Spinal muscular atrophy astrocytes exhibit abnormal calcium regulation and reduced growth factor production

Abstract

Spinal muscular atrophy is a genetic disorder caused by deletion of the survival motor neuron 1 (SMN1) gene that leads to loss of motor neurons in the spinal cord. Though motor neurons are selectively lost during SMA pathology, selective replacement of SMN in motor neurons does not lead to full rescue in mouse models. Due to the ubiquitous expression of SMN, it is likely that other cell types besides motor neurons are affected by its disruption and therefore may contribute to disease pathology. Here we show that astrocytes in SMAΔ7 mouse spinal cord and from SMA induced pluripotent stem cells (iPSCs) exhibit morphological and cellular changes indicative of activation prior to overt motor neuron loss. Furthermore, our in vitro studies show mis regulation of basal calcium and decreased response to ATP stimulation indicating abnormal astrocyte function. Together, these data show for the first time early disruptions in astrocytes that may contribute to SMA disease pathology.

A large animal model of spinal muscular atrophy and correction of phenotype

“…Another interesting aspect of motor neuron disorders is a role for non-motoneuron cells of the CNS in the development of the phenotype 51, 52 . In SMA, cells such as astrocytes, schwann cells and sensory neurons have been evoked 53–55 . However whether changes seen contribute to the pathology of SMA or are a result of motoneuron distress in response to low SMN levels remain unclear.…”

New insights into SMA pathogenesis: immune dysfunction and neuroinflammation

“…More specifically, increased astrogliosis was observed in necropsies of patients74, 75, 76, 77 and in the Smn ∆7 mouse model at both presymptomatic and symptomatic stages 78. SMA patient induced pluripotent stem cell‐derived astrocytes revealed abnormal calcium regulation, decreased glial cell‐derived neurotrophic factor (GDNF) production but normal GLT1 expression 78. There is no doubt that astrocyte intrinsic abnormalities contribute to SMA pathogenesis, however their link to neuroinflammation and motor neuron death has not been determined 79.…”

“…In contrast to ALS, microglia and T‐cells have been mainly overlooked while some reports have highlighted the contributions of astrocytes to disease pathogenesis. More specifically, increased astrogliosis was observed in necropsies of patients74, 75, 76, 77 and in the Smn ∆7 mouse model at both presymptomatic and symptomatic stages 78. SMA patient induced pluripotent stem cell‐derived astrocytes revealed abnormal calcium regulation, decreased glial cell‐derived neurotrophic factor (GDNF) production but normal GLT1 expression 78.…”

Early disruption of neurovascular units and microcirculatory dysfunction in the spinal cord in spinal muscular atrophy type I

“…Astrocytes in the ventral horn in an animal model of SMA-I show activation and abnormal functions prior to overt motor neuron loss [18]. This may suggest early disruption of the NVU and a stressful neurovascular environment in the anterior horn in SMA-I.…”