Parkinson’s disease: experimental models and reality

Abstract

Parkinson’s disease (PD) is a chronic, progressive movement disorder of adults and the second most common neurodegenerative disease after Alzheimer’s disease. Neuropathologic diagnosis of PD requires moderate-to-marked neuronal loss in the ventrolateral substantia nigra pars compacta and α-synuclein (αS) Lewy body pathology. Nigrostriatal dopaminergic neurodegeneration correlates with the Parkinsonian motor features, but involvement of other peripheral and central nervous system regions leads to a wide range of non-motor features. Nigrostriatal dopaminergic neurodegeneration is shared with other parkinsonian disorders, including some genetic forms of parkinsonism, but many of these disorders do not have Lewy bodies. An ideal animal model for PD, therefore, should exhibit age-dependent and progressive dopaminergic neurodegeneration, motor dysfunction, and abnormal αS pathology. Rodent models of PD using genetic or toxin based strategies have been widely used in the past several decades to investigate the pathogenesis and therapeutics of PD, but few recapitulate all the major clinical and pathologic features of PD. It is likely that new strategies or better understanding of fundamental disease processes may facilitate development of better animal models. In this review, we highlight progress in generating rodent models of PD based on impairments of four major cellular functions: mitochondrial oxidative phosphorylation, autophagy-lysosomal metabolism, ubiquitin–proteasome protein degradation, and endoplasmic reticulum stress/unfolded protein response. We attempt to evaluate how impairment of these major cellular systems contribute to PD and how they can be exploited in rodent models. In addition, we review recent cell biological studies suggesting a link between αS aggregation and impairment of nuclear membrane integrity, as observed during cellular models of apoptosis. We also briefly discuss the role of incompetent phagocytic clearance and how this may be a factor to consider in developing new rodent models of PD.

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Acknowledgements

This study was supported by the National Institute of Health (P50-NS072187 and R21-NS099757) and the Mangurian Foundation Lewy Body Dementia Program at Mayo Clinic (Dickson, Jiang). Neither author has actual or potential conflicts of interest.

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Correspondence to Dennis W. Dickson.

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Jiang, P., Dickson, D.W. Parkinson’s disease: experimental models and reality. Acta Neuropathol 135, 13–32 (2018). https://doi.org/10.1007/s00401-017-1788-5

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Keywords

  • Ubiquitin-proteasome Protein Degradation
  • Major Cellular Functions
  • PTEN-induced Putative Kinase 1 (PINK1)
  • Lewy-related Pathology
  • Protein Kinase RNA-like ER Kinase (PERK)