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Endosomal sorting pathways in the pathogenesis of Parkinson's disease
Lindsey A Cunningham1, Darren J Moore2
1Van Andel Institute Graduate School, Grand Rapids, MI, United States; Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, United States.
Progress in Brain Research
|April 6, 2020
Summary
Parkinson's disease (PD) is linked to endolysosomal dysfunction. Mutations in PD-associated genes disrupt endosomal sorting, highlighting this pathway as a central mechanism in PD pathogenesis.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Parkinson's disease (PD) pathogenesis is increasingly understood through genetic associations.
- Endolysosomal system dysfunction is emerging as a critical factor in PD.
Purpose of the Study:
- To review genetic and experimental evidence linking endolysosomal dysfunction to Parkinson's disease.
- To highlight endosomal sorting as a convergent pathway in PD.
Main Methods:
- Review of genetic studies identifying PD-associated genes.
- Analysis of experimental data on gene product function in disease models.
- Discussion of protein interactions within endolysosomal pathways.
Main Results:
- Familial PD genes (LRRK2, VPS35, α-synuclein) and newly identified genes (auxilin, synaptojanin-1, Rab39b) implicate endolysosomal sorting deficits.
- LRRK2 acts as a central regulator, phosphorylating key endocytic proteins and Rab GTPases.
- Rab29 and VPS35 regulate LRRK2 activity at the Golgi and endosomes, respectively.
Conclusions:
- Endolysosomal sorting pathways are a key convergence point in Parkinson's disease pathogenesis.
- Genetic mutations disrupting endolysosomal function lead to PD-like phenotypes.
- Interactions between PD-associated genes underscore the importance of the endolysosomal system.
Keywords:
AuxilinEndolysosomal sortingEndophilinGAKLRRK2Parkinson's diseaseRab GTPasesSynaptic vesicle endocytosisSynaptojanin-1VPS35α-SynucleinMore Related Videos
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