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Autophagic lysosome reformation dysfunction in glucocerebrosidase deficient cells: relevance to Parkinson disease
Joana Magalhaes1, Matthew E Gegg1, Anna Migdalska-Richards1
1Department of Clinical Neurosciences, Institute of Neurology, University College London, Rowland Hill Street, London, UK.
Abstract:
Glucocerebrosidase (GBA1) gene mutations increase the risk of Parkinson disease (PD). While the cellular mechanisms associating GBA1 mutations and PD are unknown, loss of the glucocerebrosidase enzyme (GCase) activity, inhibition of autophagy and increased α-synuclein levels have been implicated. Here we show that autophagy lysosomal reformation (ALR) is compromised in cells lacking functional GCase. ALR is a cellular process controlled by mTOR which regenerates functional lysosomes from autolysosomes formed during macroautophagy. A decrease in phopho-S6K levels, a marker of mTOR activity, was observed in models of GCase deficiency, including primary mouse neurons and the PD patient derived fibroblasts with GBA1 mutations, suggesting that ALR is compromised. Importantly Rab7, a GTPase crucial for endosome-lysosome trafficking and ALR, accumulated in GCase deficient cells, supporting the notion that lysosomal recycling is impaired. Recombinant GCase treatment reversed ALR inhibition and lysosomal dysfunction. Moreover, ALR dysfunction was accompanied by impairment of macroautophagy and chaperone-mediated autophagy, increased levels of total and phosphorylated (S129) monomeric α-synuclein, evidence of amyloid oligomers and increased α-synuclein release. Concurrently, we found increased cholesterol and altered glucosylceramide homeostasis which could compromise ALR. We propose that GCase deficiency in PD inhibits lysosomal recycling. Consequently neurons are unable to maintain the pool of mature and functional lysosomes required for the autophagic clearance of α-synuclein, leading to the accumulation and spread of pathogenic α-synuclein species in the brain. Since GCase deficiency and lysosomal dysfunction occur with ageing and sporadic PD pathology, the decrease in lysosomal reformation may be a common feature in PD.
Insights
Glucocerebrosidase (GCase) deficiency impairs lysosomal reformation, a key process for clearing α-synuclein in Parkinson disease (PD). This dysfunction leads to α-synuclein accumulation and spread, suggesting a common mechanism in PD pathogenesis.
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- Mutations in the Glucocerebrosidase (GBA1) gene are a significant risk factor for Parkinson disease (PD).
- The precise cellular mechanisms linking GBA1 mutations to PD pathogenesis remain unclear, though GCase deficiency, impaired autophagy, and elevated α-synuclein levels are implicated.
Purpose of the Study:
- To investigate the role of autophagy lysosomal reformation (ALR) in GCase deficiency models relevant to Parkinson disease.
- To elucidate the impact of compromised ALR on lysosomal function, autophagy, and α-synuclein metabolism.
Main Methods:
- Utilized primary mouse neurons and PD patient-derived fibroblasts with GBA1 mutations to model GCase deficiency.
- Assessed autophagy lysosomal reformation (ALR) by monitoring phopho-S6K levels and Rab7 GTPase accumulation.
- Evaluated macroautophagy, chaperone-mediated autophagy, α-synuclein levels (total and phosphorylated), and lysosomal homeostasis (cholesterol, glucosylceramide).
Main Results:
- GCase deficiency significantly compromises autophagy lysosomal reformation (ALR), indicated by decreased mTOR activity markers and Rab7 accumulation.
- ALR dysfunction correlates with impaired macroautophagy and chaperone-mediated autophagy, alongside increased total and phosphorylated α-synuclein.
- Recombinant GCase treatment restored ALR and lysosomal function, while GCase deficiency led to altered lipid homeostasis and increased α-synuclein release.
Conclusions:
- GCase deficiency in Parkinson disease inhibits lysosomal recycling and reformation, impairing the neuron's ability to clear α-synuclein.
- This lysosomal dysfunction contributes to the accumulation and propagation of toxic α-synuclein species in the brain.
- Decreased lysosomal reformation may represent a shared pathological feature in both genetic and sporadic forms of Parkinson disease, particularly with aging.
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