Synaptic dysfunction and septin protein family members in neurodegenerative diseases.

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.

Targeting ubiquilin-1 in Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) is a common neurodegenerative disorder affecting an increasing number of people worldwide as the population ages. Currently, there are no drugs available that could prevent AD pathogenesis or slow down its progression. Increasing evidence links ubiquilin-1, an ubiquitin-like protein, into the pathogenic mechanisms of AD and other neurodegenerative diseases. Ubiquilin-1 has been shown to play a key role in the regulation of the levels, subcellular targeting, aggregation and degradation of various neurodegenerative disease-associated proteins. These include the amyloid precursor protein and presenilins that are intimately involved in the mechanisms of AD. AREAS COVERED: Here, the properties and diverse functions of ubiquilin-1 protein in the context of the pathogenesis of AD and other neurodegenerative disorders are discussed. This review recapitulates the available knowledge on the involvement of ubiquilin-1 in the genetic and molecular mechanisms in AD. Furthermore, the association of ubiquilin-1 with specific proteins and mechanisms involved in the pathogenesis of neurodegenerative diseases is described and the known ubiquilin-1-interacting proteins summarized. EXPERT OPINION: The variety of ubiquilin-1-interacting proteins and its central role in the regulation of protein levels and degradation provides a number of novel candidates and approaches for future research and drug discovery.

Involvement of ubiquilin-1 transcript variants in protein degradation and accumulation.

Controlled management of protein levels and quality is essential for normal cellular function. Specific molecular chaperones and foldases monitor the levels and assist correct folding of proteins. The ubiquitin-proteasome system recognizes and degrades misfolded proteins that can otherwise be harmful to cells. However, when misfolded or aggregated proteins excessively accumulate, they may be sequestered to the microtubule-organizing center to form aggresomes. These may then be removed from cells by autophagocytosis. Abnormal protein accumulation and aggregation is a common hallmark of many neurodegenerative diseases. In a recent study, we provide evidence that specific transcript variants (TVs) of ubiquilin-1, which are genetically and functionally associated to Alzheimer's disease (AD), regulate proteasomal and aggresomal targeting of presenilin-1 (PS1), a key player in AD pathogenesis. Our study together with current data provide interesting implications for ubiquilin-1 and its TVs in the pathogenesis of AD and other neurodegenerative diseases involving abnormal protein aggregation.