Mesenchymal Stem Cells Stabilize Axonal Transports for Autophagic Clearance of α-Synuclein in Parkinsonian Models

Abstract

Genome-wide association studies have identified two loci, SNCA and the microtubule (MT)-associated protein tau, as common risk factors for Parkinson's disease (PD). Specifically, α-synuclein directly destabilizes MT via tau phosphorylation and induces axonal transport deficits that are the primary events leading to an abnormal accumulation of α-synuclein that causes nigral dopaminergic cell loss. In this study, we demonstrated that mesenchymal stem cells (MSCs) could modulate cytoskeletal networks and trafficking to exert neuroprotective properties in wild-type or A53T α-synuclein overexpressing cells and mice. Moreover, we found that eukaryotic elongation factor 1A-2, a soluble factor derived from MSCs, stabilized MT assembly by decreasing calcium/calmodulin-dependent tau phosphorylation and induced autophagolysosome fusion, which was accompanied by an increase in the axonal motor proteins and increased neuronal survival. Our data suggest that MSCs have beneficial effects on axonal transports via MT stability by controlling α-synuclein-induced tau phosphorylation, indicating that MSCs may exert a protective role in the early stages of axonal transport defects in α-synucleinopathies. Stem Cells 2017;35:1934-1947.

Cytosolic Trapping of a Mitochondrial Heat Shock Protein Is an Early Pathological Event in Synucleinopathies

“…Dysfunctional mitochondria produce less ATP and more ROS, and because of the high energy demand in the synaptic compartment, lowering ATP leads to synaptic dysfunction (Rangaraju et al 2014) and triggers aSyn accumulation (Nakata et al, 2012). In addition, mitochondrial health correlates with axonal transport, regeneration (Smith and Gallo, 2018), and, consequently, the clearance of aSyn (Oh et al, 2017). Similarly, increased ROS levels facilitate aSyn aggregation (Tabner et al, 2006;Fernandes et al, 2014).…”

Phase I Trial of Intra-arterial Administration of Autologous Bone Marrow-Derived Mesenchymal Stem Cells in Patients with Multiple System Atrophy

“…It is well established that MSCs can migrate to injury sites and secrete various neurotrophic factors that exert neuroprotective effects [15,24], via anti-apoptotic [25], supportive (i.e., stimulation of mitosis, proliferation, and differentiation) [26], and angiogenic effects [25]. In our previous experimental studies, we have demonstrated the therapeutic potential of MSCs in animal models of parkinsonian disorders through antiin ammatory action [27], autophagy modulation [28], stabilization of axonal transport [18], control of microglia M2 polarization [29], proteolysis of α-synuclein aggregates [17], and inhibition of α-synuclein transmission [16], which might modulate α-synuclein-related microenvironments. Furthermore, in two previous clinical trials [12,13], we demonstrated the safety and clinical e cacy of intra-arterial and intravenous administration of autologous BM-MSCs in patients with MSA-C.…”

“…To ensure that patients with relatively early-stage MSA were enrolled, the following inclusion criteria were implemented: (1) total Uni ed MSA Rating Scale (UMSARS) score between 30 and 50; (2) disease duration of < 5 years since MS diagnosis. The other inclusion criteria were (1) age between 30 and 75 years; (2) supportive ndings from structural and/or functional imaging studies at the time of diagnosis (i.e., cerebellar atrophy on brain magnetic resonance imaging [MRI] or decreased glucose metabolism in the cerebellum on 18 (2) diagnosis of dementia according to the DSM-IV criteria; (3) severe white matter hyperintensities or cerebrovascular lesions on brain MRI; (4) mutations in spinocerebellar ataxia type 1, 2, 3, 6, 7, 8, and 17 genes; (5) other major neurological disorders (e.g. stroke or brain surgery); (6) severe medical comorbidities (e.g.…”

“…Only the administration of autologous mesenchymal stem cells (MSCs) via the intra-arterial/intravenous [12,13] or intrathecal routes [14] have shown any effect. Indeed, MSCs secrete various cytokines and growth factors that exert neuroprotective effects [15] and directly modulate α-synuclein-related neurodegeneration [16][17][18][19]. As such, MSCs may be the most suitable candidate for MSA treatment.…”

Cell secretome based approaches in Parkinson’s disease regenerative medicine

“…MSCs) a potential therapeutic tool for central nervous system (CNS) applications [48][49][50][51][52]. Indeed, the capacity to adapt and grow into different culture conditions indicates that MSCs could be able to change/modulate their own secretome according with the conditions in which they are cultured [53][54][55]. Besides the secretome modulation at the intracellular level, the modulation of external cues present in cells' microenvironment and their impact on paracrine signaling have also been explored (Figure 1).…”