Temporal Control of Axonal Transport: The Extreme Case of Organismal Ageing

Abstract

A fundamental question in cell biology is how cellular components are delivered to their destination with spatial and temporal precision within the crowded cytoplasmic environment. The long processes of neurons represent a significant spatial challenge and make these cells particularly dependent on mechanisms for long-range cytoskeletal transport of proteins, RNA and organelles. Although many studies have substantiated a role for defective transport of axonal cargoes in the pathogenesis of neurodevelopmental and neurodegenerative diseases, remarkably little is known about how transport is regulated throughout ageing. The scale of the challenge posed by ageing is considerable because, in this case, the temporal regulation of transport is ultimately dictated by the length of organismal lifespan, which can extend to days, years or decades. Recent methodological advances to study live axonal transport during ageing in situ have provided new tools to scratch beneath the surface of this complex problem and revealed that age-dependent decline in the transport of mitochondria is a common feature across different neuronal populations of several model organisms. In certain instances, the molecular pathways that affect transport in ageing animals have begun to emerge. However, the functional implications of these observations are still not fully understood. Whether transport decline is a significant determinant of neuronal ageing or a mere consequence of decreased cellular fitness remains an open question. In this review, we discuss the latest developments in axonal trafficking in the ageing nervous system, along with the early studies that inaugurated this new area of research. We explore the possibility that the interplay between mitochondrial function and motility represents a crucial driver of ageing in neurons and put forward the hypothesis that declining axonal transport may be legitimately considered a hallmark of neuronal ageing.

Altered Sensory Neuron Development in CMT2D Mice Is Site-Specific and Linked to Increased GlyRS Levels

“…Decreased neuronal health may, therefore, be contributing to reduced mitochondrial motility, as may the process of aging. Indeed, we have previously reported that the dynamics of signaling endosome transport in vivo remain unaltered in aged wild-type mice (Sleigh and Schiavo, 2016 ; Sleigh et al, 2020a ), whereas mitochondrial transport is known to be altered in old animals (Mattedi and Vagnoni, 2019 ).…”

A common theme for axonopathies? The dependency cycle of local axon homeostasis

“…They comprise the ‘dying‐back’ pathology, that is, the degeneration of axons starting at their distal ends; this can be observed in hereditary diseases including CMT and hereditary motor sensory neuropathy (HMSN), HSP, giant axonal neuropathy (GAN), adrenomyeloneuropathy (AMN) and in most forms of acquired axonopathies (Boxes 1 and 2). A further common observation is the occurrence of blocked transport as a key feature of axonopathy (Brady & Morfini, 2017; De Vos, Grierson, Ackerley, & Miller, 2008; Guo, Stoklund Dittlau, & Van Den Bosch, 2020; Millecamps & Julien, 2013; Prior et al, 2017; Sleigh, Rossor, Fellows, Tosolini, & Schiavo, 2019), which is also considered a hallmark of ageing neurons (Mattedi & Vagnoni, 2019). Furthermore, there are many reports of axon swellings; as pointed out by Mike Coleman: ‘axonal spheroids, or smaller varicosities, which can be broadly termed axonal dystrophy, are almost universal in neurodegenerative diseases of the CNS, probably as manifestations of a major pathway of CNS axonal death’ (Coleman, 2005).…”

Decreasing pdzd8-mediated mitochondrial-ER contacts in neurons improves fitness by increasing mitophagy

“…In contrast to the detrimental effects of increased tethering, reducing MERCs by knockdown of pdzd8 in Drosophila neurons dramatically delayed age-associated decline in locomotor activity and significantly extended median lifespan compared to control animals. Since decline in mitochondrial transport is proposed to contribute to neuronal aging (Vagnoni & Bullock, 2018), we hypothesized that reducing tethering in the aging flies might be protective by allowing sustained mitochondrial motility (Mattedi & Vagnoni, 2019). However, we detected no change in the percentage of motile mitochondria in larval neurons with reduced pdzd8 expression.…”

“…While mitochondrial motility is important for neuronal health, it remains an open question whether decline of mitochondrial transport in neurons contributes to aging (reviewed in (Mattedi and Vagnoni 2019)). We first tested the hypothesis that decreased ER-mitochondrial tethering contributes to the protective effect of pdzd8 downregulation in aging through changes in mitochondrial motility.…”