Synaptic dysfunction and septin protein family members in neurodegenerative diseases

Abstract

Cognitive decline and disease progression in different neurodegenerative diseases typically involves synaptic dysfunction preceding the neuronal loss. The synaptic dysfunction is suggested to be caused by imbalanced synaptic plasticity i.e. enhanced induction of long-term depression and concomitantly decreased long-term potentiation accompanied with excess stimulation of extrasynaptic N-Methyl-D-aspartate (NMDA) receptors due to various disturbances in pre- and postsynaptic sites. Recent research has identified neurodegenerative disease-related changes in protein accumulation and aggregation, gene expression, and protein functions, which may contribute to imbalanced synaptic function. Nevertheless, a comprehensive understanding of the mechanisms regulating synaptic plasticity in health and disease is still lacking and therefore characterization of new candidates involved in these mechanisms is needed. Septins, a highly conserved group of guanosine-5'-triphosphate (GTP)-binding proteins, show high neuronal expression and are implicated in the regulation of synaptic vesicle trafficking and neurotransmitter release. In this review, we first summarize the evidence how synaptic dysfunction is related to the pathogenesis of Alzheimer’s, Parkinson’s and Huntington’s disease and frontotemporal lobar degeneration. Then, we discuss different aspects of the potential involvement of the septin family members in the regulation of synaptic function in relation to the pathogenesis of neurodegenerative diseases.

Septin Mutations in Human Cancers

“…To date, septins are linked to various disease states including neurodegenerative, neuromuscular and blood disorders as well as infertility and developmental disabilities (Dolat et al, 2014a; Marttinen et al, 2015). Notably, septin expression levels are widely altered in almost every cancer type from leukemias and epithelial carcinomas to melanomas and gliomas (Cerveira et al, 2011; Connolly et al, 2011a; Dolat et al, 2014a).…”

SEPT8 modulates β-amyloidogenic processing of APP by affecting the sorting and accumulation of BACE1

“…Septins are a conserved family of GTP-binding proteins, which are highly expressed in the brain and known to take part in the formation, growth and stability of axons and dendrites, synaptic plasticity and vesicular trafficking (Marttinen et al, 2015). Beyond these physiological functions, septins have been linked to different neurodegenerative and psychiatric disorders, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal dementia, Down syndrome and schizophrenia (Ageta-Ishihara et al, 2013; Barr et al, 2004;Dong et al, 2003;Gozal et al, 2011;Ihara et al, 2007;Kinoshita et al, 1998;Pissuti Damalio et al, 2012;Zhang et al, 2000).…”

“…Collectively, in order to identify factors that could be utilized as novel drug targets or predictive biomarkers in Alzheimer's disease, it is necessary to focus on the cellular processes involved in the early steps of Alzheimer's disease pathogenesis. Septins (denoted SEPT) are a conserved family of GTP-binding proteins, which are highly expressed in the brain (Marttinen et al, 2015). The septin protein family is composed of 13 genes, which are divided into four subgroups based on their sequence homology and domain composition: the SEPT2 group (SEPT1, SEPT2, SEPT4 and SEPT5), SEPT3 group (SEPT3, SEPT9 and SEPT12), SEPT6 group (SEPT6, SEPT8, SEPT10, SEPT11 and SEPT14) and SEPT7 group (SEPT7 only).…”

M30 Antagonizes Indoleamine 2,3-Dioxygenase Activation and Neurodegeneration Induced by Corticosterone in the Hippocampus

“…Synaptic degeneration is suggested to be closely connected to the pathogenesis of depression, resulting from a significant loss of pre- and post-synaptic proteins [55, 56]. Pre-synaptic vesicle proteins play a role in the release of neurotransmitter into the synaptic cleft facilitating the neuronal communication while post-synaptic proteins orchestra the received pre-synaptic signal that in turn to adjust and fine-tune the activity of the dendritic spine [57, 58].…”