Rapamycin rescues TDP-43 mislocalization and the associated low molecular mass neurofilament instability.
TDP-43 is a nuclear protein involved in exon skipping and alternative splicing. Recently, TDP-43 has been identified as the pathological signature protein in frontotemporal lobar degeneration with ubiquitin-positive inclusions and in amyotrophic lateral sclerosis. In addition, TDP-43-positive inclusions are present in Parkinson disease, dementia with Lewy bodies, and 30% of Alzheimer disease cases. Pathological TDP-43 is redistributed from the nucleus to the cytoplasm, where it accumulates. An approximately 25-kDa C-terminal fragment of TDP-43 accumulates in affected brain regions, suggesting that it may be involved in the disease pathogenesis. Here, we show that overexpression of the 25-kDa C-terminal fragment is sufficient to cause the mislocalization and cytoplasmic accumulation of endogenous full-length TDP-43 in two different cell lines, thus recapitulating a key biochemical characteristic of TDP-43 proteinopathies. We also found that TDP-43 mislocalization is associated with a reduction in the low molecular mass neurofilament mRNA levels. Notably, we show that the autophagic system plays a role in TDP-43 metabolism. Specifically, we found that autophagy inhibition increases the accumulation of the C-terminal fragments of TDP-43, whereas inhibition of mTOR, a key protein kinase involved in autophagy regulation, reduces the 25-kDa C-terminal fragment accumulation and restores TDP-43 localization. Our results suggest that autophagy induction may be a valid therapeutic target for TDP-43 proteinopathies.
Caccamo
Antonella
A
Department of Physiology, University of Texas Health Science Center, San Antonio, Texas 78229, USA.
Majumder
Smita
S
Deng
Janice J
JJ
Bai
Yidong
Y
Thornton
Fiona B
FB
Oddo
Salvatore
S
D000595:Amino Acid Sequence; D000818:Animals; D001343:Autophagy; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D008970:Molecular Weight; D016900:Neurofilament Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D055550:Protein Stability / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology*
D004268:DNA-Binding Proteins; D016900:Neurofilament Proteins; D012333:RNA, Messenger; D020123:Sirolimus