Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice

Macroautophagy has a neuroprotective function.

“The neuroprotective function of macroautophagy has become an interesting focus in neurodegenerative disease, exemplified in Huntington's disease (Menzies et al., 2006;Mizushima et al., 2008), as well as in animal models (Hara et al., 2006;Komatsu et al., 2006).”

Autophagy could protect cells from death, especially in motor neurons.

“Autophagy could protect cells from death (Hara et al., 2006; Komatsu et al., 2006), especially in motor neurons (Barmada et al., 2014).”

Autophagy protects cells from death, especially motor neurons.

“Autophagy could protect cells from death (Hara et al., 2006; Komatsu et al., 2006), especially in the case of motor neurons (Barmada et al., 2014).”

Autophagy is protective for neuronal survival in neurodegenerative diseases.

“Autophagy is now recognized as protective for neuronal survival in neurodegenerative diseases (Hara et al., 2006; Komatsu et al., 2006; Lee, 2012).”

Reduced basal autophagy in the mouse nervous system leads to neurodegeneration.

“Reduced basal autophagy in the mouse nervous system similarly leads to neurodegeneration (54,55).”

Basal autophagy in neurons is essential for maintaining long-term neuronal health, since disruption of baseline autophagic activity in vivo causes neurodegeneration and the accumulation of inclusions containing polyubiquitinated proteins.

“Basal autophagy in neurons is essential for maintaining long-term neuronal health, since disruption of baseline autophagic activity in vivo causes neurodegeneration and the accumulation of inclusions containing polyubiquitinated proteins [380,381].”

Astrocytes have greater proteostatic reserve compared to neurons.

“implying greater proteostatic reserve in astrocytes compared to neurons.”

Unlike neurons, astrocytic loss of Atg7 or Atg5 is insufficient to cause cell death or the accumulation of misfolded and ubiquitinated proteins.

“Unlike neurons, astrocytic loss of Atg7 or Atg5 is insufficient to cause cell death or the accumulation of misfolded and ubiquitinated proteins [380,381]”

Mice that developmentally lack autophagy in the neuronal compartment display shortened lifespan and early-onset neurodegenerative pathologies associated with pathological accumulation of proteinaceous aggregates in multiple neuronal populations.

“mice that developmentally lack autophagy in the neuronal compartment display shortened lifespan and early‐onset neurodegenerative pathologies (whose severity varies depending on the targeted gene), associated with the pathological accumulation of proteinaceous aggregates in multiple neuronal populations (Hara et al, 2006; Komatsu et al, 2006; Metcalf et al, 2012).”

Brain-specific deletion of Atg5 or Atg7 in mice reveals a critical role of autophagy in the removal of aggregated proteins.

“Although the phenotypes of mice harboring brain-specific deletion of Atg5 or Atg7 reveal the critical role of autophagy in the removal of aggregated proteins7,8”

Brain-specific conditional knockouts of Atg5 and Atg7 show shortened lifespan and accelerated age-related neuronal degeneration.

“Nonetheless, two subsequent studies that used brain-specific conditional knockouts of Atg5 and Atg7 revealed that, in these animals, the absence of autophagy leads to a shortened lifespan and an accelerated form of age-related neuronal degeneration 80, 81 .”