dopaminergic nigral cell bodies, to the degenerative process in PD (Cheng et al. 2010).”
BackgroundImpaired neurotransmission caused by overexpression of α-synuclein in nigral dopamine neurons
Lundblad, M., Decressac, M., Mattsson, B., & Björklund, A. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1200575109 · Cited by 292 · see citing works
Decressac, M., Mattsson, B., Lundblad, M., Weikop, P., & Björklund, A. (2011) · Neurobiology of Disease · doi:10.1016/j.nbd.2011.12.013 · Cited by 286 · see citing works
“This retrograde progression of neurodegeneration is strikingly similar to that described to occur in PD (Cheng et al., 2010), although the progression of changes seen in the AAV-α-syn model is much faster than in the human disease.”
Deep learning based diagnosis of Parkinson’s disease using convolutional neural network
Sivaranjini, S., & Sujatha, C. M. (2019) · Multimedia Tools and Applications · doi:10.1007/s11042-019-7469-8 · Cited by 282 · see citing works
Sulzer, D. L., Cassidy, C., Horga, G., Kang, U. J., Fahn, S., Casella, L., Pezzoli, G., Langley, J. A., Hu, X. P., Zucca, F. A., et al. (2018) · npj Parkinson s Disease · doi:10.1038/s41531-018-0047-3 · Cited by 277 · see citing works
“PD diagnosis occurs only when the motor symptoms are apparent and 30% or more of the substantia nigra (SN) dopamine neurons have already died.(5) This presents a fundamental challenge to clinical treatment: while there are multiple promising therapies under exploration, including the use of growth factors,(6) ion chan…”
BackgroundRetrograde Axonal Degeneration in Parkinson Disease
Tagliaferro, P., & Burke, R. E. (2016) · Journal of Parkinson’s Disease · doi:10.3233/jpd-150769 · Cited by 272 · see citing works
“Among three independent quantitative morphologic studies there was a remarkable consistency, with each suggesting about a 30% loss of SN neurons at the time of onset of motor signs [8–10] (reviewed in Cheng et al., 2010 [11]).”
BackgroundInfluentialSelf-citationBorghammer, P. (2021) · Journal of Parkinson's Disease · doi:10.3233/jpd-202481 · Cited by 259 · see citing works
“The mesencephalon is next in line and once approximately 50% of the nigrostriatal dopaminergic terminals have degenerated, motor symptoms appear [68].”
BackgroundCaudo‐rostral brain spreading of α‐synuclein through vagal connections
Ulusoy, A., Rusconi, R., Pérez‐Revuelta, B. I., Musgrove, R. E., Helwig, M., Winzen‐Reichert, B., & Monte, D. A. D. (2013) · EMBO Molecular Medicine · doi:10.1002/emmm.201302475 · Cited by 250 · see citing works
“Indeed, previously published experimental work supports the notion that a ‐ syn pathology affects fi rst axonal projections and then neuronal cell bodies, mimicking a retrograde progression of degenerative changes that has also been proposed for PD (Decressac et al, 2012, Cheng et al, 2010).”
Uchihara, T., & Giasson, B. I. (2016) · Acta Neuropathologica · doi:10.1007/s00401-015-1485-1 · Cited by 249 · see citing works
“Deficiency of dopamine at their axon terminals in caudate/putamen is more profound (30 % of agematched control) [32] than the loss of nigral neurons [85], indicating distally accentuated gradient of degeneration, also confirmed by PET studies in PD patients at the onset of motor deficits.”
BackgroundResultReich, N., & Hölscher, C. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.970925 · Cited by 248 · see citing works
Biomarkers in Parkinson’s disease (recent update)
Sharma, S. K., Moon, C. S., Khogali, A., Haidous, A., Chabenne, A., Ojo, C., Jelebinkov, M., Kurdi, Y., & Ebadi, M. (2013) · Neurochemistry International · doi:10.1016/j.neuint.2013.06.005 · Cited by 242 · see citing works
“Furthermore, Cheng et al. (2010) proposed that degeneration of axons, not cell bodies, is the primary determinant of clinically apparent progression of disease, and that future experimental therapeutics intended to halt disease progression will benefit from the distinct mechanisms of axonal degeneration. Shtilbans and…”
InfluentialCutaneous neuropathy in Parkinson’s disease: a window into brain pathology
Doppler, K., Ebert, S., Üçeyler, N., Trenkwalder, C., Ebentheuer, J., Volkmann, J., & Sommer, C. (2014) · Acta Neuropathologica · doi:10.1007/s00401-014-1284-0 · Cited by 239 · see citing works
“While detailed knowledge of the involvement of different regions of the brain in the course of disease has been gained in recent years [3], the question where the neurodegenerative process begins on the cellular level is still unanswered [6].”
BackgroundAnimal models of α-synucleinopathy for Parkinson disease drug development
Koprich, J. B., Kalia, L. V., & Brotchie, J. M. (2017) · Nature reviews. Neuroscience · doi:10.1038/nrn.2017.75 · Cited by 235 · see citing works
NURR1 in Parkinson disease—from pathogenesis to therapeutic potential
Decressac, M., Volakakis, N., Björklund, A., & Perlmann, T. (2013) · Nature Reviews Neurology · doi:10.1038/nrneurol.2013.209 · Cited by 234 · see citing works
Parkinson's Disease Genetics and Pathophysiology
Vázquez-Vélez, G. E., & Zoghbi, H. Y. (2021) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-100720-034518 · Cited by 237 · see citing works
Loss of Mitochondrial Fission Depletes Axonal Mitochondria in Midbrain Dopamine Neurons
Berthet, A., Margolis, E. B., Zhang, J., Hsieh, I., Zhang, J.-S., Hnasko, T., Ahmad, J., Edwards, R., Sesaki, H., Huang, E., et al. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.0930-14.2014 · Cited by 187 · see citing works
“Understanding mitochondrial biology in this compartment is critical, as axons are consistently lost before the cell body in neurodegenerative diseases that are thought to involve energy depletion (Li et al., 2001; Scheff et al., 2007; Cheng et al., 2010).”
Parkinson’s disease as a result of aging
Rodriguez, M., Rodriguez‐Sabate, C., Morales, I., Sanchez, A., & Sabate, M. (2015) · Aging Cell · doi:10.1111/acel.12312 · Cited by 214 · see citing works
“There is evidence suggesting that PD starts with axonal damage and progresses by a ‘dying back’ process to the DAn somata (Cheng et al., 2010).”
BackgroundInfluentialDopamine induces soluble α-synuclein oligomers and nigrostriatal degeneration
Mor, D. E., Tsika, E., Mazzulli, J. R., Gould, N. S., Kim, H., Daniels, M. J., Doshi, S., Gupta, P., Grossman, J., Tan, V. X., et al. (2017) · Nature Neuroscience · doi:10.1038/nn.4641 · Cited by 219 · see citing works
Sommerauer, M., Fedorova, T. D., Hansen, A. K., Knudsen, K., Otto, M., Jeppesen, J., Frederiksen, Y., Blicher, J. U., Geday, J., Nahimi, A., et al. (2017) · Brain · doi:10.1093/brain/awx348 · Cited by 218 · see citing works
Therapies in Parkinsonʼs disease
Jankovic, J. J., & Poewe, W. H. (2012) · Current Opinion in Neurology · doi:10.1097/wco.0b013e3283542fc2 · Cited by 213 · see citing works
The role of dopaminergic imaging in patients with symptoms of dopaminergic system neurodegeneration
Cummings, J. L., Henchcliffe, C., Schaier, S., Simuni, T., Waxman, A., & Kemp, P. M. (2011) · Brain · doi:10.1093/brain/awr177 · Cited by 213 · see citing works
Stokholm, M. G., Iranzo, Á., Østergaard, K., Serradell, M., Otto, M., Svendsen, K. B., Garrido, A., Vilas, D., Borghammer, P., Santamaría, J., et al. (2017) · The Lancet Neurology · doi:10.1016/s1474-4422(17)30173-4 · Cited by 210 · see citing works
Raman Spectroscopy: An Emerging Tool in Neurodegenerative Disease Research and Diagnosis
Devitt, G., Howard, K., Mudher, A. K., & Mahajan, S. (2018) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.7b00413 · Cited by 208 · see citing works
The Interplay of Axonal Energy Homeostasis and Mitochondrial Trafficking and Anchoring
Sheng, Z.-H. (2017) · Trends in Cell Biology · doi:10.1016/j.tcb.2017.01.005 · Cited by 221 · see citing works
“Because ATP has a limited diffusion capacity in the long axonal process [7, 8], a fundamental question remains: do energy deficits or bioenergetic failure occur early in distal axons under physiological and pathological stress conditions? This is particularly an important question relevant to a range of neurodegenerat…”
BackgroundImpaired dopamine release in Parkinson’s disease
Cramb, K. M. L., Beccano-Kelly, D., Cragg, S. J., & Wade-Martins, R. (2023) · Brain · doi:10.1093/brain/awad064 · Cited by 207 · see citing works
“Dopaminergic axons are affected early in Parkinson’s disease, with synaptic decay preceding neuron death.(18,19) This concept is not unique to Parkinson’s disease; impaired synaptic activity and function, referred to as synaptopathy, is observed in a wide variety of neurodegenerative diseases, including Huntington’s,…”
BackgroundLRRK2 Parkinson disease mutations enhance its microtubule association
Kett, L. R., Boassa, D., Ho, C. C., Rideout, H. J., Hu, J., Terada, M., Ellisman, M. H., & Dauer, W. T. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr526 · Cited by 196 · see citing works
Mitofusin2 Mutations Disrupt Axonal Mitochondrial Positioning and Promote Axon Degeneration
Misko, A. L., Sasaki, Y., Tuck, E. J., Milbrandt, J., & Baloh, R. H. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.6338-11.2012 · Cited by 195 · see citing works
“Evidence supports that axonal degeneration precedes cell body death in amyotrophic lateral sclerosis (Fischer and Glass, 2007), Parkinson’s disease (Cheng et al., 2010), Alzheimer’s disease (Vickers et al.”
Mitochondria as a central sensor for axonal degenerative stimuli
Court, F. A., & Coleman, M. P. (2012) · Trends in Neurosciences · doi:10.1016/j.tins.2012.04.001 · Cited by 193 · see citing works
Outside in: Unraveling the Role of Neuroinflammation in the Progression of Parkinson's Disease
Troncoso-Escudero, P., Parra, A., Nassif, M., & Vidal, R. L. (2018) · Frontiers in Neurology · doi:10.3389/fneur.2018.00860 · Cited by 191 · see citing works
Synaptic Changes in Parkinson Disease Assessed with in vivo Imaging
Matuskey, D., Tinaz, S., Wilcox, K. C., Naganawa, M., Toyonaga, T., Dias, M., Henry, S. E., Pittman, B. P., Ropchan, J. R., Nabulsi, N., et al. (2020) · Annals of Neurology · doi:10.1002/ana.25682 · Cited by 180 · see citing works
“Postmortem tissue studies estimate that 30 to 80% of dopamine neurons in the SN are lost when motor symptoms are present.(39) Previous PET studies have used radiotracers more specific to the monoamine systems, and found differences of around 20 to 40% in mild to advancing PD for vesicular monoamine transporter type 2(…”
BackgroundTonges, L., Frank, T., Tatenhorst, L., Saal, K. A., Koch, J. C., Szego, E. M., Bahr, M., Weishaupt, J. H., & Lingor, P. (2012) · Brain · doi:10.1093/brain/aws254 · Cited by 176 · see citing works
“…experimental approaches have not adequately focused on prevention or restoration of axonal pathology in Parkinson’s disease, which is at least as important for the development of clinical disease as is the cellular damage of substantia nigra pars compacta neurons (Burke, 2010; Cheng et al., 2010).”
BackgroundNeuropathobiology of non-motor symptoms in Parkinson disease
Jellinger, K. A. (2015) · Journal of Neural Transmission · doi:10.1007/s00702-015-1405-5 · Cited by 177 · see citing works
“…striatal or putaminal dopamine are lost (Bernheimer et al. 1973; Riederer and Wuketich 1976) has recently been changed by the suggestion that at the time of first diagnosis of PD only about 30 % of dopaminergic nigral neurons but 50–60 % of their axon terminals have been lost (Cheng et al. 2010).”
BackgroundMitofusin 2 is necessary for striatal axonal projections of midbrain dopamine neurons
Lee, S., Sterky, F. H., Mourier, A., Terzioglu, M., Cullheim, S., Olson, L., & Larsson, N. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds352 · Cited by 177 · see citing works
“These experimental findings shed important new light on the possible role of mitochondrial dysfunction in PD and are consistent with observations that the DA neuron pathology in human PD patients starts peripherally with the degeneration of the striatal DA nerve terminals (28).”
BackgroundResultThe concept of alpha-synuclein as a prion-like protein: ten years after
Steiner, J. A., Quansah, E., & Brundin, P. (2018) · Cell and Tissue Research · doi:10.1007/s00441-018-2814-1 · Cited by 183 · see citing works
“synaptic terminals are lost at the time of onset of motor symptoms (Cheng et al. 2010; Spillantini and Goedert 2017).”
Ip, C. W., Klaus, L.-C., Karikari, A. A., Visanji, N. P., Brotchie, J. M., Lang, A. E., Volkmann, J., & Koprich, J. B. (2017) · Acta Neuropathologica Communications · doi:10.1186/s40478-017-0416-x · Cited by 173 · see citing works
“*P < 0.05, **P < 0.01, ***P < 0.001 were considered as significant P-values.”
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 · see citing works
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 · see citing works
“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 166 · see citing works
“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 · see citing works
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 · see citing works
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 171 · see citing works
“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 · see citing works
“(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 162 · see citing works
Ba, F., & Martin, W. R. W. (2014) · Parkinsonism & Related Disorders · doi:10.1016/j.parkreldis.2014.11.007 · Cited by 160 · see citing works
“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 161 · see citing works
Pathak, D., Berthet, A., & Nakamura, K. (2013) · Annals of Neurology · doi:10.1002/ana.24014 · Cited by 157 · see citing works
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 156 · see citing works
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 150 · see citing works
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 · see citing works
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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 · see citing works
“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 153 · see citing works
“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 154 · see citing works
“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 153 · see citing works
Regulation of motor proteins, axonal transport deficits and adult-onset neurodegenerative diseases
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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 149 · see citing works
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“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).”
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Dopaminergic pathway reconstruction by Akt/Rheb‐induced axon regeneration
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“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 140 · see citing works
“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 145 · see citing works
“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
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“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 136 · see citing works
“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 136 · see citing works
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 · see citing works
“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…”
BackgroundResult<i>In vivo</i>imaging of neuromelanin in Parkinson’s disease using<sup>18</sup>F-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 · see citing works
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“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 129 · see citing works
“…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 · see citing works
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 130 · see citing works
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 128 · see citing works
“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 · see citing works
“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 127 · see citing works
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 133 · see citing works
“Moreover, neuroanatomical studies of post mortem brain samples from familial PD cases support the idea that synaptic decay precedes neuronal death [131, 132].”
Result
- 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 › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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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