Regulation of Neuronal Survival Factor MEF2D by Chaperone-Mediated Autophagy

Abstract

Chaperone-mediated autophagy controls the degradation of selective cytosolic proteins and may protect neurons against degeneration. In a neuronal cell line, we found that chaperone-mediated autophagy regulated the activity of myocyte enhancer factor 2D (MEF2D), a transcription factor required for neuronal survival. MEF2D was observed to continuously shuttle to the cytoplasm, interact with the chaperone Hsc70, and undergo degradation. Inhibition of chaperone-mediated autophagy caused accumulation of inactive MEF2D in the cytoplasm. MEF2D levels were increased in the brains of α-synuclein transgenic mice and patients with Parkinson's disease. Wild-type α-synuclein and a Parkinson's disease-associated mutant disrupted the MEF2D-Hsc70 binding and led to neuronal death. Thus, chaperone-mediated autophagy modulates the neuronal survival machinery, and dysregulation of this pathway is associated with Parkinson's disease.In neurodegenerative diseases, certain populations of adult neurons are gradually lost because of toxic stress. The four myocyte enhancer factor 2 (MEF2) transcription factors, MEF2A to MEF2D, have been shown to play an important role in the survival of several types of neurons, and a genetic polymorphism of the MEF2A gene has been linked to the risk of late onset of Alzheimer's disease (1-3). In cellular models, inhibition of MEF2s contributes to neuronal death. Enhancing MEF2 activity protects neurons from death in vitro and in the substantia nigra pars compacta in a mouse model of Parkinson's disease (PD) (4). Neurotoxic insults cause MEF2 degradation in part by a caspase-dependent mechanism (5), but how MEF2 is regulated under basal conditions without overt toxicity is unknown. Autophagy refers to the degradation of intracellular components by lysosomes. Relative to macro-and microautophagy, chaperonemediated autophagy (CMA) selectively degrades cytosolic proteins (6). This process involves binding of heat shock protein Hsc70 to substrate proteins via a KFERQ-like motif and their subsequent targeting to lysosomes via the lysosomal membrane receptor Lamp2a. Dysregulation of autophagy plays a role in neurodegeneration (7-9). However, the direct mechanism by which CMA modulates neuronal survival or death is unclear.

Salidroside Protects Against 6-Hydroxydopamine-Induced Cytotoxicity by Attenuating ER Stress

“…Western blotting was performed as previously described [18]. After treatment with 6-OHDA for 4 h, SN4741 cells were washed three times with room-temperature PBS and suspended in lysis buffer (100 lL buffer per 6-cm plate).…”

Oxidation of Survival Factor MEF2D in Neuronal Death and Parkinson's Disease

“…Several survival and death signals converge on MEF2D and regulate its activity. Recent studies showed that CMA plays a critical role in degrading nonfunctional MEF2D from DA neurons, and this process may be disrupted under the pathological conditions which are associated with PD (40). Furthermore, MEF2D is present in mitochondria and regulates complex I activity.…”

Chaperone-mediated autophagy: roles in disease and aging

“…For example, degradation of the transcription factor Pax2 by CMA in kidney is important to control tubular cell growth [40], and explains why in conditions such as diabetes when CMA is compromised, kidneys undergo pronounced hypertrophy [41]. Selective degradation of a neuronal survival factor, transcription factor myocyte enhancer factor 2D, has been shown to occur, at least in part by CMA, and this is essential to assure proper neuronal response to injury [42]. In this case, intuitively a reduction of CMA activity could be considered beneficial as it should contribute to increasing cellular levels of myocyte enhancer factor 2D.…”