For the last two decades, pathogenic concepts in Parkinson disease (PD) have revolved around the toxicity and spread of α-synuclein. Thus, α-synuclein would follow caudo-rostral propagation from the periphery to the central nervous system, first producing non-motor manifestations (such as constipation, sleep disorders and hyposmia), and subsequently impinging upon the mesencephalon to account for the cardinal motor features before reaching the neocortex as the disease evolves towards dementia. This model is the prevailing theory of the principal neurobiological mechanism of disease. Here, we scrutinize the temporal evolution of motor and non-motor manifestations in PD and suggest that, even though the postulated bottom-up mechanisms are likely to be involved, early involvement of the nigrostriatal system is a key and prominent pathophysiological mechanism. Upcoming studies of detailed clinical manifestations with newer neuroimaging techniques will allow us to more closely define, in vivo, the role of α-synuclein aggregates with respect to neuronal loss during the onset and progression of PD.
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We thank Lawrence Phillips for English language editing of this manuscript. J.A.O. is currently funded by CIBERNED, the Ministry of Science and Education of Spain (PID2019-111045RB-100), grant S2017/BMD-3700 (NEUROMETAB-CM) from Comunidad de Madrid co-financed with the Structural Funds of the European Union. J.B. is currently funded by the Carlos III Health Institute’s Miguel Servet Program (CP19/00200) and FIS (PI20/00403) and Fundación Tatiana Pérez de Guzmán el Bueno. G.F. is funded by the Department of Economy, Industry and Competitiveness and Co-financed by the European Union (FEDER) “A way to make Europe” (grant SAF2017-86246-R) and by “la Caixa” Foundation (grant LCF/PR/HR20/52400012). B.D. is currently funded by Fondation de France Grant number 00066525, a France Parkinson Grant, an IDEX Emergence Grant number OPE-2018-410, and the Michael J. Fox Foundation (Project Grant No. MJFF-008814). E.B. is currently funded by Agence Nationale de la Recherche of France, Michael J. Fox Foundation (USA), France Parkinson, Fondation pour la Recherche Médicale, France PSP, the “Grand Prix” from the Del Duca foundation, the European Research Council (ERC-2020-SyG GA no. 951284), and the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No. 116060 (IMPRiND). This study received financial support from the French government in the framework of the University of Bordeaux’s IdEx “Investments for the Future” program/GPR BRAIN_2030. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. This work is supported by the Swiss State Secretariat for Education‚ Research and Innovation (SERI) under contract number 17.00038. The opinions expressed and arguments employed herein do not necessarily reflect the official views of these funding bodies.
The authors declare no competing interests.
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The loss of ability to move your muscles voluntarily.
Reduced ability to smell and to detect odours.
- Lewy bodies
(LBs). Abnormal deposits of proteins in the brain named after Frederich H. Lewy, who discovered them.
Abnormally small handwriting that is characteristic of Parkinson disease.
- Nosological hurdle
Difficulty regarding the classification of diseases.
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Blesa, J., Foffani, G., Dehay, B. et al. Motor and non-motor circuit disturbances in early Parkinson disease: which happens first?. Nat Rev Neurosci 23, 115–128 (2022). https://doi.org/10.1038/s41583-021-00542-9
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