Oral Presentation 2014 International Biophysics Congress

Different autophagy gene knockout mice show distinct neurodegenerative defects (#100)

Hong Zhang 1
  1. Institute of Biophysics, Chinese Academy of Sciences, Chaoyang, China

Autophagy is a lysosome-mediated degradation system, in which a portion of cytosol is engulfed in an enclosed double-membrane vesicle, termed the autophagosome, and subsequently delivered to the lysosome for degradation. The basal constitutive level of autophagy functions as a quality control mechanism by removing misfolded proteins and/or damaged organelles. A group of evolutionarily conserved Atg genes has been identified that act at distinct steps of the autophagy pathway. Neural-specific mouse knockouts of genes essential for autophagosome formation, including Atg5, Atg7 and FIP200, exhibit massive neuron loss and axonal degeneration, accompanied by dramatic accumulation of ubiquitinated protein aggregates. However, these knockout mice do not exhibit the core feature of neurodegenerative diseases, namely selective age-dependent vulnerability of certain neuronal populations.

Genetic screens in C. elegans identified epg-4, epg-5 and epg-6 as metazoan specific autophagy genes that act at distinct steps of the autophagy pathway. We generated knockout mice for mammalian homologs Ei24/Epg4, Epg5 and Wipi4/Epg6 to investigate their physiological functions. Neural-specific depletion of Ei24 causes massive neurodegeneration in various regions of CNS. Epg5 deficient mice exhibit selective damage of cortical layer 5 pyramidal neurons and spinal cord motor neurons, muscle denervation and atrophy, late-onset progressive hindquarter paralysis and dramatically reduced survival, recapitulating key features of amyotrophic lateral sclerosis. Human genetic studies revealed that de novo mutations in WIPI4 cause BPAN (beta-propeller protein-associated neurodegeneration), which is a subtype of NBIA (neurodegeneration with brain iron accumulation). Neural specific Wipi4 knockout mice demonstrate learning and memory defect and axonal degeneration. Thus, the Wipi4 KO mice recapitulate some hallmarks of BPAN, including cognitive impairment and axonal degeneration. Our study indicates that mice deficient for autophagy genes that function at distinct steps show distinct neuropathological deficits.