Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron degenerative disease. ALS-affected motor neurons exhibit aberrant localization of a nuclear RNA binding protein, TDP-43, into cytoplasmic aggregates, which contributes to pathology via unclear mechanisms. Here, we demonstrate that TDP-43 turnover and toxicity depend in part upon the endocytosis pathway. TDP-43 inhibits endocytosis, and co-localizes strongly with endocytic proteins, including in ALS patient tissue. Impairing endocytosis increases TDP-43 toxicity, aggregation, and protein levels, whereas enhancing endocytosis reverses these phenotypes. Locomotor dysfunction in a TDP-43 ALS fly model is also exacerbated and suppressed by impairment and enhancement of endocytic function, respectively. Thus, endocytosis dysfunction may be an underlying cause of ALS pathology.
Highlights
Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron degenerative disease
To determine if endocytic and autophagic functions can act in parallel in human cells to clear TAR DNA-binding protein 43 (TDP-43) protein, we examined the effect of Atg[5] KD, dynasore treatment, or a combination of both upon endogenous TDP-43 protein levels
We propose this as in yeast, blocking autophagy and the proteasome had little effect on TDP-43 protein levels or stability under normal conditions (Fig. 1a; Supplementary Fig. 1c, d)
Summary
Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron degenerative disease. ALSaffected motor neurons exhibit aberrant localization of a nuclear RNA binding protein, TDP43, into cytoplasmic aggregates, which contributes to pathology via unclear mechanisms. TDP-43 is a nuclear protein with many roles in messenger RNA (mRNA) metabolism, but in ALS, TDP-43 relocalizes to cytoplasmic aggregates. Several studies suggest these TDP-43 aggregates induce disease partly via a toxic gain of function. Many genes that are mutated in ALS include RNA binding proteins that localize in SGs (e.g., TDP-43, FUS, hnRNPA1, Ataxin-26). Such mutations usually make these proteins more aggregation prone, which can lead to more rapid or persistent SG assembly[7]. Induction of non-selective autophagy rescues TDP-43 toxicity in human iPSC-derived neurons, astrocytes, and a mouse frontotemporal lobar dementia model[12, 13]
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