Neuron-specific knock-down of SMN1 causes neuron degeneration and death through an apoptotic mechanism

Abstract

Spinal muscular atrophy is a devastating disease that is characterized by degeneration and death of a specific subclass of motor neurons in the anterior horn of the spinal cord. Although the gene responsible, survival motor neuron 1 (SMN1), was identified 20 years ago, it has proven difficult to investigate its effects in vivo. Consequently, a number of key questions regarding the molecular and cellular functions of this molecule have remained unanswered. We developed a Caenorhabditis elegans model of smn-1 loss-of-function using a neuron-specific RNA interference strategy to knock-down smn-1 selectively in a subclass of motor neurons. The transgenic animals presented a cell-autonomous, age-dependent degeneration of motor neurons detected as locomotory defects and the disappearance of presynaptic and cytoplasmic fluorescent markers in targeted neurons. This degeneration led to neuronal death as revealed by positive reactivity to genetic and chemical cell-death markers. We show that genes of the classical apoptosis pathway are involved in the smn-1-mediated neuronal death, and that this phenotype can be rescued by the expression of human SMN1, indicating a functional conservation between the two orthologs. Finally, we determined that Plastin3/plst-1 genetically interacts with smn-1 to prevent degeneration, and that treatment with valproic acid is able to rescue the degenerative phenotype. These results provide novel insights into the cellular and molecular mechanisms that lead to the loss of motor neurons when SMN1 function is reduced.

WDR79/TCAB1 plays a conserved role in the control of locomotion and ameliorates phenotypic defects in SMA models

“…ceWDR79(RNAi) animals showed 20% reduction (P = 7,5E-06) in locomotion compared to controls ( Figure 1B). RNAi against the C. elegans homolog of SMN, smn-1 (henceforth designed as ceSmn1), also led to locomotion defects ( Figure 1B), as previously reported (BURT et al 2006;GALLOTTA et al 2016).…”

“…In addition, the combined use of Drosophila and C. elegans identified several genetic modifiers of the SMNdependent phenotype (DIMITRIADI et al 2010). For example, Plastin3 was shown to act as an Smn loss-of-function modifier in both animal models (DIMITRIADI et al 2010;GALLOTTA et al 2016).…”

Green kiwifruit extracts protect motor neurons from death in a spinal muscular atrophy model in Caenorhabditis elegans

“…After having clarified that green kiwifruit extracts cause a significant reduction in the number of dying MNs, we wondered whether these extracts were also able to promote healthy cell survival, at the dilution found to be effective to partially prevent neuronal death. In fact, the early signs of degeneration in our model are detectable in double transgenic animals with smn‐1 silencing and GFP expression in MNs as the disappearance of GFP‐expressing neurons (Gallotta et al, ). We have demonstrated that healthy neurons silenced in smn‐1 initially degenerate and do not express GFP anymore, and then accumulate apoptotic fluorescence, a late event in neuronal death, occurring after the activation of the cell death pathway genes and associated with indicators of cell death.…”

“…smn‐1 silencing in MNs causes the death of neurons, detectable as the accumulation of apoptotic‐related fluorescence in dying MNs, whose nature has been confirmed using cell death markers and genetic mutants (Gallotta et al, ). This accumulation is a late event in neuronal death and independent of the origin, is a specific, late sign of the degeneration of the MNs in which smn‐1 has been knocked down, and is never observed in negative controls.…”

The Clinical and Pathological Spectrum of Idiopathic Inflammatory Myopathies : Implications for pathogenesis, classification and diagnosis

“…Apoptosis was early reported to have a crucial importance in the primary lymph organs in the positive and negative selection of maturing effector cells [192] and for the abrogation of immune responses [193], where dysfunction soon was connected to immune diseases or malignancies [194,195]. Apoptosis has also been shown to have a role in degenerative diseases of the nervous system [196][197][198] and in diseases in other organs such as liver, heart and kidneys [199][200][201].…”