Retromer-dependent lysosomal stress in Parkinson's disease

Dario R. Alessi, Peter J. Cullen, Mark Cookson, Kalpana M. Merchant, Scott A. Small (Lead / Corresponding author)

Research output: Contribution to journalReview articlepeer-review

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While causative mutations in complex disorders are rare, they can be used to extract a biological pathway whose pathogenicity can generalize to common forms of the disease. Here we begin by relying on the biological consequences of mutations in LRRK2 and VPS35, genetic causes of autosomal-dominant Parkinson's disease, to hypothesize that 'Retromer-dependent lysosomal stress' represents a pathway that can generalize to idiopathic Parkinson's disease. Next, we outline a series of studies that can test this hypothesis, including the development of biomarkers of pathway dysfunction. If validated, the hypothesis can suggest a unified mechanism of disease and might inform future diagnostic and therapeutic investigations. This article is part of a discussion meeting issue 'Understanding the endo-lysosomal network in neurodegeneration'.

Original languageEnglish
Article number20220376
Number of pages5
JournalPhilosophical transactions of the Royal Society of London. Series B, Biological sciences
Issue number1899
Early online date19 Feb 2024
Publication statusPublished - 8 Apr 2024


  • Parkinson's disease
  • retromer
  • LRRK2
  • VPS35


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