TMEM175 deficiency impairs lysosomal and mitochondrial function and increases α-synuclein aggregation

Abstract

Parkinson disease (PD) is a neurodegenerative disorder pathologically characterized by nigrostriatal dopamine neuron loss and the postmortem presence of Lewy bodies, depositions of insoluble α-synuclein, and other proteins that likely contribute to cellular toxicity and death during the disease. Genetic and biochemical studies have implicated impaired lysosomal and mitochondrial function in the pathogenesis of PD. Transmembrane protein 175 (TMEM175), the lysosomal K + channel, is centered under a major genome-wide association studies peak for PD, making it a potential candidate risk factor for the disease. To address the possibility that variation in TMEM175 could play a role in PD pathogenesis, TMEM175 function was investigated in a neuronal model system. Studies confirmed that TMEM175 deficiency results in unstable lysosomal pH, which led to decreased lysosomal catalytic activity, decreased glucocerebrosidase activity, impaired autophagosome clearance by the lysosome, and decreased mitochondrial respiration. Moreover, TMEM175 deficiency in rat primary neurons resulted in increased susceptibility to exogenous α-synuclein fibrils. Following α-synuclein fibril treatment, neurons deficient in TMEM175 were found to have increased phosphorylated and detergent-insoluble α-synuclein deposits. Taken together, data from these studies suggest that TMEM175 plays a direct and critical role in lysosomal and mitochondrial function and PD pathogenesis and highlight this ion channel as a potential therapeutic target for treating PD.

In vitro models of synucleinopathies: informing on molecular mechanisms and protective strategies

“…Consistently, the inhibition of lysosomal activity following the blockade of an endosomal K + channel, which was recently identified as a potential PD risk gene, increased α‐Syn aggregation in rat primary hippocampal neurons upon treatment with α‐Syn preformed fibrils (Jinn et al . ). In contrast, the activity of a major lysosomal protease cathepsin B (CtsB), surprisingly facilitated the formation of aggregation induced by exogenous α‐Syn fibrils within lysosomes (Tsujimura et al .…”

Exploring genetic modifiers of Gaucher disease: The next horizon

“…Another potential modifier gene, TMEM175 (transmembrane protein 175), a lysosomal K+ channel, was shown to destabilize lysosomal pH, decrease GCase activity, and increase susceptibility to exogenous α‐synuclein fibrils. These observations suggest a direct role for TMEM175 in lysosomal dysfunction and increased susceptibility for PD (Jinn et al., ). Though such studies are intriguing, more research is required to further validate these genes and to elucidate additional modifier genes.…”

Role of the endolysosomal system in Parkinson’s disease

“…The inability of auxilin to compensate for GAK in these mice suggests another unique role for GAK in neurons, perhaps a significant one in dopaminergic neurons. Further TMEM175 deficiency is noted to cause PD‐like α‐synuclein aggregation, along with impairment of lysosomal and mitochondrial function (Jinn et al ). Clarity on the role of GAK will prove to be crucial not only in establishing its involvement in PD but also in consolidating CME as the prime target in PD pathogenesis.…”