Abstract

Synapses must be preserved throughout an organism's lifespan to allow for normal brain function and behavior. Synapse maintenance is challenging given the long distances between the termini and the cell body, reliance on axonal transport for delivery of newly synthesized presynaptic proteins, and high rates of synaptic vesicle exo- and endocytosis. Hence, synapses rely on efficient proteostasis mechanisms to preserve their structure and function. To this end, the synaptic compartment has specific chaperones to support its functions. Without proper synaptic chaperone activity, local proteostasis imbalances lead to neurotransmission deficits, dismantling of synapses, and neurodegeneration. In this review, we address the roles of four synaptic chaperones in the maintenance of the nerve terminal, as well as their genetic links to neurodegenerative disease. Three of these are Hsp40 co-chaperones (DNAJs): Cysteine String Protein alpha (CSPα; DNAJC5), auxilin (DNAJC6), and Receptor-Mediated Endocytosis 8 (RME-8; DNAJC13). These co-chaperones contain a conserved J domain through which they form a complex with heat shock cognate 70 (Hsc70), enhancing the chaperone's ATPase activity. CSPα is a synaptic vesicle protein known to chaperone the t-SNARE SNAP-25 and the endocytic GTPase dynamin-1, thereby regulating synaptic vesicle exocytosis and endocytosis. Auxilin binds assembled clathrin cages, and through its interactions with Hsc70 leads to the uncoating of clathrin-coated vesicles, a process necessary for the regeneration of synaptic vesicles. RME-8 is a co-chaperone on endosomes and may have a role in clathrin-coated vesicle endocytosis on this organelle. These three co-chaperones maintain client function by preserving folding and assembly to prevent client aggregation, but they do not break down aggregates that have already formed. The fourth synaptic chaperone we will discuss is Heat shock protein 110 (Hsp110), which interacts with Hsc70, DNAJAs, and DNAJBs to constitute a disaggregase. Hsp110-related disaggregase activity is present at the synapse and is known to protect against aggregation of proteins such as α-synuclein. Congruent with their importance in the nervous system, mutations of these co-chaperones lead to familial neurodegenerative disease. CSPα mutations cause adult neuronal ceroid lipofuscinosis, while auxilin mutations result in early-onset Parkinson's disease, demonstrating their significance in preservation of the nervous system.

Highlights

  • Reviewed by: Jeff Brodsky, University of Pittsburgh, United States Rafael Fernández-Chacón, Instituto de Biomedicina de Sevilla (CSIC) and Centro de Investigación

  • We address the roles of four synaptic chaperones in the maintenance of the nerve terminal, as well as their genetic links to neurodegenerative disease

  • The fourth synaptic chaperone we will discuss is Heat shock protein 110 (Hsp110), which interacts with heat shock cognate 70 (Hsc70), DNAJAs, and DNAJBs to constitute a disaggregase

Read more

Summary

PROTEIN FOLDING AND CHAPERONES

Proteins must fold into unique three-dimensional structures to fulfill their biological functions. As proteins are inherently structurally dynamic, they are apt to misfold into conformations that prevent their function or lead to toxic aggregates (Bukau et al, 2006; Hartl et al, 2011). This potential for misfolding can be exacerbated by cellular stress, such as that caused by heat shock or hypoxia (Bukau et al, 2006; Hartl et al, 2011). Mitochondria-specific chaperones include mHsp and Hsp that are involved in importing mitochondrial proteins into the matrix and folding them (Manning-Krieg et al, 1991). Hsp100s and small Hsps are nearly ubiquitous in terms of cellular localization (Haslbeck and Vierling, 2015; Zuo et al, 2016)

UNIQUE REQUIREMENTS FOR SYNAPTIC PROTEOSTASIS
CCT family
Compound heterozygote Homozygote Compound heterozygote Homozygote Homozygote
Findings
FUTURE DIRECTIONS
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call