Abnormal mitochondrial transport and morphology as early pathological changes in human models of spinal muscular atrophy

Abstract

Spinal muscular atrophy (SMA), characterized by specific degeneration of spinal motor neurons, is caused by mutations in the survival of motor neuron 1, telomeric (SMN1) gene and subsequent decreased levels of functional SMN. How the deficiency of SMN, a ubiquitously expressed protein, leads to spinal motor neuron-specific degeneration in individuals affected by SMA remains unknown. In this study, we examined the role of SMN in mitochondrial axonal transport and morphology in human motor neurons by generating SMA type 1 patient-specific induced pluripotent stem cells (iPSCs) and differentiating these cells into spinal motor neurons. The initial specification of spinal motor neurons was not affected, but these SMA spinal motor neurons specifically degenerated following long-term culture. Moreover, at an early stage in SMA spinal motor neurons, but not in SMA forebrain neurons, the number of mitochondria, mitochondrial area and mitochondrial transport were significantly reduced in axons. Knocking down of SMN expression led to similar mitochondrial defects in spinal motor neurons derived from human embryonic stem cells, confirming that SMN deficiency results in impaired mitochondrial dynamics. Finally, the application of N-acetylcysteine (NAC) mitigated the impairment in mitochondrial transport and morphology and rescued motor neuron degeneration in SMA long-term cultures. Furthermore, NAC ameliorated the reduction in mitochondrial membrane potential in SMA spinal motor neurons, suggesting that NAC might rescue apoptosis and motor neuron degeneration by improving mitochondrial health. Overall, our data demonstrate that SMN deficiency results in abnormal mitochondrial transport and morphology and a subsequent reduction in mitochondrial health, which are implicated in the specific degeneration of spinal motor neurons in SMA.

Emerging therapies and challenges in spinal muscular atrophy

“…Consequently, SMN deficiency may impair targeting and local translation of axonal mRNAs essential for motor neuron development and maintenance 44, 45. Furthermore, SMN regulates several other fundamental cellular processes in the neuronal cytoplasm that are critical for maintaining axonal and synaptic health, including endocytic pathways, local translation, mitochondrial transport, and targeting to axons and ubiquitin homeostasis 46, 47, 48, 49, 50, 51…”

SMN regulation in SMA and in response to stress: new paradigms and therapeutic possibilities

“…Using live cell imaging of motor neurons derived from SMA type 1 iPSCs, Xu et al (2016) found a reduction in size, number and axonal transport of mitochondria in the SMA cells compared to WT cells. NAC treatment returned mitochondrial numbers and transport to WT levels.…”

Modeling axonal defects in hereditary spastic paraplegia with human pluripotent stem cells

“…Interestingly, we have observed the axonal transporter defects in spinal muscular atrophy (SMA) iPSC-derived motor neurons (Xu et al, 2016). Spinal muscular atrophy (SMA), the leading genetic cause of death in infants and toddlers, is caused by homologous deletion or mutations of the survival of motor neuron 1 ( SMN1 ) gene (Lefebvre et al, 1995).…”

“…Spinal motor neurons are specifically degenerated in SMA, yet the underlying mechanisms are not known. Using human pluripotent stem cell-based SMA cell models, we observed early mitochondrial defects in spinal motor neurons (Wang et al, 2013b, Xu et al, 2016), which is implicated in the specific degeneration of spinal motor neurons in SMA. Interestingly, mitochondrial dysfunction has also been as a major pathological process in many other neurodegenerative diseases, such as ALS, Parkinson’s disease, and Huntington’s disease (Chen and Chan, 2009, Magrane et al, 2014).…”