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Published on: June 23, 2023
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TMEM175 deficiency impairs lysosomal and mitochondrial function and increases α-synuclein aggregation
Sarah Jinn1,2, Robert E Drolet3, Paige E Cramer3
1Target and Pathway Biology, Genetics and Pharmacogenomics, Merck Research Laboratories, Merck & Co., Inc., Boston, MA 02115.
Summary
Deficiency in TMEM175, a lysosomal channel, disrupts cellular functions crucial for Parkinson disease (PD) pathogenesis. This TMEM175 dysfunction impairs lysosomal and mitochondrial health, increasing susceptibility to alpha-synuclein toxicity in PD models.
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- Parkinson disease (PD) involves dopamine neuron loss and alpha-synuclein aggregates.
- Lysosomal and mitochondrial dysfunction are implicated in PD pathogenesis.
- TMEM175, a lysosomal K+ channel, is genetically linked to PD risk.
Purpose of the Study:
- Investigate the role of TMEM175 in neuronal function and PD pathogenesis.
- Determine if TMEM175 variations contribute to PD risk.
Main Methods:
- Utilized a neuronal model system to study TMEM175 function.
- Examined lysosomal pH, enzyme activity, and autophagosome clearance in TMEM175-deficient neurons.
- Assessed mitochondrial respiration and neuronal response to alpha-synuclein fibrils.
Main Results:
- TMEM175 deficiency caused unstable lysosomal pH, reduced enzyme activity, and impaired autophagosome clearance.
- Mitochondrial respiration decreased in TMEM175-deficient neurons.
- Neurons lacking TMEM175 showed increased susceptibility to alpha-synuclein fibrils, leading to more protein aggregation.
Conclusions:
- TMEM175 plays a critical role in maintaining lysosomal and mitochondrial health.
- TMEM175 dysfunction contributes to Parkinson disease pathogenesis.
- TMEM175 represents a potential therapeutic target for Parkinson disease.
