Unraveling the role of motoneuron autophagy in ALS

ABSTRACT

In recent years, the role of autophagy in the pathogenesis of most neurodegenerative diseases has transitioned into a limbo of protective or detrimental effects. Genetic evidence indicates that mutations in autophagy-regulatory genes can result in the occurrence of amyotrophic lateral sclerosis (ALS), suggesting a physiological role of the pathway to motoneuron function. However, experimental manipulation of autophagy in ALS models led to conflicting results depending on the intervention strategy and the disease model used. A recent work by the Maniatis group systematically explored the role of cell-specific autophagy in motoneurons at different disease stages, revealing surprising and unexpected findings. Autophagy activity at early stages may contribute to maintaining the structure and function of neuromuscular junctions, whereas at later steps of the disease it has a pathogenic activity possibly involving cell-nonautonomous mechanisms related to glial activation. This new study adds a new layer of complexity in the field, suggesting an intricate interplay between proteostasis alterations, the time-differential function of autophagy in neurons, and muscle innervation in ALS.

KEYWORDS:

• ALS
• amyotrophic lateral sclerosis
• autophagy
• cell-nonautonomous
• motoneuron
• neuromuscular junction
• SOD1

Acknowledgments

This work was funded by FONDECYT under grant 11160288 (MN) and FONDECYT under grant 3170622 and ALSA 17-PDF-362 (VV), FONDECYT under grant 1140549, FONDAP program under grant 15150012, Millennium Institute under grant P09-015-F, European Commission R&D MSCA-RISE under grant #734749 (CH). We also thank the support from Michael J Fox Foundation for Parkinson´s Research – Target Validation grant No 9277, FONDEF ID16I10223, FONDEF D11E1007, US Office of Naval Research-Global (ONR-G) N62909-16-1-2003, U.S. Air Force Office of Scientific Research FA9550-16-1-0384, ALSRP Therapeutic Idea Award AL150111, Muscular Dystrophy Association 382453, and CONICYT-Brazil 441921/2016-7 (CH).

Disclosure of potential conflicts of interest

No potential conflict of interest was reported by the authors

Additional information

Funding

Michael J. Fox Foundation for Parkinson's Research (MJFF) [grant number 9277], Muscular Dystrophy Association (MDA) [grant number 382453], ALSRP Therapeutic Idea Award [grant number AL150111], US Air Force Office of Scientific Research [grant number FA9550-16-1-0384], ONR-G [grant number N62909-16-1-2003], Fondo de Fomento al Desarrollo Científico y Tecnológico [grant number D11E1007], Fondo de Fomento al Desarrollo Científico y Tecnológico [grant number ID16I10223], ALSA (VV) [grant number 17-PDF-362], European Commission R&D MSCA-RISE [grant number 734749], Westmead Millennium Institute for Medical Research [grant number P09-015-F], FONDAP [grant number 15150012], Fondo Nacional de Desarrollo Científico y Tecnológico [grant number 1140549], FONDECYT (MN) [grant number 11160288], FONDECYT (VV) [grant number 3170622]