Autophagy is an evolutionarily-conserved catabolic process initiated by the engulfment of cytosolic components in a crescent-shaped structure, called phagophore that expands and fuses to form a closed double-membrane vesicle, the autophagosome. Autophagosomes are subsequently targeted to the lysosome/vacuole with which they fuse to degrade their content. The formation of autophagosome is carried out by a set of autophagy-related (Atg) proteins, highly conserved form yeast to mammals. The Atg8s are ubiquitin-like (Ubl) proteins that play an essential role in autophagosome biogenesis. This family of proteins comprises a single member in yeast and several mammalian homologues grouped into three subfamilies: LC3, GABARAP and GATE-16. The Atg8s are synthesized as cytosolic precursors but can undergo a series of post-translational modifications leading to their tight association with autophagosomal structures upon autophagy induction. Autophagy dysfunction has been implicated in a group of progressive neurodegenerative diseases, and has been reported to play a major role in the pathogenesis of these disorders. We have recently reported a recessive mutation in TECPR2, an autophagy-implicated WD repeat-containing protein, in five individuals with a novel form of monogenic hereditary spastic paraparesis (HSP). We found that diseased skin fibroblasts had a decreased accumulation of the autophagy-initiation protein MAP1LC3B (LC3), and an attenuated delivery of both LC3 and the cargo-recruiting protein SQSTM1 (p62) to lysosomal degradation. The discovered TECPR2 mutation reveals for the first time a role for aberrant autophagy in a major class of Mendelian neurodegenerative diseases, and suggests mechanisms by which impaired autophagy may impinge on a broader scope of neurodegeneration.
- Intracellular trafficking, Autophagy, Neurodegenration
Awards and Honors:
- 1989: M. Landau distinction prize
- 1990: Fulbright Researcher award.
- 1992: Recipient of Fogarty International Fellowship
- 1993: Miriam and Benedict Wolf Fellow
- 1996: Incumbent of the Shlomo and Michaela Tomarin Career Development Chair of Membrane Physiology
- 2009: Incumbent of the Harold Korda Chair of Biology
- 2008: President of the Israeli Cell Biology Society