Reduced P53 levels ameliorate neuromuscular junction loss without affecting motor neuron pathology in a mouse model of spinal muscular atrophy

Abstract

Spinal Muscular Atrophy (SMA) is a childhood motor neuron disease caused by mutations or deletions within the SMN1 gene. At endstages of disease there is profound loss of motor neurons, loss of axons within ventral roots and defects at the neuromuscular junctions (NMJ), as evidenced by pathological features such as pre-synaptic loss and swelling and post-synaptic shrinkage. Although these motor unit defects have been widely described, the time course and interdependancy of these aspects of motor unit degeneration are unclear. Recent reports have also revealed an early upregulation of transcripts associated with the P53 signalling pathway. The relationship between the upregulation of these transcripts and pathology within the motor unit is also unclear. In this study, we exploit the prolonged disease timecourse and defined pre-symptomatic period in the Smn 2B/ − mouse model to perform a temporal analysis of the different elements of motor unit pathology. We demonstrate that NMJ loss occurs prior to cell body loss, and coincides with the onset of symptoms. The onset of NMJ pathology also coincides with an increase in P53-related transcripts at the cell body. Finally, using a tamoxifen inducible P53 knockout, we demonstrate that post-natal reduction in P53 levels can reduce NMJ loss, but does not affect other aspects of NMJ pathology, motor neuron loss or the phenotype of the Smn 2B/− mouse model. Together this work provides a detailed temporal description of pathology within motor units of an SMA mouse model, and demonstrates that NMJ loss is a P53-dependant process. This work supports the role for P53 as an effector of synaptic and axonal degeneration in a die-back neuropathy.

Central synaptopathy is the most conserved feature of motor circuit pathology across spinal muscular atrophy mouse models

“…In accordance, the SMNΔ7 mouse model exhibits pronounced NMJ pathology predominantly in proximal muscles ( Kong et al, 2021 ; Ling et al., 2012 ; Ruiz et al., 2010 ) that reliably reflects the proximo-distal disease progression in patients with SMA ( Dubowitz, 2009 ). In contrast, the Taiwanese and Smn 2B/ - models exhibit only modest NMJ denervation ( Bowerman et al., 2012 ; Courtney et al, 2019b ; Lin et al., 2016 ). Moreover, while the degeneration and dysfunction of proprioceptive synapses onto motor neurons have been shown as one of the earliest pathological events in SMNΔ7 mice ( Fletcher et al., 2017 ; Mentis et al., 2011 ; Simon et al., 2019 ; Vukojicic et al., 2019 ), they have only been investigated at end-stage in the other two models ( Ackermann et al., 2013 ; Cervero et al., 2018 ; Hosseinibarkooie et al., 2016 ; Shorrock et al., 2018 ).…”

Motor transmission defects with sex differences in a new mouse model of mild spinal muscular atrophy

“…Recent studies have identified the P53 pathway as the likely culprit whose activation leads to the motor neuron degeneration in SMA [50,51]. Inhibiting the P53 pathway led to an almost complete rescue of motor neurons, but motor deficits, weight and survival were not rescued, highlighting that motor neuron loss is likely a late consequence of disease pathogenesis [51,52]. It is possible that it may simply not be present during a very mild disease course despite clinical motor dysfunction.…”

In Search of a Cure: The Development of Therapeutics to Alter the Progression of Spinal Muscular Atrophy

“…The molecular mechanisms evoking distinct spinal motoneuron death in SMA remain unresolved [127]. While the c-Jun N-terminal kinase (JNK)/c-jun signaling axis and the p53 signaling pathway have been implicated in severe SMA mouse models [128][129][130], the molecular mechanisms carrying out spinal motoneuron loss in SMA are likely complex, potentially context dependent, and may differ based on disease severity of the SMA model [131,132].…”