Abstract
Most neurons are born with the potential to live for the entire lifespan of the organism. In addition, neurons are highly polarized cells with often long axons, extensively branched dendritic trees and many synaptic contacts. Longevity together with morphological complexity results in a formidable challenge to maintain synapses healthy and functional. This challenge is often evoked to explain adult-onset degeneration in numerous neurodegenerative disorders that result from otherwise divergent causes. However, comparably little is known about the basic cell biological mechanisms that keep normal synapses alive and functional in the first place. How the basic maintenance mechanisms are related to slow adult-onset degeneration in different diseasesis largely unclear. In this review we focus on two basic and interconnected cell biological mechanisms that are required for synaptic maintenance: endomembrane recycling and calcium (Ca2+) homeostasis. We propose that subtle defects in these homeostatic processes can lead to late onset synaptic degeneration. Moreover, the same basic mechanisms are hijacked, impaired or overstimulated in numerous neurodegenerative disorders. Understanding the pathogenesis of these disorders requires an understanding of both the initial cause of the disease and the on-going changes in basic maintenance mechanisms. Here we discuss the mechanisms that keep synapses functional over long periods of time with the emphasis on their role in slow adult-onset neurodegeneration.
Highlights
Proteins and organelles in all cells can become dysfunctional over time
Synaptic degeneration and Ca2+ homeostasis In Section 1.2 we proposed that synaptic maintenance requires a balance between “long-term potentiation (LTP)-like” (CaMKII-mediated) and “long-term depression (LTD)-like” (CaN-mediated) synaptic signaling pathways
We previously demonstrated that in addition to acting as the catalytic component of the γ-secretase complex, presenilins function as passive endoplasmic reticulum (ER) Ca2+ leak channels, a function disrupted by many familial AD (FAD) mutations
Summary
Proteins and organelles in all cells can become dysfunctional over time. Organisms utilize a variety of mechanisms to maintain cellular function and organ integrity. The maintenance problem of synapses in neurodegenerative diseases The study of molecular neurodegeneration largely focuses on the investigation of known neurotoxic insults that include Abeta peptides in Alzheimer’s Disease (AD), polyQ proteins in Huntington Disease (HD) and Ataxias, alpha-Synuclein in Parkinson’s Disease (PD), or tau tangles in tauopathies, to name but a few [5] All these neurotoxic insults affect the neuronal physiology, including ion homeostasis, intracellular membrane trafficking and degradation machineries. Niemann-Pick disease type C is caused by mutations in the endolysosomal membrane protein NPC1 and characterized by cholesterol accumulation in late endosomal or lysosomal compartments Synapses of both excitatory and inhibitory neurons deficient for NPC1 develop normally, but exhibit progressive functional defects [134]. It is possible that a therapeutic strategy that favors synaptic maintenance (such as for example selective activation of endomembrane degradation or inhibition of CaN) may proof beneficial in these disorders as well by making synapses more resistant to further toxic insults
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