Targeting AMPK Signaling as a Neuroprotective Strategy in Parkinson's Disease

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disorder. It is characterized by the accumulation of intracellular α-synuclein aggregates and the degeneration of nigrostriatal dopaminergic neurons. While no treatment strategy has been proven to slow or halt the progression of the disease, there is mounting evidence from preclinical PD models that activation of 5'-AMP-activated protein kinase (AMPK) may have broad neuroprotective effects. Numerous dietary supplements and pharmaceuticals (e.g., metformin) that increase AMPK activity are available for use in humans, but clinical studies of their effects in PD patients are limited. AMPK is an evolutionarily conserved serine/threonine kinase that is activated by falling energy levels and functions to restore cellular energy balance. However, in response to certain cellular stressors, AMPK activation may exacerbate neuronal atrophy and cell death. This review describes the regulation and functions of AMPK, evaluates the controversies in the field, and assesses the potential of targeting AMPK signaling as a neuroprotective treatment for PD.

Keywords: 5′-AMP-activated protein kinase; Parkinson’s disease; alpha-synuclein; autophagy; metformin; mitochondria; resveratrol.

Fig.1

AMPK signaling. AMPK activity is regulated by the ratio of AMP to ATP and by at least 3 upstream kinases. Metformin, β-guanidinopropionic acid (GPA), and resveratrol activate AMPK by increasing the AMP:ATP ratio and/or by stimulating liver kinase B1 (LKB1) mediated phosphorylation of AMPK. AMPK has numerous functions, including changes to cellular energy metabolism, increased macroautophagy, enhanced mitochondrial quality control, redox homeostasis, and anti-inflammatory effects. A few specific functions within each area are listed, with direct phosphorylation targets of AMPK shaded. These functions are explained in more detail in the text.

Fig.2

AMPK regulates mitochondrial quality control. AMPK facilitates mitochondrial quality control through direct phosphorylation of target proteins and transcriptional regulation of relevant genes. AMPK promotes mitochondrial biogenesis via increased transcription and post-translational phosphorylation of PGC-1α. PGC-1α is a master regulator of mitochondrial biogenesis that activates mitochondrial transcription factor A (TFAM), which drives transcription and replication of mitochondrial DNA. PGC-1α also facilitates mitochondrial fission and fusion through expression of Drp1 and Mitofusin2 (MFN2), and it promotes mitophagy and lysosomal biogenesis via activation of transcription factor EB (TFEB). AMPK can further promote mitophagy through phosphorylation of ULK1, which facilitates autophagosome formation and targeting of damaged mitochondria to lysosomes. Additionally, phosphorylation of mitochondrial fission factor (MFF) facilitates mitophagy through increased fission.

Fig.3

Metformin and AMPK have divergent effects on alpha-synuclein S129 phosphorylation. αSyn becomes increasingly phosphorylated at S129 in patients with PD. Multiple kinases are responsible for αSyn phosphorylation, including AMPK. pS129 may promote macroautophagic clearance of aggregated αSyn, but it may also increase the toxicity αSyn. Thus, the pathological role of pS129 in PD is complex and may change depending on disease severity. pS129 is dephosphorylated by PP2A, and unphosphorylated αSyn increases the activity of PP2A, while pS129-αSyn decreases PP2A activity. PP2A can also dephosphorylate and inhibit AMPK at pThr172. Thus, AMPK may be regulated in part by the phosphorylation state of αSyn. Metformin activates PP2A via an AMPK independent mechanism with higher potency than it activates AMPK, at least in vitro, and thereby promotes the dephosphorylation of pS129-αSyn.