Transcription Factor EB Is Selectively Reduced in the Nuclear Fractions of Alzheimer’s and Amyotrophic Lateral Sclerosis Brains
2016
Multiple studies suggest that autophagy is strongly dysregulated in Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS), as evidenced by accumulation of numerous
autophagosomes, lysosomes with discontinuous membranes, and aggregated proteins in the patients’ brains. Transcription factor EB (
TFEB) was recently discovered to be a master regulator of lysosome biogenesis and autophagy. To examine whether aberrant autophagy in AD and ALS is due to alterations in
TFEBexpression, we systematically quantified the levels of
TFEBin these brains by immunoblotting. Interestingly, cytoplasmic fractions of AD brains showed increased levels of normalized (to tubulin)
TFEBonly at
Braak stageIV (61%, ). Most importantly, normalized (to lamin)
TFEBlevels in the nuclear fractions were consistently reduced starting from
Braak stageIV (52%, ), stage V (67%, ), and stage VI (85%, ) when compared to normal control (NC) brains. In the ALS brains also, nuclear
TFEBlevels were reduced by 62% (). These data suggest that nuclear
TFEBis selectively lost in ALS as well as AD brains, in which
TFEBreduction was
Braak-stage-dependent. Taken together, the observed reductions in
TFEBprotein levels may be responsible for the widely reported autophagy defects in these disorders.
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