Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron degenerative disease. TDP-43 (TAR DNA-binding protein 43) and FUS (fused in sarcoma) are aggregation-prone RNA-binding proteins that in ALS can mis-localize to the cytoplasm of affected motor neuron cells, often forming cytoplasmic aggregates in the process. Such mis-localization and aggregation are implicated in ALS pathology, though the mechanisms of TDP-43 and FUS cytoplasmic toxicity remains unclear. Recently, we determined that the endocytic function aids turnover of TDP-43 and reduces TDP-43 toxicity. Here, we identified that Cdc48 and Ubx3, a Cdc48 co-factor implicated in endocytic function, regulates the turnover and toxicity of TDP-43 and FUS expressed in S. cerevisiae. Cdc48 physically interacts and co-localizes with TDP-43, as does VCP in ALS patient tissue. In yeast, FUS toxicity also depends strongly on endocytic function, but not autophagy under normal conditions. FUS expression also impairs endocytic function, as previously observed with TDP-43. Taken together, our data identifies a role for Cdc48/VCP and endocytosis function in regulating TDP-43 and FUS toxicity and turnover. Furthermore, endocytic dysfunction may be a common defect affecting cytoplasmic clearance of ALS aggregation-prone proteins and may represent a novel therapeutic target of promise.
Abbreviations
- ALS
- Amyotrophic Lateral Sclerosis
- CORVET
- class C core vacuole/endosome tethering
- CHX
- Cycloheximide
- EGFR
- Epidermal growth factor receptor
- FTLD
- Frontotemporal lobar dementia
- FUS
- Fused in Sarcoma
- HOPS
- homotypic fusion and vacuole protein sorting
- IBMPFD
- Inclusion Body Myopathy with early onset Pagets disease and Frontotemporal Dementia
- RRM
- RNA Recognition Motif
- SG
- Stress granule
- TDP-43
- TAR DNA binding protein 43
- VCP
- Vasolin containing protein