Autophagy and Its Impact on Neurodegenerative Diseases: New Roles for TDP-43 and C9orf72

Abstract

Autophagy is a catabolic mechanism where intracellular material is degraded by vesicular structures called autophagolysosomes. Autophagy is necessary to maintain the normal function of the central nervous system (CNS), avoiding the accumulation of misfolded and aggregated proteins. Consistently, impaired autophagy has been associated with the pathogenesis of various neurodegenerative diseases. The proteins TAR DNA-binding protein-43 (TDP-43), which regulates RNA processing at different levels, and chromosome 9 open reading frame 72 (C9orf72), probably involved in membrane trafficking, are crucial in the development of neurodegenerative diseases such as Amyotrophic lateral sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD). Additionally, recent studies have identified a role for these proteins in the control of autophagy. In this manuscript, we review what is known regarding the autophagic mechanism and discuss the involvement of TDP-43 and C9orf72 in autophagy and their impact on neurodegenerative diseases.

TDP-43-Mediated Toxicity in HEK293T Cells: A Fast and Reproducible Protocol To Be Employed in the Search of New Therapeutic Options against Amyotrophic Lateral Sclerosis

“…Although there is controversy regarding whether TDP-43 is overexpressed in ALS patients [13], the presence of CTFs could represent a consequence of loss in protein homeostasis that leads to protein accumulation. This is supported by the finding that TDP-43 accumulation in the cytoplasm deregulates autophagy and proteasome functions [14][15][16]. Further, the presence of CTFs could represent a cellular way to cope with the increase in protein accumulation, by cleaving it in smaller pieces that could more easily enter the ubiquitin-proteasome system (UPS) and autophagy systems [17,18].…”

PAMAM dendrimers as a carbamazepine delivery system for neurodegenerative diseases: A biophysical and nanotoxicological characterization

“…The generation of highly diffusible small oligomers, fibrils and large aggregates with amyloid properties are implicated in these abnormal processes (Vidal et al, 2014). Lately, due to the selective degradation of abnormally folded protein by the lysosomal pathway and the disruption of aggregated proteins, the enhancers of natural autophagy process have become attractive as a treatment for these neurodegenerative disorders (Budini et al, 2017;Harris & Rubinsztein, 2012;Hidvegi et al, 2010;Vidal et al, 2014).…”

Differences of basic and induced autophagic activity between K562 and K562/ADM cells

“…Abnormal basal autophagy can lead to various human diseases including cancer, neurodegenerative disorders, autoimmunity disease and inflammation (12)(13)(14)(15). Autophagy can be induced in response to several stressors including: nutrient deprivation, chemotherapeutics, hypoxia, pathogen infection and endoplasmic reticulum stress (16)(17)(18).…”