Small heat shock proteins determine synapse number and neuronal activity during development

Abstract

Environmental changes cause stress, Reactive Oxygen Species and unfolded protein accumulation which hamper synaptic activity and trigger cell death. Heat shock proteins (HSPs) assist protein refolding to maintain proteostasis and cellular integrity. Mechanisms regulating the activity of HSPs include transcription factors and posttranslational modifications that ensure a rapid response. HSPs preserve synaptic function in the nervous system upon environmental insults or pathological factors and contribute to the coupling between environmental cues and neuron control of development. We have performed a biased screening in Drosophila melanogaster searching for synaptogenic modulators among HSPs during development. We explore the role of two small-HSPs (sHSPs), sHSP23 and sHSP26 in synaptogenesis and neuronal activity. Both sHSPs immunoprecipitate together and the equilibrium between both chaperones is required for neuronal development and activity. The molecular mechanism controlling HSP23 and HSP26 accumulation in neurons relies on a novel gene (CG1561), which we name Pinkman (pkm). We propose that sHSPs and Pkm are targets to modulate the impact of stress in neurons and to prevent synapse loss.

Neural functions of small heat shock proteins

“…Genetic modifications that affect the expression of sHsp23 or sHsp26, provokes an imbalance in chaperones equilibrium that causes a reduction in synapse number, reinforcing the idea of chaperone complex and protein quality system equilibrium. Thus, sHSPs in neurons participate in synapse maintenance and modulation of neuronal function (Santana et al, 2020).…”

“…Thus, the phosphorylation state can alter protein activity and interactions with chaperones clients as a key-mechanism to sHSPs regulation. In our recent work, we propose that that sHSP23 and 26 neuronal functions are mediated by a novel putative kinase protein CG1561, named Pinkman (Pkm) (Santana et al, 2020).…”

Homeostatic Roles of the Proteostasis Network in Dendrites

“…Chaperones contribute a great deal to cytoskeletal stability, which is especially important for neurons to sustain their complex processes ( Table 2; Bakthisaran et al, 2015;Nefedova et al, 2015;Nefedova et al, 2017;Kelliher et al, 2019;Muranova et al, 2019;Vallin and Grantham, 2019;Muranova et al, 2020). Many chaperones are implicated specifically in axonal morphology: manipulation of several small heat shock proteins as well as Hsp70 and 90 was found to significantly decrease synapse number in Drosophila neuromuscular junctions (Santana et al, 2020), and an Hsp70 orthologue has been found to assist in polarized trafficking of synaptic vesicle proteins to axons (Fukuzono et al, 2016).…”

“…The interaction of chaperones may be the key to regulation of neuronal processes. Hspb6 has been found to act as a modulator of activity for other small Hsps in human cell culture (Weeks et al, 2018;Mymrikov et al, 2020;Santana et al, 2020). Furthermore, individual overexpression of Hsp23 or Hsp26 led to decreased number of synapses in the Drosophila neuromuscular junction, but combined overexpression of Hsp23 and Hsp26 together resulted in an increase in synapse numbers.…”

“…Furthermore, individual overexpression of Hsp23 or Hsp26 led to decreased number of synapses in the Drosophila neuromuscular junction, but combined overexpression of Hsp23 and Hsp26 together resulted in an increase in synapse numbers. From these surprising results and additional interactions with the novel kinase Pinkman, the authors hypothesize that Hsp23 and Hsp26 form a complex promoting synaptic formation and that the imbalance of the two chaperones may be the cause of synaptic dysregulation, rather than loss or gain of each individually (Santana et al, 2020).…”