The role of sirtuin 2 in oligodendroglia on dopaminergic neuron differentiation and regeneration

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder, characterized by an extensive dopaminergic neuron loss from the substantia nigra pars compacta (SNpc), resulting in synaptic loss in the striatum and in reduced dopamine levels. The ability to regenerate of the still existing neurons is very low or inhibited. Sirtuins are a family of proteins highly expressed in the central nervous system (CNS). The NAD+-dependent deacetylase Sirtuin 2 (SIRT2) is present in many CNS cells, and was described to be expressed by oligodendrocytes and modulate oligodendroglial differentiation possibly through its tubulin deacetylation activity. Therefore, we hypothesized that SIRT2 might influence the differentiation of dopaminergic neurons and axonal regeneration by modulating a) oligodendroglial and b) neuronal functions. In the present study, we attempted to elucidate the role that SIRT2 plays in oligodendrocytes and how relevant this could be for the development of the SNpc and for neuronal regeneration. We addressed these questions by analyzing the number of tyrosine-hydroxylase-positive (TH+) dopaminergic neurons in the SNpc of conditional neuronal and oligodendroglial Sirt2-KO mice, and further explored the role of oligodendroglial SIRT2 in two distinct cell models. We observed that SIRT2 overexpression exerts potentially beneficial effects on cell metabolism in OLN-93 oligodendroglial cells. Since the ratio of oligodendroglia in primary cortical cultures is low, we could not detect changes in the levels of ubiquitously expressed or neuronal proteins, such as GAP-43. Interestingly, although the oligodendroglial CNP expression was not altered, differentiation of those cells might change. Along with the absence of GAP-43 regulation, we also did not detect changes in axonal regeneration in the scratch model. However, when SIRT2 is missing during the total development of the brain, it affects the number of TH+ cells in the SNpc, as we found less dopaminergic neurons in the SNpc of neuronal Sirt2-KO mice, and more in oligodendroglial Sirt2-KO mice. In summary, oligodendroglial SIRT2 plays an important role in neuronal development in the SNpc, most probably in terminating the differentiation progress. In contrast, neuronal SIRT2 seems to be important for the differentiation per se. Additionally, oligodendroglial SIRT2 regulates mitochondrial respiration. Our study contributes to the understanding of the SIRT2-mediated axonal-glia interaction, in particular in dopaminergic neuronal differentiation. This may impact on the molecular mechanisms underlying PD, and may open novel avenues for the development of effective therapeutic strategies against this devastating disorder