Inclusion body formation, macroautophagy, and the role of HDAC6 in neurodegeneration

Christiane Richter-Landsberg, Janina Leyk
Acta Neuropathologica 2013, 126 (6): 793-807
The failure to clear misfolded or aggregated proteins from the cytoplasm of nerve cells and glia is a common pathogenic event in a variety of neurodegenerative disorders. This might be causally related to defects in the major proteolytic systems, i.e., the ubiquitin-proteasomal system and the autophagic pathway. Large protein aggregates and defective organelles are excluded from the proteasome. They can be degraded only by macroautophagy, which is a highly selective process. It requires p62 to act as a bridge connecting ubiquitinated protein aggregates and autophagosomes, and the tubulin deacetylase histone deacetylase 6 (HDAC6). HDAC6 has recently been identified as a constituent in Lewy bodies of Parkinson disease and glial cytoplasmic inclusions of multiple system atrophy. It is considered a sensor of proteasomal inhibition and a cellular stress surveillance factor, and plays a central role in autophagy by controlling the fusion process of autophagosomes with lysosomes. Upon proteasomal inhibition, HDAC6 is relocated and recruited to polyubiquitin-positive aggresomes. Tubulin acetylation is a major consequence of HDAC6 inhibition, and HDAC6 inhibition restores microtubule (MT)-dependent transport mechanisms in neurons. This suggests the involvement of HDAC6 in neurodegenerative diseases. Furthermore, the protein tau seems to be a substrate for HDAC6. Tau acetylation impairs MT assembly and promotes tau fibrillization in vitro. It has been suggested that acetylation and phosphorylation of tau at multiples sites may act synergistically in the pathogenesis of tau fibrillization. In this review, we will survey the process of aggresome formation, macroautophagy and the role of autophagosomal proteins and HDAC6 in inclusion body formation.

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