MUFA synthesis and stearoyl-CoA desaturase as a new pharmacological target for modulation of lipid and alpha-synuclein interaction against Parkinson's disease synucleinopathy.

Protein pathology spreading within the nervous system, accompanies neurodegeneration and a spectrum of motor and cognitive dysfunctions. Currently available therapies against Parkinson's disease and other synucleinopathies are mostly symptomatic and fail to slow the disease progression in the long term. Modification of α-synuclein (αS) aggregation and toxicity of its pathogenic forms is one of the main goals in neuroprotective approach. Since the discovery of lipid component of Lewy bodies, fatty acids became a crucial, yet little explored target for research. MUFAs (monounsaturated fatty acids) are substrates for lipids, such as phospholipids, triglycerides and cholesteryl esters. They regulate membrane fluidity, take part in signal transduction, cellular differentiation and other fundamental processes. αS and MUFA interactions are essential for Lewy body pathology. αS increases levels of MUFAs, mainly oleic acid, which in turn can enhance αS toxicity and aggregation. Thus, reduction of MUFAs synthesis by inhibition of stearoyl-CoA desaturase (SCD) activity could be the new way to prevent aggravation of αS pathology. Due to the limited distribution in peripheral tissues, SCD5 is a potential target in novel therapies and therefore could be an important starting point in search for disease-modifying neuroprotective therapy. Here we summarize facts about physiology and pathology of αS, explain recently discovered lipid-αS interactions, review SCD function and involved mechanisms, present available SCD inhibitors and discuss their pharmacological potential in disease management. Modulation of MUFA synthesis, decreasing αS and lipid toxicity is clearly essential, but unexplored avenue in pharmacotherapy of Parkinson's disease and synucleinopathies.

Diverse action of repeated corticosterone treatment on synaptic transmission, neuronal plasticity, and morphology in superficial and deep layers of the rat motor cortex.

One of the adverse effects of prolonged stress in rats is impaired performance of skilled reaching and walking tasks. The mechanisms that lead to these abnormalities are incompletely understood. Therefore, we compared the effects of twice daily repeated corticosterone injections for 7 days on miniature excitatory postsynaptic currents (mEPSCs), as well as on synaptic plasticity and morphology of layers II/III and V pyramidal neurons of the primary motor cortex (M1) of male Wistar rats. Corticosterone treatment resulted in increased frequency, but not amplitude, of mEPSCs in layer II/III neurons accompanied by increased complexity of the apical part of their dendritic tree, with no changes in the density of dendritic spines. The frequency and amplitude of mEPSCs as well as the parameters characterizing the complexity of the dendritic tree were not changed in layer V cells; however, their dendritic spine density was increased. While corticosterone treatment resulted in an increase in the amplitude of field potentials evoked in intralaminar connections within layer II/III, it did not influence field responses in layer V intralaminar connections, as well as the extent of chemically induced layer V long-term potentiation (chemLTP) by the application of tetraethylammonium (TEA, 25 mM). However, chemLTP induction in layer II/III was impaired in slices prepared from corticosterone-treated animals. These data indicate that repeated 7-day administration of exogenous corticosterone induces structural and functional plasticity in the M1, which occurs mainly in layer II/III pyramidal neurons. These findings shed light on potential sites of action and mechanisms underlying stress-induced impairment of motor functions.

Short-term repeated corticosterone administration enhances glutamatergic but not GABAergic transmission in the rat motor cortex.

It has been demonstrated that stress impairs performance of skilled reaching and walking tasks in rats due to the action of glucocorticoids involved in the stress response. Skilled reaching and walking are controlled by the primary motor cortex (M1); however, it is not known whether stress-related impairments in skilled motor tasks are related to functional and/or structural alterations within the M1. We studied the effects of single and repeated injections of corticosterone (twice daily for 7 days) on spontaneous excitatory and inhibitory postsynaptic currents (sEPSCs and sIPSCs) recorded from layer II/III pyramidal neurons in ex vivo slices of the M1, prepared 2 days after the last administration of the hormone. We also measured the density of dendritic spines on pyramidal cells and the protein levels of selected subunits of AMPA, NMDA, and GABAA receptors after repeated corticosterone administration. Repeatedly administered corticosterone induced an increase in the frequency but not in the amplitude of sEPSCs, while a single administration had no effect on the recorded excitatory currents. The frequency and amplitude of sIPSCs as well as the excitability of pyramidal cells were changed neither after single nor after repeated corticosterone administration. Treatment with corticosterone for 7 days did not modify the density of dendritic spines on pyramidal neurons. Corticosterone influenced neither the protein levels of GluA1, GluA2, GluN1, GluN2A, and GluN2B subunits of glutamate receptors nor those of α1, ß2, and γ2 subunits of the GABAA receptor. The increase in sEPSCs frequency induced by repeated corticosterone administration faded out within 7 days. These data indicate that prolonged administration of exogenous corticosterone selectively and reversibly enhances glutamatergic, but not GABAergic transmission in the rat motor cortex. Our results suggest that corticosterone treatment results in an enhancement of spontaneous glutamate release from presynaptic terminals in the M1 and thereby uncovers a potential mechanism underlying stress-induced motor functions impairment.