Zinc induces depletion and aggregation of endogenous TDP-43.
Ubiquitinated neuronal aggregates containing TDP-43 are pathological hallmarks in the spectrum of frontotemporal lobar dementia (FTLD) and amyotrophic lateral sclerosis (ALS). In affected neurons, TDP-43 undergoes C-terminal fragmentation, phosphorylation, and ubiquitination and forms aggregates in the cytoplasm or nucleus. Although in vitro studies have been able to recapitulate these features using transfected cell culture models, little is known about the biochemical mechanisms that underlie pathological changes to endogenous TDP-43. As altered metal ion homeostasis and increased oxidative stress are central features of neurodegeneration, including FTLD and ALS, we sought to determine the affects of these factors on endogenous TDP-43 metabolism in mammalian cells. Treatment of SY5Y neuronal-like cells expressing endogenous TDP-43 with zinc (Zn) induced depletion of TDP-43 expression and formation of inclusions that were TDP-43 positive. TDP-43 was also detected in the cytosol of Zn-affected cells but this was not aggregated. No evidence of C-terminal fragmentation, phosphorylation, or ubiquitination was observed. The depletion and aggregation of TDP-43 were associated with the specific action of Zn but were not seen with copper, iron, or H(2)O(2). These studies describe for the first time specific induction of endogenous TDP-43 aggregation in neuronal-like cells and suggest that specific Zn-associated processes could affect TDP-43 metabolism in neurodegenerative diseases.
Department of Pathology, The University of Melbourne, Melbourne, VIC 3010, Australia.
Aphrodite
A
Caragounis
Katherine Ann
KA
Price
Cynthia P W
CP
Soon
Gulay
G
Filiz
Colin L
CL
Masters
Qiao-Xin
QX
Li
Peter J
PJ
Crouch
Anthony R
AR
White
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002712:Chlorides / Q000633:toxicity*; D004268:DNA-Binding Proteins / Q000187:drug effects* / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D002479:Inclusion Bodies / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017967:Zinc Compounds / Q000633:toxicity*
D002712:Chlorides; D004268:DNA-Binding Proteins; D017967:Zinc Compounds; C016837:zinc chloride