HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS

Abstract

A prominent feature of late-onset neurodegenerative diseases is accumulation of misfolded protein in vulnerable neurons. When levels of misfolded protein overwhelm degradative pathways, the result is cellular toxicity and neurodegeneration. Cellular mechanisms for degrading misfolded protein include the ubiquitin-proteasome system (UPS), the main non-lysosomal degradative pathway for ubiquitinated proteins, and autophagy, a lysosome-mediated degradative pathway. The UPS and autophagy have long been viewed as complementary degradation systems with no point of intersection. This view has been challenged by two observations suggesting an apparent interaction: impairment of the UPS induces autophagy in vitro, and conditional knockout of autophagy in the mouse brain leads to neurodegeneration with ubiquitin-positive pathology. It is not known whether autophagy is strictly a parallel degradation system, or whether it is a compensatory degradation system when the UPS is impaired; furthermore, if there is a compensatory interaction between these systems, the molecular link is not known. Here we show that autophagy acts as a compensatory degradation system when the UPS is impaired in Drosophila melanogaster, and that histone deacetylase 6 (HDAC6), a microtubule-associated deacetylase that interacts with polyubiquitinated proteins, is an essential mechanistic link in this compensatory interaction. We found that compensatory autophagy was induced in response to mutations affecting the proteasome and in response to UPS impairment in a fly model of the neurodegenerative disease spinobulbar muscular atrophy. Autophagy compensated for impaired UPS function in an HDAC6-dependent manner. Furthermore, expression of HDAC6 was sufficient to rescue degeneration associated with UPS dysfunction in vivo in an autophagy-dependent manner. This study suggests that impairment of autophagy (for example, associated with ageing or genetic variation) might predispose to neurodegeneration. Morover, these findings suggest that it may be possible to intervene in neurodegeneration by augmenting HDAC6 to enhance autophagy.

HDAC6 and RhoA are novel players in Abeta-driven disruption of neuronal polarity

“…It was also shown that phosphorylation of HDAC6, activating its deacetylase activity, promotes proper aggresome formation and protects from toxicity 50 . Indeed, HDAC6 inhibition would impair the removal of aggregated protein by retrograde transport to autophagosomes and lysosomes as it was shown that tubacin treatment decreased the recruitment of Atg/LC3, a crucial component of autophagic transport 51 , and that HDAC6 expression rescued neurodegeneration in a model of spinal and bulbar muscular atrophy 52 . HDAC6 has been shown also to protect dopaminergic neurons from alpha-synuclein-induced toxicity 53 .…”

The initiator caspase Dronc is subject of enhanced autophagy upon proteasome impairment in Drosophila

“…To explain the synergistic control of Dronc protein levels by the UPS and autophagy, we considered that, because the UPS and autophagy are mechanistically linked, impairment of the UPS can enhance autophagy, which is often referred to as compensatory autophagy 1,[19][20][21][22][23][24][25][26][27] (reviewed by Park and Cuervo, 3 Wojcik 28 and Lamark and Johansen 29 ). For example, in Drosophila, compensatory autophagy after proteasome impairment has been reported in neurons, in fat body cells and in adult flies.…”

“…For example, in Drosophila, compensatory autophagy after proteasome impairment has been reported in neurons, in fat body cells and in adult flies. 22,27,57 To examine this possibility in epithelial cells of eye imaginal discs, we monitored autophagy using a tandem fusion protein GFP-mCherry-Atg8a as reporter for autophagic flux. 18 This reporter is incorporated into autophagosomes, which mature into autolysosomes.…”

“…16 The incorporation of Atg8 fusion proteins (for example, with green fluorescent protein (GFP) and/or mCherry) into autophagosomes is often used as a marker for autophagosomes 17 and autophagic flux. 18 Although it was initially assumed that the UPS and autophagy are independent of each other, recent evidence has suggested that there is crosstalk and feedback between the two 1,[19][20][21][22][23][24][25][26][27] (reviewed by Park and Cuervo, 3 Wojcik 28 and Lamark and Johansen 29 ). This is mostly due to the observation that autophagy can also degrade ubiquitylated proteins.…”

The role of lysosomes in iron metabolism and recycling

“…Some molecules have half-lives of a few minutes while others may last for weeks. The turnover of cytosolic proteins and organelles is mainly dependent on the proteasomal and lysosomal pathways, which partly are able to substitute for each other (Fuertes et al, 2003, Pandey et al, 2007, Terman and Sandberg, 2002.…”