4.4 Review

Motor and non-motor circuit disturbances in early Parkinson disease: which happens first?

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NATURE REVIEWS NEUROSCIENCE
卷 23, 期 2, 页码 115-128

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NATURE PORTFOLIO
DOI: 10.1038/s41583-021-00542-9

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资金

  1. CIBERNED
  2. Ministry of Science and Education of Spain [PID2019-111045RB-100]
  3. (NEUROMETAB-CM) from Comunidad de Madrid [S2017/BMD-3700]
  4. Structural Funds of the European Union
  5. Carlos III Health Institute's Miguel Servet Program [CP19/00200]
  6. FIS [PI20/00403]
  7. Fundacion Tatiana Perez de Guzman el Bueno
  8. Department of Economy, Industry and Competitiveness
  9. European Union (FEDER) A way to make Europe [SAF2017-86246-R]
  10. la Caixa Foundation [LCF/PR/HR20/52400012]
  11. Fondation de France [00066525]
  12. France Parkinson Grant
  13. IDEX Emergence Grant [OPE-2018-410]
  14. Michael J. Fox Foundation [MJFF-008814]
  15. Agence Nationale de la Recherche of France
  16. France PSP
  17. Del Duca foundation
  18. European Research Council [951284]
  19. Innovative Medicines Initiative 2 Joint Undertaking (IMPRiND) [116060]
  20. French government in the framework of the University of Bordeaux's IdEx Investments for the Future program [GPR BRAIN_2030]
  21. European Union
  22. EFPIA
  23. Swiss State Secretariat for Education, Research and Innovation (SERI) [17.00038]
  24. European Research Council (ERC) [951284] Funding Source: European Research Council (ERC)

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The prevailing theory of Parkinson disease pathogenesis involves the spread of alpha-synuclein toxicity from the periphery to the brain. While this bottom-up mechanism is implicated, early neuronal loss in the nigrostriatal system also plays a prominent role.
For the last two decades, pathogenic concepts in Parkinson disease (PD) have revolved around the toxicity and spread of alpha-synuclein. Thus, alpha-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 alpha-synuclein aggregates with respect to neuronal loss during the onset and progression of PD. A prevailing theory of Parkinson disease pathogenesis revolves around the spread of alpha-synuclein toxicity from the periphery to the brain. In this Review, Blesa and colleagues discuss the idea that, although these bottom-up mechanisms are involved, early neuronal loss in the nigrostriatal system also plays a prominent role.

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