Plastin 3 ameliorates spinal muscular atrophy via delayed axon pruning and improves neuromuscular junction functionality

Abstract

F-actin bundling plastin 3 (PLS3) is a fully protective modifier of the neuromuscular disease spinal muscular atrophy (SMA), the most common genetic cause of infant death. The generation of a conditional PLS3-over-expressing mouse and its breeding into an SMA background allowed us to decipher the exact biological mechanism underlying PLS3-mediated SMA protection. We show that PLS3 is a key regulator that restores main processes depending on actin dynamics in SMA motor neurons (MNs). MN soma size significantly increased and a higher number of afferent proprioceptive inputs were counted in SMAPLS3 compared with SMA mice. PLS3 increased presynaptic F-actin amount, rescued synaptic vesicle and active zones content, restored the organization of readily releasable pool of vesicles and increased the quantal content of the neuromuscular junctions (NMJs). Most remarkably, PLS3 over-expression led to a stabilization of axons which, in turn, resulted in a significant delay of axon pruning, counteracting poor axonal connectivity at SMA NMJs. These findings together with the observation of increased endplate and muscle fiber size upon MN-specific PLS3 over-expression suggest that PLS3 significantly improves neuromuscular transmission. Indeed, ubiquitous over-expression moderately improved survival and motor function in SMA mice. As PLS3 seems to act independently of Smn, PLS3 might be a potential therapeutic target not only in SMA but also in other MN diseases.

PLS3 Mutations in X-Linked Osteoporosis with Fractures

“…Overexpression of PLS3 has been reported to act as a protective modifier of spinal muscular atrophy, facilitating axonal growth and presynaptic F-actin-dependent processes at the neuromuscular junction. 17,18 A knockdown of pls3 in zebrafish was used in an investigation of motor axon development. 17 Since no other animal models were available, we used this model 17 to analyze the role of PLS3 in skeletal development.…”

Osteoporosis Caused by Mutations in PLS3: Clinical and Bone Tissue Characteristics

“…It is possible that there is functional redundancy of plastin 3 with other actin-binding proteins in humans. Studies on the bone phenotype of mouse models that are deficient in PLS3 or overexpress PLS3 (43) may provide important insights into the function of plastin 3 in the skeleton of mammalians. Such models could also be used to assess mechanosensitivity in vivo, for example by measuring the bone formation response to defined mechanical stimuli.…”

Plastin 3 is upregulated in iPSC-derived motoneurons from asymptomatic SMN1-deleted individuals

“…Moreover the proprioceptive input on MN somata was restored in PLS3 overexpressing SMA mice in comparison to SMA mice. Thus, high PLS3 levels restore impaired MN and NMJ functions caused by reduced SMN levels [18]. In contrast, overall survival rate is only very moderately prolonged in this severe SMA mouse model owing to impairment of other organs such as heart, lung and intestine [18].…”

“…It is being discussed that PLS3 exerts a protective effect in stabilising neuromuscular connectivity and improved MN-synapse architecture as demonstrated in a PLS3 overexpressing mouse model [18]. Therefore, triple immunocytochemical staining of axonal marker microtubule-associated protein tau (MAPT), PLS3 and actin was performed in MN cultures on d27.…”