Retromer-dependent lysosomal stress in Parkinson&apos;s disease

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Abstract

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’.

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Alzheimer's disease

Philip Scheltens, Bart De Strooper, Miia Kivipelto … (2021)

In this Seminar, we highlight the main developments in the field of Alzheimer's disease. The most recent data indicate that, by 2050, the prevalence of dementia will double in Europe and triple worldwide, and that estimate is 3 times higher when based on a biological (rather than clinical) definition of Alzheimer's disease. The earliest phase of Alzheimer's disease (cellular phase) happens in parallel with accumulating amyloid β, inducing the spread of tau pathology. The risk of Alzheimer's disease is 60-80% dependent on heritable factors, with more than 40 Alzheimer's disease-associated genetic risk loci already identified, of which the APOE alleles have the strongest association with the disease. Novel biomarkers include PET scans and plasma assays for amyloid β and phosphorylated tau, which show great promise for clinical and research use. Multidomain lifestyle-based prevention trials suggest cognitive benefits in participants with increased risk of dementia. Lifestyle factors do not directly affect Alzheimer's disease pathology, but can still contribute to a positive outcome in individuals with Alzheimer's disease. Promising pharmacological treatments are poised at advanced stages of clinical trials and include anti-amyloid β, anti-tau, and anti-inflammatory strategies.

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Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases

Martin Steger, Francesca Tonelli, Genta Ito … (2016)

Mutations in Park8, encoding for the multidomain Leucine-rich repeat kinase 2 (LRRK2) protein, comprise the predominant genetic cause of Parkinson's disease (PD). G2019S, the most common amino acid substitution activates the kinase two- to threefold. This has motivated the development of LRRK2 kinase inhibitors; however, poor consensus on physiological LRRK2 substrates has hampered clinical development of such therapeutics. We employ a combination of phosphoproteomics, genetics, and pharmacology to unambiguously identify a subset of Rab GTPases as key LRRK2 substrates. LRRK2 directly phosphorylates these both in vivo and in vitro on an evolutionary conserved residue in the switch II domain. Pathogenic LRRK2 variants mapping to different functional domains increase phosphorylation of Rabs and this strongly decreases their affinity to regulatory proteins including Rab GDP dissociation inhibitors (GDIs). Our findings uncover a key class of bona-fide LRRK2 substrates and a novel regulatory mechanism of Rabs that connects them to PD. DOI: http://dx.doi.org/10.7554/eLife.12813.001

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A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease.

Alexander Zimprich, Anna Benet-Pagès, Walter Struhal … (2011)

To identify rare causal variants in late-onset Parkinson disease (PD), we investigated an Austrian family with 16 affected individuals by exome sequencing. We found a missense mutation, c.1858G>A (p.Asp620Asn), in the VPS35 gene in all seven affected family members who are alive. By screening additional PD cases, we saw the same variant cosegregating with the disease in an autosomal-dominant mode with high but incomplete penetrance in two further families with five and ten affected members, respectively. The mean age of onset in the affected individuals was 53 years. Genotyping showed that the shared haplotype extends across 65 kilobases around VPS35. Screening the entire VPS35 coding sequence in an additional 860 cases and 1014 controls revealed six further nonsynonymous missense variants. Three were only present in cases, two were only present in controls, and one was present in cases and controls. The familial mutation p.Asp620Asn and a further variant, c.1570C>T (p.Arg524Trp), detected in a sporadic PD case were predicted to be damaging by sequence-based and molecular-dynamics analyses. VPS35 is a component of the retromer complex and mediates retrograde transport between endosomes and the trans-Golgi network, and it has recently been found to be involved in Alzheimer disease. Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

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Author and article information

Contributors

Dario R. Alessi: Role: Writing – original draftRole: Writing – review & editing

Peter J. Cullen: Role: Writing – original draftRole: Writing – review & editing

Mark Cookson: Role: Writing – original draftRole: Writing – review & editing

Kalpana M. Merchant: Role: Writing – original draft

Scott A. Small:

ORCID: http://orcid.org/0000-0002-4777-1502

Role: Writing – original draftRole: Writing – review & editing

Journal

Journal ID (nlm-ta): Philos Trans R Soc Lond B Biol Sci

Journal ID (iso-abbrev): Philos Trans R Soc Lond B Biol Sci

Journal ID (publisher-id): RSTB

Journal ID (hwp): royptb

Title: Philosophical Transactions of the Royal Society B: Biological Sciences

Publisher: The Royal Society

ISSN (Print): 0962-8436

ISSN (Electronic): 1471-2970

Publication date (Print, pub): April 8, 2024

Publication date (Electronic, pub): February 19, 2024

Publication date PMC-release: February 19, 2024

Volume: 379

Issue: 1899 , Discussion meeting issue ‘Understanding the endo-lysosomal network in neurodegeneration’ organised and edited by Peter Cullen, Henne Holstege, Scott Small and Peter St. George-Hyslop

Electronic Location Identifier: 20220376

Affiliations

[ ¹ ] MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, , Dow Street, Dundee DD1 5EH, UK

[ ² ] School of Biochemistry, University of Bristol, , Biomedical Sciences Building, Bristol BS8 1TD, UK

[ ³ ] Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, , Bethesda, MD 20892, USA

[ ⁴ ] Department of Neurology, Feinberg School of Medicine, Northwestern University, , Chicago, IL 60208, USA

[ ⁵ ] Department of Neurology and the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, , New York, NY 10032, USA

Author notes

One contribution of 10 to a discussion meeting issue ‘ Understanding the endo-lysosomal network in neurodegeneration’.

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Scott A. Small http://orcid.org/0000-0002-4777-1502

Article

Publisher ID: rstb20220376

DOI: 10.1098/rstb.2022.0376

PMC ID: 10874697

SO-VID: 81f8e585-f0a5-4d55-b86c-b16e77760fdc

License:

Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited.

History

Date received : March 7, 2023

Date accepted : November 27, 2023

Funding

Funded by: Michael J. Fox Foundation for Parkinson's Research, http://dx.doi.org/10.13039/100000864;

Funded by: National Institute of Health;

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cover-date April 8, 2024

ScienceOpen disciplines: Philosophy of science

Keywords: parkinson's disease,retromer,lrrk2,vps35

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ScienceOpen disciplines: Philosophy of science

Keywords: parkinson's disease, retromer, lrrk2, vps35

Retromer-dependent lysosomal stress in Parkinson's disease

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Most cited references 40

Alzheimer's disease

Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases

A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease.

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