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Elovl5 knock-out mice as a model of spinocerebellar ataxia 38

Eriola Hoxha1, 2, Rebecca M. Gabriele1, Ilaria Balbo1, Linda Masante1, Vanessa Zambelli1, Nico Mitro3, Donatella Caruso3, Alfredo Brusco4, Barbara Borroni5 and Filippo Tempia1, 2*
  • 1 Neuroscience Institute Cavalieri Ottolenghi, Neurophysiology of Neurodegenerative Diseases, Italy
  • 2 University of Torino, Dept. of Neuroscience, Italy
  • 3 University of Milano, Dept. of Pharmacological and Biomolecular Sciences, Italy
  • 4 University of Torino, Department of Medical Sciences, Italy
  • 5 University of Brescia, Department of Clinical and Experimental Sciences, Italy

SCA38 is a novel form of spinocerebellar ataxia caused by missense mutations in the very long chain fatty acid elongase 5 gene, ELOVL5 (Di Gregorio et al., 2014). The ELOVL5 gene codes for an enzyme involved in omega-3 and omega-6 fatty acids (FA) biosynthesis. The main clinical features of SCA38 patients are cerebellar ataxia, gait ataxia, nystagmus, cerebellar atrophy and hyposmia (Borroni et al., 2016). The main hypothesis of SCA38 is a loss of function of ELOVL5. In the brain, ELOVL5 is selectively expressed by cerebellar Purkinje cells and by mitral cells of the olfactory bulb, in line with the principal SCA38 symptoms, cerebellar ataxia and anosmia. ELOVL5 is essential for the elongation of C18-CoAs of both omega-3 and omega-6 FA, which serve as precursors for longer polyunsaturated fatty acids (PUFAs), including arachidonic acid (AA) and docosahexaenoic acid (DHA), required for different physiological functions. In fact, patients with SCA38 have reduced plasmatic levels of AA and DHA (Di Gregorio et al., 2014). From AA and DHA, a variety of signaling molecules involved in different phases of inflammation are produced, including prostaglandins, leukotrienes, tromboxane, resolvins, protectins and maresins (Serhan, 2015). Besides the actions of AA and DHA in inflammatory responses, compelling evidence indicates that they exert important roles in brain signaling ranging from membrane excitability to synaptic transmission regulation. Such effects of AA and DHA on brain signaling are largely mediated by their bioactive metabolites. Indeed, prostaglandin E2 (a lipid mediator of AA) regulates membrane excitability and hippocampal LTP (Chen and Bazan, 2005; Sang and Chen, 2006). Interestingly, neuroprotectin D1 (a lipid mediator of DHA) is able to attenuate evoked epileptic activity in the hippocampus (Musto et al., 2011). Therefore, it can be hypothesized that the pathogenic effects of Elovl5 loss of function might be due to the lack of either structural functions of downstream PUFAs on lipid membranes, or signaling molecules derived from PUFAs. In autoptic cerebellar tissue from SCA38 patients, we showed that the ELOVL5 protein was localized in the soma of Purkinje cells and in small cells of the white matter (Di Gregorio et al., 2014). Such localization was confirmed in the mouse (Di Gregorio et al., 2014). Furthermore, double labeling experiments in mice showed that, in the white matter, Elovl5 was co-localized with Olig2, a marker for immature oligodendrocytes. Our co-localization data point to central myelination defects as a potentially contributing factor in SCA38, in line with sensory loss or paresthesia in 50% of patients (Borroni et al., 2016). Furthermore, we exploited Elovl5 KO mice (Moon et al., 2009) as a model of the loss of function hypothesis. Starting at 3 months of age Elovl5 KO mice showed a significant motor impairment in the balance beam test (P< 0.001). In the repeated rotarod test, which detects motor learning deficits, Elovl5 KO mice displayed a deficit starting from the age of 6 months (P< 0.05). The motor training on the rotarod apparatus was repeated every 3 months. The performance of the first day of each training session was taken as a measure of long-term motor memory, revealing a significant retention deficit in Elovl5 KO mice (P< 0.05). However, Elovl5 KO mice showed normal gait parameters on the footprinting test and normal performance in the ladder rung test. In accordance with the expression of Elovl5 in mitral cells and with the symptoms of SCA38 patients, at 12 months of age, Elovl5 KO mice also displayed hyposmia (P< 0.05). Morphological analysis revealed a reduction in thickness of the molecular layer in the third cerebellar lobule in 12 months old Elovl5 KO mice (P< 0.05). However, we observed unaltered thickness of the granular layer and a preserved number of Purkinje cells. Our results suggest, in agreement with the loss of function hypothesis, that the deletion of Elovl5 in mice reproduces the main symptoms of SCA38 patients, which can be attributed to dysfunction of the cerebellum and olfactory bulb.

Acknowledgements

This research was supported by the financial support of Telethon-Italy (GGP14225).

References

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Keywords: Ataxia, spino-cerebellar ataxia, SCA38, Purkinje cell, Cerebellum, mitral cell, polyunsaturated fatty acids

Conference: The Cerebellum inside out: cells, circuits and functions , ERICE (Trapani), Italy, 1 Dec - 5 Dec, 2016.

Presentation Type: poster

Topic: Neuropathologies

Citation: Hoxha E, Gabriele RM, Balbo I, Masante L, Zambelli V, Mitro N, Caruso D, Brusco A, Borroni B and Tempia F (2019). Elovl5 knock-out mice as a model of spinocerebellar ataxia 38. Conference Abstract: The Cerebellum inside out: cells, circuits and functions . doi: 10.3389/conf.fncel.2017.37.00007

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Received: 15 Nov 2016; Published Online: 25 Jan 2019.

* Correspondence: Prof. Filippo Tempia, Neuroscience Institute Cavalieri Ottolenghi, Neurophysiology of Neurodegenerative Diseases, Orbassano, Turin, 10043, Italy, filippo.tempia@unito.it