Adaptive autophagy in Alexander disease-affected astrocytes.
The ubiquitin-proteasome and autophagy-lysosomal pathways are the two main routes of protein and organelle clearance in eukaryotic cells. The proteasome system is responsible for unfolded, short-lived proteins, which precludes the clearance of oligomeric and aggregated proteins, whereas macroautophagy, a process generally referred to as autophagy, mediates mainly the bulk degradation of long-lived cytoplasmic proteins, large protein complexes or organelles.(1) Recently, the autophagy-lysosomal pathway has been implicated in neurodegenerative disorders as an important pathway for the clearance of abnormally accumulated intracellular proteins, such as huntingtin, tau and mutant and modified alpha-synuclein.(1-6) Our recent study illustrated the induction of adaptive autophagy in response to mutant glial fibrillary acidic protein (GFAP) accumulation in astrocytes, in the brains of patients with Alexander disease (AxD), and in mutant GFAP knock-in mouse brains.(7) This autophagic response is negatively regulated by mammalian target of rapamycin (mTOR). The activation of p38 MAPK by GFAP accumulation is responsible for mTOR inactivation and the induction of autophagy. We also found that the accumulation of GFAP impairs proteasome activity.(8) In this commentary we discuss the potential compensatory relationship between an impaired proteasome and activated autophagy, and propose that the MLK-MAPK (mixed lineage kinase-mitogen-activated protein kinase) cascade is a regulator of this crosstalk.
Tang
Guomei
G
Department of Pathology and Cell Biology, Columbia University, New York, New York 10032, USA.
Yue
Zhenyu
Z
Talloczy
Zsolt
Z
Goldman
James E
JE
D038261:Alexander Disease / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D000818:Animals; D001253:Astrocytes / Q000201:enzymology / Q000473:pathology*; D001343:Autophagy / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D061988:Proteasome Inhibitors
D005904:Glial Fibrillary Acidic Protein; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex