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.