Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, characterized by tremor at rest, bradykinesia and rigidity as cardinal signs. Motor symptoms originate from the degeneration of dopaminergic neurones of the substantia nigra pars compacta, with a consequent loss of dopamine in the striatum and downstream functional alterations in the basal ganglia circuitry; non-motor symptoms of various types (autonomic impairment, gastrointestinal dysfunctions, cognitive defects, sleep disorders) frequently complete the clinical picture. Although PD is mostly a sporadic disorder, the contribution of genetic factors is being increasingly recognized; indeed, 15–30% of all PD cases are currently linked to a genetic background. Genetic causes of PD have allowed researchers to develop innovative cellular and animal models of PD pathogenesis and to look for specific alterations of biochemical pathways in PD patients carrying genetic mutations. Consequently, mechanisms arising from single protein modifications have been progressively linked together, so that we are now able to draw a quite extended map of how the different contributing factors to PD pathogenesis are interconnected.
The first review in this minireview series by Alberio, Lopiano and Fasano focuses on cellular models of PD. In vitro models represent the most environmentally controlled systems for investigating a complex, multifactorial disease. Cellular models are especially useful for exploring a particular pathogenetic mechanism and the genes/proteins involved, thus allowing investigators to dissect the complex pathogenetic cascade into simpler molecular events. Cellular investigations have the intrinsic advantage of being performed in a fast and reproducible way, directly targeting specific molecular pathways at the basis of the progression of PD. The review describes the contribution of PD models based on cellular systems to the understanding of molecular neurodegeneration mechanisms in PD, such as apoptosis and oxidative stress, mitochondrial impairment, unfolded protein stress and the removal of misfolded proteins.
Conversely, cellular models lack the cellular microenvironment critical for disease development, which is present in animal models, although differences in brain structures and the methods used to induce parkinsonism constitute an important limitation. The second review by Blandini and Armentero focuses on these issues. The authors describe the rationale for developing animal models of PD, discussing the limitations and advantages of toxic and transgenic animal models. Models based on the systemic or local administration of neurotoxins represent the classic and oldest method of reproducing experimental parkinsonism in animals. With this approach, substantial nigrostriatal degeneration is generally obtained, with good replication of PD motor symptoms (particularly in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkeys), although no consistent Lewy body pathology. On the other hand, transgenic models offer the invaluable possibility of looking into selected molecular aspects of PD pathogenesis, particularly for the familial forms. Nevertheless, the absence of consistent neuronal damage in the nigrostriatal pathway remains a major limitation of these models.
Because PD is a complex disease observed only in humans, several clinical issues cannot be investigated using models. Furthermore, PD mainly affects brain regions that can only be reached by brain autopsy. This subject is discussed in the third review by Ravid and Ferrer. Here, critical aspects of brain banking procedures (from ethical aspects to sampling and storage procedures) are approached to obtain the best reproducibility and the broadest distribution of a restricted number of human specimens to the largest number of basic science laboratories. The review also illustrates the relevance of post-mortem studies for investigating pathological and neurochemical correlates of non-motor symptoms and cognitive impairment in PD.
[ Mauro Fasano was born in 1965 in Asti, Italy. After a MS Degree in Chemistry and a PhD in Chemical Sciences at the University of Torino, he was appointed to an Assistant Professor position in Torino for 8 years. During this period, he worked on biochemistry of the iron–neuromelanin system in Parkinson’s disease. Since 2000, he has been an Associate Professor of Biochemistry at the University of Insubria. Here, he established the neuroproteomics laboratory, with a focus on the molecular mechanisms of Parkinson’s disease and the discovery of biomarkers. He has been the President of the Biological Chemistry Division of the Italian Chemical Society. ]