MicroRNA profiles of MS gray matter lesions identify modulators of the synaptic protein synaptotagmin‐7

Abstract

We established microRNA (miRNA) profiles in gray and white matter multiple sclerosis (MS) lesions and identified seven miRNAs which were significantly more upregulated in the gray matter lesions. Five of those seven miRNAs, miR-330-3p, miR-4286, miR-4488, let-7e-5p, miR-432-5p shared the common target synaptotagmin7 (Syt7). Immunohistochemistry and transcript analyses using nanostring technology revealed a maldistribution of Syt7, with Syt7 accumulation in neuronal soma and decreased expression in axonal structures. This maldistribution could be at least partially explained by an axonal Syt7 transport disturbance. Since Syt7 is a synapseassociated molecule, this maldistribution could result in impairment of neuronal functions in MS patients. Thus, our results lead to the hypothesis that the overexpression of these five miRNAs in gray matter lesions is a cellular mechanism to reduce further endogenous neuronal Syt7 production. Therefore, miRNAs seem to play an important role as modulators of neuronal structures in MS.

MicroRNAs in gray and white matter multiple sclerosis lesions: impact on pathophysiology

“…To date, there are relatively few studies of miRNA profiles in CNS tissue (WML, GML or NAWM) of MS patients, as opposed to similar studies investigating miRNA alterations in CSF and blood [2][3][4][5][6]33,34]. Despite their scarcity, these studies found that miRNAs were distinctively and reproducibly altered in MSaffected CNS tissues, depending on the localization (white or gray matter) as well as on the inflammatory activity of the lesions (Table 1).…”

“…Remarkably, each type of lesion has its own distinctive set of upregulated and downregulated miRNAs, and even NAWM shows alterations in miRNA expression profiles compared with healthy controls [2][3][4][5][6]. As we will show below, despite methodological differences (see supplementary material, Table S1), there is good overlap of miRNAs between the individual studies and different lesion types that are repeatedly detected.…”

“…These advances result in part because miRNAs are stable even in formalin-fixed paraffin-embedded tissue and can therefore be reliably detected in archived tissue [1]. Thus, in MS, miRNA profiles have now been determined from normalappearing white matter (NAWM), white matter lesions (WML) and different types of gray matter lesion (GML) (subpial and leukocortical) and show characteristic alterations [2][3][4][5][6]. Concepts concerning pathomechanisms in MS lesions have been developed based on these miRNA profiles, which is the basis of this review.…”

“…S Teuber-Hanselmann et al miRNAs in GML (let-7e-5p, miR-4286, miR-432-5p, miR-4488 and miR-574-5p), and one additional miRNA that was relatively upregulated in GML compared with chronic inactive WML (miR-330-3p), which all targeted the synaptic protein Syt7 [3]. In addition, there was a clear disturbance of the axonal transport of Syt7, which accumulated retrogradely in neuronal cell bodies.…”

“…In addition, there was a clear disturbance of the axonal transport of Syt7, which accumulated retrogradely in neuronal cell bodies. It was hypothesized that upregulation of the abovementioned miRNAs modulates the endogenous synthesis of Syt7 [3] ( Figure 2). miRNAs of the let-7 family have been repeatedly described to modulate neurogenesis and axonal guidance [63][64][65][66][67] and dysregulation of miR-let-7 has been associated with neurodegenerative processes [68,69].…”