Elsevier

Brain Research

Volume 956, Issue 2, 29 November 2002, Pages 358-366
Brain Research

Research report
Selective changes in the levels of nicotinic acetylcholine receptor protein and of corresponding mRNA species in the brains of patients with Parkinson’s disease

https://doi.org/10.1016/S0006-8993(02)03571-0Get rights and content

Abstract

Reductions in the number of neuronal nicotinic acetylcholine receptors (nAChRs) have been shown to occur in connection with Parkinson’s disease (PD), but it is still unclear which subtype of this receptor is affected. In the present study we examined various nAChR subtypes employing ligand binding, as well as levels of subunit protein and mRNA in the brains of PD patients and age-matched controls. Binding of [3H]epibatidine and levels of α3 mRNA in the caudate nucleus and temporal cortex, but not in the hippocampus were significantly decreased in the PD brain. The level of the α3 protein subunit was significantly reduced in all these brain regions but there was no change in the level of α4. The level of the β2 protein subunit in the temporal cortex and hippocampus and the β2 mRNA in the temporal cortex was lowered. Both the levels of the α7 subunit protein and [125I]α-bungarotoxin binding were significantly increased in the temporal cortex of PD patients whereas the α7 mRNA level was unchanged. These findings reveal selective losses of the α3- and β2-containing nAChRs and an increase in the α7 nAChRs that might be related to the pathogenesis of PD.

Introduction

Parkinson’s disease (PD), a common neurodegenerative disorder, is characterized by both motor symptoms (including resting tremor, cogwheel rigidity, bradykinesia and loss of postural reflex) and disturbed cognitive function, with or without dementia [23], [28]. Biochemically, impairment of the dopaminergic system is responsible for most of the clinical symptoms observed [35].

Cholinergic dysfunction in the brain of patients with PD has also been reported. The activity of choline acetyltransferase in the cortex and hippocampus has been found to be reduced [38], [40], [48]. Furthermore, the number of muscarinic binding sites appears to be increased in the neocortical regions [2], [24], [43] and unchanged in the hippocampus and striatum [2], [24].

The neuronal nicotinic acetylcholine receptors (nAChRs) are transmitter-gated ion channels consisting of α and β subunits. To date, nine different α subunits (α2–α10) and three β subunits (β2–β4) have been cloned. Different combinations of α and β subunits or of α subunits alone give rise to various receptor subtypes exhibiting different physiological, pharmacological and anatomical distributions [13], [39]. nAChRs play major roles in cognitive processes such as learning and memory [19], [37]. The reduced number of nAChRs observed in connection with neurodegenerative diseases such as PD and Alzheimer’s disease (AD) [27], [36], [41] and with schizophrenia [1], [14] has awakened an interest in developing subtype-specific nAChR agonists for treatment of these disorders.

Alterations in the nAChRs in several regions of the brain of patients with PD have been observed. Deficits in nicotine binding sites have been demonstrated in the striatum [3], [7], [41], [47], the cortical areas [47], [56], the hippocampus [42], [47], the dorsolateral tegmentum and substantia nigra [40]. In some studies, however, no significant alteration in the number of nAChR binding sites in the striatum of PD patients has been detected [10], [24].

In order to elucidate in more detail the changes in different nAChR subtypes which occur in connection with PD, we have measured binding sites for [3H]epibatidine (α3, α4 nAChRs) and [125I]α-bungarotoxin (α-BTX) (α7 nAChRs), as well as subunit protein and mRNA levels in several regions of the PD brain. Our findings reveal selective alterations in the α3β2 and α7 nAChR subtypes in the brain of PD patients.

Section snippets

Postmortem samples of human brain

All autopsy brain tissues were obtained from the Department of Neurology, Turku University, Finland and stored at −80 °C until use. There were a total of 12 cases of PD and 12 age-matched controls, and they were respectively divided into two groups for the different detections due to the limited amount of tissues (Table 1). The patients had at least two of the cardinal features of PD: resting tremor, bradykinesia or rigidity. In addition, they had good response to levodopa and showed no atypical

Binding sites for [3H]epibatidine and [125I]α-BTX in PD and control brains

Binding sites for [3H]epibatidine and [125I]α-BTX in PD and control brain tissues were measured using a single concentration of these ligands (0.02 nM and 2 nM, respectively). [3H]Epibatidine binding in the caudate nucleus and temporal cortex of the PD patients was significantly decreased compared to aged-matched controls (Fig. 1); while a smaller but statistically non-significant reduction in the number of [3H]epibatidine binding sites in the hippocampus was observed (Fig. 1). The specific

Discussion

A progressive extrapyramidal movement disorder associated with PD is accompanied by progressive reduction of the level of dopamine and a severely reduced number of sites for dopamine uptake in the striatum area that includes the caudate nucleus and putamen [44], [57]. Since nAChRs in the striatum are involved in regulating the release of dopamine, many investigations have focused on changes in these receptors in the regions of brain affected by PD. Our present results concerning the [3

Acknowledgements

This work was supported financially by grants from the Swedish Medical Research Council (project no 05817), Stiftelsen för Gamla Tjänarinnor, Stiftelsen för Ragnhild och Einar Lundströms Minne, Loo and Hans Osterman’s Foundation, the KI Foundations, Gun and Bertil Stohne’s Foundation and Swedish Match.

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