Retromer-dependent lysosomal stress in Parkinson's disease.

Dario R Alessi, Peter J Cullen, Mark Cookson, Kalpana M Merchant, Scott A Small

Philosophical transactions of the Royal Society of London. Series B, Biological sciences 2024 Apr 08

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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'.

Citation

Dario R Alessi, Peter J Cullen, Mark Cookson, Kalpana M Merchant, Scott A Small. Retromer-dependent lysosomal stress in Parkinson's disease. Philosophical transactions of the Royal Society of London. Series B, Biological sciences. 2024 Apr 08;379(1899):20220376