Autophagy in Neurodegenerative Diseases: A Hunter for Aggregates

Cells have developed elaborate quality-control mechanisms for proteins and organelles to maintain cellular homeostasis. Such quality-control mechanisms are maintained by conformational folding via molecular chaperones and by degradation through the ubiquitin-proteasome or autophagy-lysosome system. Accumulating evidence suggests that impaired autophagy contributes to the accumulation of intracellular inclusion bodies consisting of misfolded proteins, which is a hallmark of most neurodegenerative diseases. In addition, genetic mutations in core autophagy-related genes have been reported to be linked to neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. Conversely, the pathogenic proteins, such as amyloid β and α-synuclein, are detrimental to the autophagy pathway. Here, we review the recent advances in understanding the relationship between autophagic defects and the pathogenesis of neurodegenerative diseases and suggest autophagy induction as a promising strategy for the treatment of these conditions.

Expanded Polyglutamine-containing N-terminal Huntingtin Fragments Are Entirely Degraded by Mammalian Proteasomes

Huntington disease is a neurodegenerative disorder caused by an expanded polyglutamine (polyQ) repeat within the protein huntingtin (Htt). N-terminal fragments of the mutant Htt (mHtt) proteins containing the polyQ repeat are aggregation-prone and form intracellular inclusion bodies. Improving the clearance of mHtt fragments by intracellular degradation pathways is relevant to obviate toxic mHtt species and subsequent neurodegeneration. Because the proteasomal degradation pathway has been the subject of controversy regarding the processing of expanded polyQ repeats, we examined whether the proteasome can efficiently degrade Htt-exon1 with an expanded polyQ stretch both in neuronal cells and in vitro. Upon targeting mHtt-exon1 to the proteasome, rapid and complete clearance of mHtt-exon1 was observed. Proteasomal degradation of mHtt-exon1 was devoid of polyQ peptides as partial cleavage products by incomplete proteolysis, indicating that mammalian proteasomes are capable of efficiently degrading expanded polyQ sequences without an inhibitory effect on the proteasomal activity.

Analysis of the PixA Inclusion Body Protein of Xenorhabdus nematophila

ABSTRACT The symbiotic pathogenic bacterium Xenorhabdus nematophila produces two distinct intracellular inclusion bodies. The pixA gene, which encodes the 185-residue methionine-rich PixA inclusion body protein, was analyzed in the present study. The pixA gene was optimally expressed under stationary-phase conditions but its expression did not require RpoS. Analysis of a pixA mutant strain showed that PixA was not required for virulence towards the insect host or for colonization of or survival within the nematode host, and was not essential for nematode reproduction. The pixA gene was not present in the genome of Xenorhabdus bovienii, which also produces proteinaceous inclusions, indicating that PixA is specifically produced in X. nematophila.