Abstract
A serendipitous pharmacogenetic finding links the vulnerability to developing levodopa-induced dyskinesia to the age of onset of Huntington's disease. Huntington's disease is caused by a polyglutamate expansion of the protein huntingtin. Aberrant huntingtin is less capable of binding to a member of membrane-associated guanylate kinase family (MAGUKs): postsynaptic density- (PSD-) 95. This leaves more PSD-95 available to stabilize NR2B subunit carrying NMDA receptors in the synaptic membrane. This results in increased excitotoxicity for which particularly striatal medium spiny neurons from the indirect extrapyramidal pathway are sensitive. In Parkinson's disease the sensitivity for excitotoxicity is related to increased oxidative stress due to genetically determined abnormal metabolism of dopamine or related products. This probably also increases the sensitivity of medium spiny neurons for exogenous levodopa. Particularly the combination of increased oxidative stress due to aberrant dopamine metabolism, increased vulnerability to NMDA induced excitotoxicity, and the particular sensitivity of indirect pathway medium spiny neurons for this excitotoxicity may explain the observed increased prevalence of levodopa-induced dyskinesia.
Highlights
Over 45 years after discovery of its beneficial effects [1, 2], levodopa remains the mainstay of treatment of Parkinson’s disease (PD)
We want to hypothesize that NMDA receptor related excitotoxicity plays an important role in both Huntington’s disease (HD) and levodopa-induced dyskinesia (LID)
In HD, excitotoxicity is caused by disinhibition of NR2B carrying NMDA receptors which are more extensively stabilized within the synaptic membrane and are regularly too active
Summary
Over 45 years after discovery of its beneficial effects [1, 2], levodopa remains the mainstay of treatment of Parkinson’s disease (PD). Long-term levodopa treatment of PD is frequently complicated by motor fluctuations and dyskinesia [3,4,5,6]. No effective drug treatment of levodopa-induced dyskinesia (LID) has been developed [8]. Our analysis revealed that two GRIN2A variants, rs7192557 and rs8057394, were most frequently associated with dyskinesia in our control group of patients with neurological disorders (101 with Parkinson’s disease, 21 with essential tremor, and 21 with different forms of dystonia). In the current paper we try to examine a possible similarity between the pathological mechanisms of LID and HD based on the found association of two GRIN2A variants and the progression of both diseases.
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