Abstract
The accumulation of aggregated forms of the α-synuclein (αSN) is associated with the pathogenesis of Parkinson’s disease (PD) and Dementia with Lewy Bodies. The loss of synapses is an important event in the pathogenesis of these diseases. Here we show that aggregated recombinant human αSN, but not βSN, triggered synapse damage in cultured neurons as measured by the loss of synaptic proteins. Pre-treatment with the selective cytoplasmic phospholipase A2 (cPLA2) inhibitors AACOCF3 and MAFP protected neurons against αSN-induced synapse damage. Synapse damage was associated with the αSN-induced activation of synaptic cPLA2 and the production of prostaglandin E2. The activation of cPLA2 is the first step in the generation of platelet-activating factor (PAF) and PAF receptor antagonists (ginkgolide B or Hexa-PAF) also protect neurons against αSN-induced synapse damage. αSN-induced synapse damage was also reduced in neurons pre-treated with the cholesterol synthesis inhibitor (squalestatin). These results are consistent with the hypothesis that αSN triggered synapse damage via hyperactivation of cPLA2. They also indicate that αSN-induced activation of cPLA2 is influenced by the cholesterol content of membranes. Inhibitors of this pathway that can cross the blood brain barrier may protect against the synapse damage seen during PD.
Highlights
Parkinson’s disease (PD) is a major neurodegenerative motor disorder which affects approximately2% of the population over 65
The synapse damage seen in PD and Dementia with Lewy Bodies is closely associated with SN
Incubation with SN did not affect the amounts of caveolin in neuronal cultures, nor did it significantly reduce cell viability as measured by the thiazolyl blue tetrazolium (MTT) method, indicating that there was no significant neuronal death in these cultures (98% cell viability ± 6 compared with 100% ± 5, n = 9, p = 0.43)
Summary
Parkinson’s disease (PD) is a major neurodegenerative motor disorder which affects approximately2% of the population over 65. Parkinson’s disease (PD) is a major neurodegenerative motor disorder which affects approximately. In addition to the defining characteristics of bradykinesia, resting tremor and rigidity, there significant psychiatric and autonomic symptoms are observed in a large % of patients [1]. The most common of the non-motor symptoms is Parkinson’s disease dementia (PDD), with a cumulative prevalence up to 75% of cases [2]. Observed in PD patients is Dementia with. Lewy Bodies, a similar condition to PDD in which dementia, rather than motor symptoms, are the primary clinical manifestations. Dementia with Lewy Bodies is the second most common cause of dementia after Alzheimer’s disease and is characterized by progressive cognitive decline and parkinsonism [3].
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