Astrocytes influence the severity of spinal muscular atrophy

Abstract

Systemically low levels of survival motor neuron-1 (SMN1) protein cause spinal muscular atrophy (SMA). α-Motor neurons of the spinal cord are considered particularly vulnerable in this genetic disorder and their dysfunction and loss cause progressive muscle weakness, paralysis and eventually premature death of afflicted individuals. Historically, SMA was therefore considered a motor neuron-autonomous disease. However, depletion of SMN in motor neurons of normal mice elicited only a very mild phenotype. Conversely, restoration of SMN to motor neurons in an SMA mouse model had only modest effects on the SMA phenotype and survival. Collectively, these results suggested that additional cell types contribute to the pathogenesis of SMA, and understanding the non-autonomous requirements is crucial for developing effective therapies. Astrocytes are critical for regulating synapse formation and function as well as metabolic support for neurons. We hypothesized that astrocyte functions are disrupted in SMA, exacerbating disease progression. Using viral-based restoration of SMN specifically to astrocytes, survival in severe and intermediate SMA mice was observed. In addition, neuromuscular circuitry was improved. Astrogliosis was prominent in end-stage SMA mice and in post-mortem patient spinal cords. Increased expression of proinflammatory cytokines was partially normalized in treated mice, suggesting that astrocytes contribute to the pathogenesis of SMA.

New insights into SMA pathogenesis: immune dysfunction and neuroinflammation

“…SMN restoration restricted to the astrocyte compartment significantly increased lifespan and motor behavior, but did not improve motor neuron survival 75. More related to the context of neuroinflammation, pro‐inflammatory cytokines could be elevated in SMA patients and mouse models 11, 75. Microglial activation has been observed in the Smn ∆7 mouse model but not in the more severe Smn −/− ;SMN2 mice 76, 77, 80.…”

“…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.…”

“…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. SMN restoration restricted to the astrocyte compartment significantly increased lifespan and motor behavior, but did not improve motor neuron survival 75. More related to the context of neuroinflammation, pro‐inflammatory cytokines could be elevated in SMA patients and mouse models 11, 75.…”

Emerging therapies and challenges in spinal muscular atrophy

“…59, 60 For example, there is now experimental evidence suggesting a non‐cell‐autonomous contribution to motor neuron degeneration from astrocytes and Schwann cells 61, 62. Likewise, low levels of SMN in skeletal muscle have been implicated in SMA pathogenesis with significant disruption of the molecular composition of skeletal muscle evident in presymptomatic severe SMA mice in the absence of detectable changes in lower motor neurons 63.…”

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

“…This may suggest early disruption of the NVU and a stressful neurovascular environment in the anterior horn in SMA-I. Restoration of SMN protein in astrocytes has been shown to rescue defects in the neuromuscular junction, partially normalize astrocyte activation, and improve the SMA phenotype [19]. The number of motor neurons remains unchanged, and SMN in astrocytes may play a role in the protection and functional enhancement of the remaining motor neurons [19].…”