Abstract
The cerebellum is an essential component in the control of motor patterns. Despite dramatic alteration of basal ganglia morpho-functionality in Parkinson’s disease (PD), cerebellar function appears to be unaffected by the disease. Only recently this brain structure has been proposed to play compensatory roles in PD-induced motor dysfunction, particularly during the initial asymptomatic stages of PD. In PD subjects and animal models of PD, such as MPTP-treated mice, brain structures other than basal ganglia are also affected by the disease, including cortical areas not involved in motor control. Thus, it is noteworthy that the cerebellum remains unaffected. In the present study, we have analyzed the lipid composition of membrane microdomains [lipid rafts (LR) and non-raft domains] and assessed the expression levels of genes encoding enzymes synthesizing membrane-related lipids. The outcomes revealed that membrane domain lipids in cerebellum are highly preserved both in control and MPTP-treated mice as compared to control animals. Likewise, only small, mostly not significant, changes were observed in the expression of lipid-related genes in the cerebellum. Indeed, most changes were related to aging rather than to the exposure to the neurotoxin. Conversely, in the same animals, lipid composition, and gene expression were dramatically altered in the occipital cortex (OC), a brain area unrelated to the control of motor function. PCR and immunohistochemical analyses of both brain areas revealed that dopamine transporter (DAT) mRNA and protein were expressed in OC but not in the cerebellum. As MPTP neurotoxicity requires the expression of DAT to access intracellular compartments, we hypothesized that the absence of DAT in cerebellum hampers MPTP-induced toxicity. We conclude that cerebellum is endowed with efficient mechanisms to preserve nerve cell lipid homeostasis, which greatly maintain the stability of membrane microdomains involved in synaptic transmission, signal transduction, and intercellular communication, which together may participate in the compensatory role of the cerebellum in PD symptomatology.
Highlights
The etiology of idiopathic Parkinsont’s disease (PD) remains unknown
We performed an exhaustive lipid analysis of both lipid raft and non-raft fractions isolated from cerebellum of the four experimental groups: 6-month old control, 14-month old control, 6-month old treated with MPTP, and 14-month old treated with MPTP
The prion protein PrP known to be integrated in neuronal lipid rafts (LR) was concentrated in F1 while the cytosolic glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and neuronuclear antigen NeuN were abundant in non-raft fractions (F4–F6)
Summary
The etiology of idiopathic Parkinsont’s disease (PD) remains unknown. It is known that idiopathic PD is more prevalent in aging populations (Van Den Eeden et al, 2003; Rodriguez et al, 2015), but little is known on the involvement of other potential factors as well as on the onset of the disease. Compelling evidence indicates that disruption of complex 1 of electron transport chain involved in mitochondrial respiration in dopaminergic neurons represents a contributing factor to idiopathic PD (Parker et al, 1989; Swerdlow et al, 1996; Perier et al, 2007). One of the best accepted animal models for sporadic PD is the MPTP (1-methyl-4-phenyl-1,2,3,6tetrahydropyridine) paradigm in mice, which develop signs, and symptoms of idiopathic PD (reviewed in Marsden and Sandler, 1986; Langston, 2017). These include a massive destruction of neurons at the substantia nigra pars compacta (SNpc) in the nigrostriatal pathway (Ricaurte et al, 1986). Once in the nerve cell its conversion to MPP+ (1-methyl 4-phenylpyridinium), it provokes a specific inhibition of mitochondrial complex 1 and subsequent oxidative stress, which eventually leads to cell death (Shoffner et al, 1991; Gerlach and Riederer, 1996; Meredith and Rademacher, 2011)
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