rs34311866 — TMEM175

Lysosomal K+/H+ channel variant (p.Met393Thr) that impairs lysosomal pH regulation, slows alpha-synuclein clearance, and increases risk for Parkinson's disease and REM sleep behavior disorder

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TMEM175 p.Met393Thr — When the Lysosomal Drain Gets Clogged

Deep inside every cell, lysosomes act as the cell's recycling plant — breaking down old proteins, clearing misfolded aggregates, and recycling the parts. Maintaining the right internal pH (around 4.5–5.0) is essential for the digestive enzymes inside to work. TMEM175 encodes a lysosomal ion channel11 lysosomal ion channel
proton-activated, proton-selective K+/H+ channel that fine-tunes lysosomal acidity — a molecular pressure-relief valve. The rs34311866 C allele introduces a methionine-to-threonine substitution at position 393 that partially disables this valve, with consequences that reach all the way to Parkinson's disease risk.

The Mechanism

The M393T substitution reduces channel current amplitude22 The M393T substitution reduces channel current amplitude compared to wild-type, placing function midway between the functional and knockout states. When the channel cannot adequately regulate lysosomal pH, two downstream failures occur: First, autophagosome clearance is impaired33 autophagosome clearance is impaired — cellular debris builds up rather than being digested. Second, and most critically for neurodegeneration, alpha-synuclein — the protein that aggregates into Lewy bodies in Parkinson's disease — accumulates in its phosphorylated (aggregation-prone) form. Wild-type TMEM175 overexpression reduces phospho-α-synuclein; M393T overexpression does not. The channel is also considered a druggable target for lysosomal dysfunction in neurodegeneration44 druggable target for lysosomal dysfunction in neurodegeneration, with selective inhibitors and activators under active investigation.

The Evidence

The genetic signal is one of the strongest in Parkinson's disease research. Chang et al. 2017 (Nature Genetics) identified the TMEM175 locus with OR 1.23, p=1×10⁻⁵⁰55 Chang et al. 2017 (Nature Genetics) identified the TMEM175 locus with OR 1.23, p=1×10⁻⁵⁰ across 26,035 cases and 403,190 controls — one of 17 novel PD risk loci. The Nalls et al. 2019 Lancet Neurology meta-analysis of 37,688 cases and 1.4 million controls66 Nalls et al. 2019 Lancet Neurology meta-analysis of 37,688 cases and 1.4 million controls confirmed the locus among 90 independent genome-wide significant signals. Functional studies by Wie et al. (Nature, 2021) quantified the C allele OR at 1.26 [95% CI 1.22–1.31]77 Wie et al. (Nature, 2021) quantified the C allele OR at 1.26 [95% CI 1.22–1.31] and found that C carriers in the University of Pennsylvania and PPMI cohorts showed faster motor decline (p=0.032) and faster cognitive decline (p=0.005) after diagnosis. Beyond PD, the Blauwendraat et al. 2019 age-at-onset GWAS88 Blauwendraat et al. 2019 age-at-onset GWAS (28,568 cases) found rs34311866 p.M393T is the primary coding signal for earlier PD onset. The Krohn et al. 2022 RBD GWAS (Nature Communications)99 Krohn et al. 2022 RBD GWAS (Nature Communications) then identified TMEM175 as one of five loci for REM sleep behavior disorder — a prodromal synucleinopathy — shared across RBD, PD, and dementia with Lewy bodies.

Practical Actions

Carriers of the C allele cannot fix the M393T variant, but they can support the cellular processes that compensate for reduced lysosomal function. The principal strategy is maintaining autophagic flux — the rate at which cells clear protein waste — through targeted supplementation and lifestyle choices. Trehalose, a disaccharide that activates the TFEB transcription factor independently of mTOR, has documented preclinical effects on TMEM175-dependent clearance pathways. Spermidine similarly induces autophagy via eIF5A hypusination. Urolithin A (a gut metabolite of ellagic acid) activates mitophagy and has Phase II trial data in humans. These are not generic supplements — they specifically address the autophagy-lysosomal axis impaired by M393T. Neurological monitoring for early-onset cognitive or motor changes is warranted, particularly given evidence of accelerated decline after diagnosis.

Interactions

TMEM175 sits in the same autophagy-lysosomal pathway1010 autophagy-lysosomal pathway as GBA1 (glucocerebrosidase) — the strongest known genetic risk factor for PD (rs76763715, N370S). Both genes affect lysosomal function and alpha-synuclein clearance, but through distinct mechanisms: TMEM175 at the pH-regulation step, GBA1 at the enzymatic glucosphingolipid-hydrolysis step. Carriers of risk alleles in both genes may face compounded impairment of lysosomal alpha-synuclein clearance. rs2736990 (SNCA intron 4) increases alpha-synuclein expression levels — a separate upstream contributor to the same aggregation cascade. The combination of elevated substrate (SNCA) and impaired clearance (TMEM175) represents a convergent risk architecture worth capturing as a compound interaction candidate.

Genotype Interpretations

What each possible genotype means for this variant.

TT Functional Channel Normal

Normal TMEM175 lysosomal channel function

You carry two copies of the common T allele at rs34311866, giving you full-length methionine at position 393 of the TMEM175 protein. Your lysosomal K+/H+ channel functions normally, maintaining the acidic environment (pH ~4.5–5.0) that lysosomes need to efficiently degrade misfolded proteins including alpha-synuclein. About 66% of people globally share this genotype, with higher prevalence in African-ancestry populations (~92%).

CT Reduced Channel Function Reduced

One copy of the lysosomal channel variant — moderately elevated PD and RBD risk

The M393T substitution reduces lysosomal K+/H+ channel conductance, impairing the cell's ability to maintain optimal lysosomal pH during periods of elevated protein clearance demand (starvation, oxidative stress, protein aggregate burden). This leads to two measurable cellular defects: slower autophagosome clearance and accumulation of phosphorylated alpha-synuclein — the aggregation-prone form that seeds Lewy bodies. The variant also increases REM sleep behavior disorder (RBD) risk, a condition now understood as a prodromal synucleinopathy that often precedes PD or Lewy body dementia by 10–15 years.

The absolute lifetime PD risk elevation from a single C allele remains modest in isolation — PD lifetime risk is ~1–2% in the general population, and an OR of 1.26 on that baseline translates to ~1.3–2.5% risk. The clinical relevance is greater when combined with other PD risk factors (age, sex, pesticide exposure, SNCA variants, GBA1 variants).

CC Homozygous Risk High Risk

Two copies of the lysosomal channel variant — elevated PD and RBD risk

With both copies of TMEM175 encoding M393T, lysosomal pH regulation relies entirely on reduced-function channels. Under protein clearance stress — during oxidative injury, inflammation, or elevated alpha-synuclein load — the system is more likely to become over-acidified or overwhelmed. Phosphorylated alpha-synuclein accumulates faster than in heterozygotes in cellular models. The combined data from Wie et al. (2021) using PD progression cohorts suggest that C-allele dose correlates with rate of motor and cognitive decline after onset.

The absolute lifetime risk elevation remains context-dependent — other genetic, environmental, and age factors dominate individual risk. However, homozygous CC carriers benefit most from proactive lysosomal support strategies and the most vigilant monitoring for prodromal synucleinopathy signs.