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From the recognition of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism to the discovery of numerous genes responsible for rare Mendelian forms of parkinsonism, our understanding of the mechanisms involved in rare causes of parkinsonism has exploded in the past 25 years. It was hoped that further understanding of the pathophysiologic mechanisms involved in these conditions would lead to novel therapeutic interventions for people afflicted with what is by far the most common form of parkinsonism, Lewy body Parkinson's disease (hereafter referred to as PD). As clues to the pathophysiology of these other forms of parkinsonism arose, cellular and animal models designed to recapitulate these mechanisms were developed. These models have enhanced our understanding of nigrostriatal degeneration and basal ganglionic circuitry.


These advancements have also laid the framework for the development of several novel therapies to alleviate the symptoms of nigrostriatal degeneration, including dopamine agonists and deep brain stimulation. In contrast, these models have also led to the development of neuroprotective strategies that have been far less successfully translated to clinical use and have led to questions about the validity of their use for this purpose.1, 2 While the reason for these failures of translation is highly debatable, at least one potential problem that must be considered is the possibility that the pathophysiologic underpinnings of these genetic and acute intoxication forms of parkinsonism may play little if any role in the pathophysiology of PD. Indeed, there are likely myriad ways to cause degeneration of what appear to be highly vulnerable dopaminergic midbrain neurons and understanding one mechanism may in no way lead to a better understanding of the others. Alternatively, while a component of a particular mechanism may be relevant in various etiologies at a downstream level, critically important upstream components may differ, and truly neuroprotective therapies may depend on modifying these essential components in the neurodegenerative cascade. For example, while inhibition of mitochondrial complex 1 may be a critical factor in some toxin-induced causes of parkinsonism, it may be present only as an effect of an upstream pathophysiologic process in PD. Similarly, it seems entirely likely that while some of the genetic causes of parkinsonism have led to important discoveries regarding the pathophysiology of PD, most notably the recognition that α-synuclein is the primary component of Lewy bodies (LBs), nonmutated forms of some of the genes implicated in Mendelian parkinsonism may play no role in the pathophysiology of PD. This seems particularly likely for causes of parkinsonism that do not share one of the two essential neuropathological hallmarks of PD, LB accumulation, which include MPTP intoxication, mutations in Parkin and potentially several other genetic causes of parkinsonism that have as yet undetermined neuropathology. An extensive review of the known neuropathology of Mendelian parkinsonism has been recently reported.3


These assumptions highlight the need to gain a better understanding of the neuropathology of PD so that improved cellular and animal models that recapitulate essential components of the pathophysiology of PD may be developed. ...

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