Abstract
Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by motor symptoms such as tremor, slowness of movement, rigidity, and postural instability, as well as non-motor features like sleep disturbances, loss of ability to smell, depression, constipation, and pain. Motor symptoms are caused by depletion of dopamine in the striatum due to the progressive loss of dopamine neurons in the substantia nigra pars compacta. Approximately 10% of PD cases are familial arising from genetic mutations in α-synuclein, LRRK2, DJ-1, PINK1, parkin, and several other proteins. The majority of PD cases are, however, idiopathic, i.e., having no clear etiology. PD is characterized by progressive accumulation of insoluble inclusions, known as Lewy bodies, mostly composed of α-synuclein and membrane components. The cause of PD is currently attributed to cellular proteostasis deregulation and mitochondrial dysfunction, which are likely interdependent. In addition, neuroinflammation is present in brains of PD patients, but whether it is the cause or consequence of neurodegeneration remains to be studied. Rodents do not develop PD or PD-like motor symptoms spontaneously; however, neurotoxins, genetic mutations, viral vector-mediated transgene expression and, recently, injections of misfolded α-synuclein have been successfully utilized to model certain aspects of the disease. Here, we critically review the advantages and drawbacks of rodent PD models and discuss approaches to advance pre-clinical PD research towards successful disease-modifying therapy. © 2020 The Authors.
Highlights
Disease Phenotypes Parkinson’s disease (PD) is a progressive neurodegenerative disease lacking diseasemodifying therapies, and current drug treatments are symptomatic
The loss of dopaminergic neurons in familial forms of PD correlates with mutations in genes such as SNCA, Parkin/PARK2, ubiquitin carboxy terminal hydrolase-1 (UCHL1), PINK1, DJ-1/PARK7, and LRRK2 (Gasser, Hardy, & Mizuno, 2011; Nalls et al, 2014)
Since there is no single cause for the neurodegeneration, one option is that selective vulnerability of substantia nigra pars compacta (SNpc) neurons–over other dopaminergic neurocircuitry–is caused by their physiological properties
Summary
Disease Phenotypes Parkinson’s disease (PD) is a progressive neurodegenerative disease lacking diseasemodifying therapies, and current drug treatments are symptomatic. A BAC transgenic model expressing C-terminal truncated human mutant Parkin (Parkin-Q311X) at physiological levels in dopaminergic neurons under control of the mouse DAT promoter have been created, aiming to test possible dominant toxic effects of this Parkin mutation These mice exhibited progressive locomotor abnormalities in open field, beam walking, cylinder, and adhesive tape removal tests, accumulation of proteinase K-resistant α-synuclein inclusions, oxidative protein damage, and age-related loss of nigral dopaminergic neurons (Lu et al, 2009). Data interpretation from this artificial model should be taken with caution, since they might not reflect the events of the clinical disease (Okuzumi et al, 2018)
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