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

Caleb Pitcairn, Willayat Yousuf Wani, Joe Mazzulli

Research output: Contribution to journalReview article

11 Citations (Scopus)

Abstract

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
Volume122
DOIs
StatePublished - Feb 1 2019

Fingerprint

Gaucher Disease
Parkinson Disease
Induced Pluripotent Stem Cells
Lewy Bodies
Mutation
Proteins
Parkinsonian Disorders
Mesencephalon
Dopamine
Homeostasis
Phenotype
Neurons
Genes

Keywords

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

ASJC Scopus subject areas

  • Neurology

Cite this

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abstract = "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.",
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Dysregulation of the autophagic-lysosomal pathway in Gaucher and Parkinson's disease. / Pitcairn, Caleb; Wani, Willayat Yousuf; Mazzulli, Joe.

In: Neurobiology of Disease, Vol. 122, 01.02.2019, p. 72-82.

Research output: Contribution to journalReview article

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