The Neuronal Kinesin UNC-104/KIF1A Is a Key Regulator of Synaptic Aging and Insulin Signaling-Regulated Memory

Abstract

Summary Aging is the greatest risk factor for a number of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease. Furthermore, normal aging is associated with a decline in sensory, motor, and cognitive functions. Emerging evidence suggests that synapse alterations, rather than neuronal cell death, are the causes of neuronal dysfunctions in normal aging, and in early stages of neurodegenerative diseases. However, little is known about the mechanisms underlying age-related synaptic decline. Here we uncover a surprising role of the anterograde molecular motor UNC-104/KIF1A as a key regulator of neural circuit deterioration in aging C. elegans. Through analyses of synapse protein localization, synaptic transmission, and animal behaviors, we find that reduced function of UNC-104 accelerates motor circuit dysfunction with age, while upregulation of UNC-104 significantly improves motor function at advanced ages and also mildly extends lifespan. In addition, UNC-104-overexpressing animals outperform wild-type controls in associative learning and memory tests. Further genetic analyses suggest that UNC-104 functions downstream of the DAF-2 signaling pathway, and is regulated by the FOXO transcription factor DAF-16, which contributes to the effects of DAF-2 in neuronal aging. Together, our cellular, electrophysiological, and behavioral analyses highlight the importance of axonal transport in the maintenance of synaptic structural integrity and function during aging, and raise the possibility of targeting kinesins to slow age-related neural circuit dysfunction.

Axon regeneration in C. elegans: Worming our way to mechanisms of axon regeneration

“…The loss of intrinsic regenerative ability in aging adult neurons is not merely a secondary consequence of a decrepit animal, but is a regulated process occurring specifically in neurons (Byrne et al, 2014). Thus, adult decline of axon regeneration is an early effect of neuronal aging, occurring before other effects such as aberrant axon branching, defects in synaptic transmission, and decreased kinesin function (Pan et al, 2011; Tank et al, 2011; Toth et al, 2012; Liu et al, 2013; Li et al, 2016). …”

Conserved regulators of cognitive aging: From worms to humans

“…Maintaining CREB activity may be a way to preserve cognitive function with age in higher organisms, because CREB levels correlate with cognitive performance in mammals [31, 80, 109, 169], but the exact location and levels of this CREB maintenance will be important to avoid deleterious effects. Loss of short-term memory with age is less studied than long term memory, but several IIS targets have been identified that are required for normal STAM performance [97], and IIS mutants maintain STAM performance with age due to preserved pre-synaptic function [117]. Future work in model systems, both vertebrate and invertebrate, will be invaluable in the study of these targets in age-related cognitive decline.…”

“…Recently, daf-2’s enhanced STAM memory performance with age was discovered to also be due to maintenance of synaptic integrity [117]. The anterograde kinesin motor UNC-104/KIF1A regulates synapse distribution, synaptic transmission, and motility with age in C. elegans [117].…”

“…The anterograde kinesin motor UNC-104/KIF1A regulates synapse distribution, synaptic transmission, and motility with age in C. elegans [117]. Li et al (2016) determined that UNC-104 levels are increased in daf-2 animals, that UNC-104 functions downstream of IIS, and that UNC-104 is required for the memory extension of daf-2 animals at Day 1 as well as their maintenance of STAM performance with age [117]. The loss of synaptic integrity is a conserved feature of cognitive aging.…”

Profiling of presynaptic mRNAs reveals a role for axonal PUMILIOs in associative memory formation

“…What processes might axonal pufs regulate? We previously found that molecules that regulate pre-synaptic transport and transmission are important for learning and associative memory formation (Arey et al, 2018;Kaletsky et al, 2016;Lakhina et al, 2015;Li et al, 2016). Furthermore, pumilio is an important regulator of long-term memory in Drosophila (Dubnau et al, 2003), and mammalian PUM1/2 regulate dendrite morphogenesis, synaptic function, neuronal excitability, and hippocampal neurogenesis (Siemen et al, 2011;Vessey et al, 2010;Zhang et al, 2017).…”