Biochemistry of Parkinson's disease 28 years later: A critical review

Abstract

In 1960, Ehringer and Hornykiewicz (1) published a seminal article describing a reduction in dopamine levels in the striatum and substantia nigra of patients with Parkinson's disease. This observation had two consequences: the discovery of the mesostriatal system in the human brain, and the possibility of improving parkinsonian motor disability by restoring dopaminergic transmission with levodopa. It was only several years later that a decrease in dopamine levels was discovered in other brain structures, suggesting that the hypothalamic, mesolimbic, and mesocortical dopaminergic systems also degenerated to a certain extent. The principal studies demonstrating loss of dopaminergic neurons and changes in dopamine receptors are summarized in Tables 1-3. During the same period, decreases in noradrenaline and serotonin concentrations were detected in the basal ganglia and cerebral cortex, suggesting that the long ascending noradrenergic (Table 4) and serotoninergic ( Table 5 ) pathways, originating in the locus ceruleus and the raphe nuclei, respectively, were dysfunctional. Another 20 years passed before the discovery that the subcorticocortical cholinergic neurons (Table 6) and several peptidergic systems (Table 7) were also affected. We still know little about the fate of receptors (Table 8) and of neurons using amino acids as transmitters, except perhaps for those containing y-aminobutyric acid (Table 9). This succession of discoveries has been the object of a large and growing body of literature. A number of reviews summarize the data (8,12,18,23,40,47,(88)(89)(90)(91)(92)(93)(94). There is even a review of the reviews (2)! Therefore, instead of elaborating a new and exhaustive description of the biochemistry of Parkinson's disease, we intend rather to show how advances in our understanding of brain function have changed our pharmacological conception of the disease (discover and compensate for a neurotransmitter deficiency) to a physiological one (understand how dysfunction of neuronal systems produce symptoms). It has indeed been discovered through anatomical and biochemical studies that the lesions underlying the symptoms are more numerous and their consequences more complicated than originally thought. Progress has

Striatal phosphoproteins in Parkinson disease and progressive supranuclear palsy.

“…A. Grebb, J.-A.G., and P.G., unpublished work). Our results are also consistent with reports of the absence of change in the levels of Dl-type dopamine receptors (15,24), glutamic acid decarboxylase, y-aminobutryic acid, and several neuropeptides (22) in the striatum of patients with Parkinson disease or progressive supranuclear palsy. However, in the latter disease restricted lesions of large cholinergic interneurons may exist (4,5) and account, at least in part, for the decrease in striatal D2-type dopamine receptors (15).…”

“…This decrease reflects the degeneration of dopaminergic terminals in these two diseases and is in agreement with the decrease in tyrosine hydroxylase activity (3,22). In contrast, no significant change occurred in the levels of DARPP-32 or of any other proteins studied in the brains of patients with Parkinson disease or progressive supranuclear palsy.…”

Impaired visual search in drivers with Parkinson's disease

“…[5][6][7]12,17 This is not unusual given that impairments in working memory, attentional control, vision, and executive functions present early in the course of PD. [1][2][3][37][38][39][40][41] Although degeneration of the noradrenergic, serotoninergic, and cholinergic systems, 42 as well as early cortical Lewy bodies, 43 may also contribute to cognitive impairment in PD, these early cognitive abnormalities are primarily attributed to dopaminergic dysregulation of the frontostriatal circuitry. 44 Although loss of dopaminergic neurons in the nigrostriatal tract in PD most prominently affects dorsal putamen, leading to motor dysfunction, dopamine is also strongly depleted in the caudate nucleus, 45 which is associated with oculomotor, "prefrontal," and "limbic" circuits of the basal ganglia loops 46 -48 and plays an important role in cognitive and behavioral aspects of the disease.…”

A Trade-Off between Feedback-Based Learning and Episodic Memory for Feedback Events: Evidence from Parkinson’s Disease

“…Parkinson’s disease (PD) is characterized by severe loss of nigrostriatal dopaminergic neurons [1,2] and is well known to impair motor function. More recently, it has been recognized that cognitive functions are impacted as well [3,4,5,6,7,8,9,10].…”