Alterations in the Na+/H+ Exchanger NHE6 and Glutamate Transporters may Influence Purkinje Cell Fate in ARSACS.

IF 2.7 3区 医学 Q3 NEUROSCIENCES
Louis-Charles Masson, Atchaya S Kanagasabai, Brenda Toscano Márquez, Julia Tourbina-Kolomiets, Francois Charron, Alanna J Watt, R Anne McKinney
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引用次数: 0

Abstract

Patterned cell death is a common feature of many neurodegenerative diseases. This is apparent in cerebellar Purkinje cells (PCs) in patients and mouse models of Autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). In ARSACS, PCs in the anterior cerebellar vermis are vulnerable to degeneration while those in the posterior vermis are resilient. As the mechanisms underpinning cerebellar pathophysiology in ARSACS are not fully understood, we chose to investigate two important regulatory pathways for cellular health in neurons: (1) the autophagy-lysosome pathway which is important for the trafficking of cargo essential for proper neuronal function, as well as (2) excitatory amino acid transporters (EAATs) that regulate extracellular glutamate levels. Using a mouse model of ARSACS (Sacs-/-), we found a significant decrease in the Na+/H+ exchanger 6 (NHE6) in the PCs in the vulnerable anterior but not resilient posterior cerebellum. We looked at two EAATs that are highly expressed in the cerebellum: EAAT1 and EAAT4. Glial EAAT1 levels were significantly reduced in both anterior and posterior lobules, which could lead to excitotoxicity. However, the neuronal EAAT4 protein was elevated only in the resilient posterior PCs, likely counteracting the effects of reduced EAAT1 in posterior cerebellum. These results point to possible impairment in the endocytic pathway in the ARSACS cerebellum, and an elevation of EAAT4 glutamate transporters in the resilient posterior lobules of the cerebellar vermis that may contribute to neuroprotection.

Na+/H+交换体NHE6和谷氨酸转运体的改变可能影响ARSACS中浦肯野细胞的命运。
模式细胞死亡是许多神经退行性疾病的共同特征。这在常染色体隐性痉挛性共济失调(ARSACS)患者和小鼠模型的小脑浦肯野细胞(PCs)中表现明显。在ARSACS中,小脑前段蚓部的pc易发生变性,而后段蚓部的pc具有弹性。由于ARSACS的小脑病理生理机制尚不完全清楚,我们选择研究神经元细胞健康的两个重要调控途径:(1)自噬-溶酶体途径,这对正常神经元功能所必需的货物运输至关重要,以及(2)调节细胞外谷氨酸水平的兴奋性氨基酸转运体(EAATs)。通过小鼠ARSACS模型(Sacs-/-),我们发现易损小脑前脑而非弹性小脑后脑PCs中的Na+/H+交换6 (NHE6)显著降低。我们观察了在小脑中高度表达的两个eaat: EAAT1和EAAT4。神经胶质前小叶和后小叶EAAT1水平显著降低,可能导致兴奋毒性。然而,神经元EAAT4蛋白仅在有弹性的后脑PCs中升高,可能抵消了后小脑EAAT1减少的影响。这些结果表明,ARSACS小脑内吞通路可能受损,小脑蚓部弹性后小叶中EAAT4谷氨酸转运蛋白的升高可能有助于神经保护。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cerebellum
Cerebellum 医学-神经科学
CiteScore
6.40
自引率
14.30%
发文量
150
审稿时长
4-8 weeks
期刊介绍: Official publication of the Society for Research on the Cerebellum devoted to genetics of cerebellar ataxias, role of cerebellum in motor control and cognitive function, and amid an ageing population, diseases associated with cerebellar dysfunction. The Cerebellum is a central source for the latest developments in fundamental neurosciences including molecular and cellular biology; behavioural neurosciences and neurochemistry; genetics; fundamental and clinical neurophysiology; neurology and neuropathology; cognition and neuroimaging. The Cerebellum benefits neuroscientists in molecular and cellular biology; neurophysiologists; researchers in neurotransmission; neurologists; radiologists; paediatricians; neuropsychologists; students of neurology and psychiatry and others.
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