Dysregulation of the autophagic-lysosomal pathway in Gaucher and Parkinson's disease

Caleb Pitcairn, Willayat Yousuf Wani, Joseph R. Mazzulli*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

31 Scopus citations


The finding that mutations in the Gaucher's Disease (GD) gene GBA1 are a strong risk factor for Parkinson's Disease (PD) has allowed for unique insights into pathophysiology centered on disruption of the autophagic-lysosomal pathway. Protein aggregations in the form of Lewy bodies and the effects of canonical PD mutations that converge on the lysosomal degradation system suggest that neurodegeneration in PD is mediated by dysregulation of protein homeostasis. The well-characterized clinical and pathological relationship between PD and the lysosomal storage disorder GD emphasizes the importance of dysregulated protein metabolism in neurodegeneration, and one intriguing piece of this relationship is a shared phenotype of autophagic-lysosomal dysfunction in both diseases. Translational application of these findings may be accelerated by the use of midbrain dopamine neuronal models derived from induced pluripotent stem cells (iPSCs) that recapitulate several pathological features of GD and PD. In this review, we discuss evidence linking autophagic dysfunction to the pathophysiology of GD and GBA1-linked parkinsonism and focus more specifically on studies performed recently in iPSC-derived neurons.

Original languageEnglish (US)
Pages (from-to)72-82
Number of pages11
JournalNeurobiology of Disease
StatePublished - Feb 2019


  • Alpha-synuclein
  • Autophagy
  • Gaucher disease
  • Lewy bodies
  • Lysosomal dysfunction
  • Lysosomal storage disease
  • Parkinson's disease
  • iPSC

ASJC Scopus subject areas

  • Neurology


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