AMP Kinase Activation is Selectively Disrupted in the Ventral Midbrain of Mice Deficient in Parkin or PINK1 Expression

Liting Hang,Kah-Leong Lim,Geraldine W Y Goh,John Thundyil

doi:10.1007/s12017-018-8517-7

Abstract

Parkinson’s disease (PD) is a prevalent neurodegenerative movement disorder that is characterized pathologically by the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) of the midbrain. Despite intensive research, the etiology of PD remains poorly understood. Interestingly, recent studies have implicated neuronal energy dysregulation as one of the key perpetrators of the disease. Supporting this, we have recently demonstrated that pharmacological or genetic activation of AMP kinase (AMPK), a master regulator of cellular energy homeostasis, rescues the pathological phenotypes of Drosophila models of PD. However, little is known about the role of AMPK in the mammalian brain. As an initial attempt to clarify this, we examined the expression of AMPK in rodent brains and found that phospho-AMPK (pAMPK) is disproportionately distributed in the adult mouse brain, being high in the ventral midbrain where the SN resides and relatively lower in regions such as the cortex—reflecting perhaps the unique energy demands of midbrain DA neurons. Importantly, the physiologically higher level of midbrain pAMPK is significantly reduced in aged mice and also in Parkin-deficient mice; the loss of function of which in humans causes recessive Parkinsonism. Not surprisingly, the expression of PGC-1α, a downstream target of AMPK activity, and a key regulator of mitochondrial biogenesis, mirrors the expression pattern of pAMPK. Similar observations were made with PINK1-deficient mice. Finally, we showed that metformin administration restores the level of midbrain pAMPK and PGC-1α expression in Parkin-deficient mice. Taken together, our results suggest that the disruption of AMPK-PGC-1α axis in the brains of individuals with Parkin or PINK1 mutations may be a precipitating factor of PD, and that pharmacological AMPK activation may represent a neuroprotective strategy for the disease.

Highlights

Parkinson’s disease (PD) is a prevalent neurodegenerative disease that affects millions of predominantly elderly individuals worldwide
Our results suggest that deficient expression of pAMPK in Parkin or PINK1 mutant midbrains may contribute to bioenergetics impairments in DA neurons and precipitate PD, and that pharmacological AMP kinase (AMPK) activation may represent a neuroprotective strategy for the disease
As AMPK is known to promote the expression of nuclear-encoded mitochondrial proteins through the activation of transcription factors, we measured the expression of TFAM and found that the level of this important nuclear-encoded mitochondrial transcription factor is elevated in the ventral midbrain region relative to other regions examined (Fig. 2c)

Summary

Introduction

Parkinson’s disease (PD) is a prevalent neurodegenerative disease that affects millions of predominantly elderly individuals worldwide. A corollary to this is that bioenergetics failure may represent a key driver of neurodegeneration in PD (Mattson and Arumugam 2018). This proposition is intuitively logical as post-mitotic neurons those with vast axonal field are known to require high energy to support their operations, which include the active transportation of components (including mitochondria) towards metabolically demanding synaptic terminals that are distally located. SNpc DA neurons are characterized by unusually large number of axon terminals and axonal arborization, which overall increase their demand for ATP (Pissadaki and Bolam 2013). Pacelli and colleagues recently demonstrated that elevated mitochondrial bioenergetics and axonal arborization underlie the selective vulnerability of SNpc DA neurons to degeneration in PD (Pacelli et al 2015). Strategies that improve the bioenergetics status of DA neurons may potentially be beneficial

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