Knockdown of α-synuclein in cerebral cortex improves neural behavior associated with apoptotic inhibition and neurotrophin expression in spinal cord transected rats

Abstract

Spinal cord injury (SCI) often causes severe functional impairment with poor recovery. The treatment, however, is far from satisfaction, and the mechanisms remain unclear. By using proteomics and western blot, we found spinal cord transection (SCT) resulted in a significant down-regulation of α-synuclein (SNCA) in the motor cortex of SCT rats at 3 days post-operation. In order to detect the role of SNCA, we used SNCA-ORF/shRNA lentivirus to upregulate or knockdown SNCA expression. In vivo, SNCA-shRNA lentivirus injection into the cerebral cortex motor area not only inhibited SNCA expression, but also significantly enhanced neurons' survival, and attenuated neuronal apoptosis, as well as promoted motor and sensory function recovery in hind limbs. While, overexpression SNCA exhibited the opposite effects. In vitro, cortical neurons transfected with SNCA-shRNA lentivirus gave rise to an optimal neuronal survival and neurite outgrowth, while it was accompanied by reverse efficiency in SNCA-ORF group. In molecular level, SNCA silence induced the upregulation of Bcl-2 and the downregulation of Bax, and the expression of NGF, BDNF and NT3 was substantially upregulated in cortical neurons. Together, endogenous SNCA play a crucial role in motor and sensory function regulation, in which, the underlying mechanism may be linked to the regulation of apoptosis associated with apoptotic gene (Bax, Bcl2) and neurotrophic factors expression (NGF, BDNF and NT3). These finds provide novel insights to understand the role of SNCA in cerebral cortex after SCT, and it may be as a novel treatment target for SCI repair in future clinic trials.

Reducing Endogenous α-Synuclein Mitigates the Degeneration of Selective Neuronal Populations in an Alzheimer's Disease Transgenic Mouse Model

“…In agreement with the finding that ␣-syn ablation might be neuroprotective, previous studies have shown that knocking down ␣-syn protects experimental models from the toxic effects of MPTP (Drolet et al, 2004;Javed et al, 2015), 3-nitropropionic acid , and spinal cord injury (Wang et al, 2016). The mechanisms through which reducing ␣-syn might protect neuronal populations from selected injuries or toxins such as A␤ oligomers are not completely understood.…”

“…In contrast, previous studies in DLB and ␣-syn Tg models have shown that ␣-syn aggregates disrupt endocytic and secretory pathways via abnormal interactions with Rab3A, Rab5, and Rab8 (Eisbach and Outeiro, 2013;Wang et al, 2014). These alterations can be reversed by overexpression of Rab1, Rab3a, and Rab11.…”

“…However, given that ␣-syn has been proposed to play a role in intracellular vesicular trafficking (Cooper et al, 2006), one possibility is that reducing ␣-syn might attenuate the A␤-triggered alterations in vesicular trafficking. In AD, previous studies have shown abnormal endocytic function with enlarged Rab5 endosomes and alterations in Rab7 that might result in defective neurotrophic factor (NTF) transport (Almeida et al, 2006;Wu et al, 2009;Ginsberg et al, 2010;Li et al, 2012;Wang et al, 2014). It has been shown that Rab1B and 6 are involved in the transport and processing of APP, and Rab6 and Rab11 facilitate BACE1 and PS1 trafficking .…”

Spag6 Mutant Mice Have Defects in Development and Function of Spiral Ganglion Neurons, Apoptosis, and Higher Sensitivity to Paclitaxel

“…Although the mechanism underlying apoptosis in Spag6 mutant SGNs needs further investigation, increased expression of Bax and the ratio of Bax and Bcl-2, the uneven distribution of cytochrome c and activated caspase 9 and 3 positive staining suggests that apoptosis was mediated through the mitochondrial pathway. Interestingly, Bcl-2 was not changed or increased significantly between the two groups, although Bax and Bcl-2 often show opposite trends in apoptosis related models 22 , 23 . Therefore, it seems that Spag6 increases Bax to alter the balance between Bax and Bcl-2, rather than decreasing Bcl-2.…”

Therapeutic Effect of Curcumin and Methylprednisolone in the Rat Spinal Cord Injury

“…SCI is one of the major causes of death and disability in clinical situations. It creates enormous psychological and economic burdens to an individual's family as well as the society as a whole (Guo et al, 2014;Du et al, 2015;Lu et al, 2015;Wang et al, 2016;Yang and Wang, 2015). In the United States, there are approximately 282,000 people suffering from SCI with an average growth of 17,000 cases annually (Jalan et al, 2016).…”