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E3 ligase NEDD4 localizes in TDP-43 aggregates.
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TDP-43 accumulation induces giant Rab7-positive vesicles.

Amyotrophic Lateral Sclerosis (ALS) is a fatal disease driven by motor-neuron atrophy, with no effective treatment or cure at present. Like many neurodegenerative diseases, defects in proteostasis occur; in particular, cytoplasmic mislocalization, accumulation and aggregation of an RNA-binding protein called TDP-43 is strongly implicated in ALS pathology for the vast majority of patients.

TDP-43 can localize in stress granules, and during our investigations of stress granule clearance mechanisms, we discovered a surprising new means of cytoplasmic TDP-43 degradation involving TDP-43 targeting to the endolysosomal pathway. We continue to work in this area to better understand mechanistically how TDP-43 degradation, including of so-called “toxic” species, can be upregulated, which may identify novel therapeutic targets in ALS. 

More broadly, we are interested in what other cytoplasmic proteins degrade via this endolysosomal mechanism, and what governs the use of different degradation mechanisms for a given protein substrate.


A. Byrd, L. Marmorale, V. Addison, S. Marcinowski, and J. R. Buchan
Rsp5/NEDD4 and ESCRT regulate TDP-43 toxicity and turnover via an endolysosomal clearance mechanism
N. Fernandes, L. Nero, S. M. Lyons, P. Ivanov, T. M. Mittelmeier, T. A. Bolger, and J. R. Buchan
Fernandes et al. Stress Granule Assembly Can Facilitate but Is Not Required for TDP-43 Cytoplasmic Aggregation. Biomolecules 2020, 10, 1367
Biomolecules 11 1895 (2021)
G. Liu, A. Byrd, A. N. Warner, F. Pei, E. Basha, A. Buchanan, and J. R. Buchan
Cdc48/VCP and Endocytosis Regulate TDP-43 and FUS Toxicity and Turnover
Molecular and Cellular Biology 40 (2020)
N. Fernandes, N. Eshleman, and J. R. Buchan
Stress Granules and ALS: A Case of Causation or Correlation?
Advances in Neurobiology 173-212 (2018)
G. Liu, A. N. Coyne, F. Pei, S. Vaughan, M. Chaung, D. C. Zarnescu, and J. R. Buchan
Endocytosis regulates TDP-43 toxicity and turnover
Nature Communications 8 (2017)