Abstract
Parkinson’s disease (PD) is not only characterized by motor disturbances but also, by cognitive, sensory, psychiatric and autonomic dysfunction. It has been proposed that some of these symptoms might be related to the widespread pathology of α-synuclein (α-syn) aggregation in different nuclei of the central and peripheral nervous system. However, the pathogenic formation of α-syn aggregates in different brain areas of PD patients is poorly understood. Most experimental models of PD are valuable to assess specific aspects of its pathogenesis, such as toxin-induced dopaminergic neurodegeneration. However, new models are required that reflect the widespread and progressive formation of α-syn aggregates in different brain areas. Such α-syn aggregation is induced in only a few animal models, for example perikaryon inclusions are found in rats administered rotenone, aggregates with a neuritic morphology develop in mice overexpressing either mutated or wild-type α-syn, and in Smad3 deficient mice, aggregates form extensively in the perikaryon and neurites of specific brain nuclei. In this review we focus on α-syn aggregation in the human disorder, its genetics and the availability of experimental models. Indeed, evidences show that dopamine (DA) metabolism may be related to α-syn and its conformational plasticity, suggesting an interesting link between the two pathological hallmarks of PD: dopaminergic neurodegeneration and Lewy body (LB) formation.
Highlights
While the first description of Parkinson’s disease (PD) may date back to ancient Indian and Chinese texts from 1000 BC, the first clear medical description of this disorder was presented by James Parkinson in 1817
In the mid-1800s, Jean-Martin Charcot separated PD from multiple sclerosis and other disorders that are characterized by tremor, and in 1895 Brissaud formulated the hypothesis that the substantia nigra (SN) is the main brain nucleus pathologically affected in PD [1]
PD is the second most common neurodegenerative disorder that affects the human brain. It is primarily characterized by motor symptoms like akinesia, rigidity, resting tremor and postural instability, manifestations that are mainly derived from the progressive degeneration of dopaminergic neurons in the SN pars compacta
Summary
While the first description of Parkinson’s disease (PD) may date back to ancient Indian and Chinese texts from 1000 BC, the first clear medical description of this disorder was presented by James Parkinson in 1817. The A53T mutation of SNCA is associated with the predominantly neuritic aggregation of α-syn in the human brain [60,61] and in a mouse model [62], as well as with severe motor impairments.
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