The Autophagy-Lysosomal Pathway in Neurodegeneration: A TFEB Perspective

Trends Neurosci. 2016 Apr;39(4):221-234. doi: 10.1016/j.tins.2016.02.002. Epub 2016 Mar 9.


The autophagy-lysosomal pathway (ALP) is involved in the degradation of long-lived proteins. Deficits in the ALP result in protein aggregation, the generation of toxic protein species, and accumulation of dysfunctional organelles, which are hallmarks of Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and prion disease. Decades of research have therefore focused on enhancing the ALP in neurodegenerative diseases. More recently, transcription factor EB (TFEB), a major regulator of autophagy and lysosomal biogenesis, has emerged as a leading factor in addressing disease pathology. We review the regulation of the ALP and TFEB and their impact on neurodegenerative diseases. We also offer our perspective on the complex role of autophagy and TFEB in disease pathogenesis and its therapeutic implications through the examination of prion disease.

Keywords: TFEB; autophagy–lysosomal pathway; neurodegenerative disease; prion disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Autophagy / physiology*
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / physiology*
  • Brain / physiopathology*
  • Humans
  • Lysosomes / physiology*
  • Nerve Degeneration / physiopathology*
  • Neurodegenerative Diseases / physiopathology*


  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • TFEB protein, human