Objective: This study aimed to explore whether the variants of Transmembrane protein 106B (TMEM106B) influence clinical phenotypes’ trajectory in Parkinson’s disease (PD).

Background: TMEM106B variations are not only genetic modifiers of risk for developing frontotemporal lobar degeneration¹, but also correlate with the heterogeneity of clinicopathological phenotypes in other neurodegenerative diseases (NDs)². Notably, recent studies from our team³ and other three teams worldwide^4-6 surprised to found that TMEM106B could indiscriminately form into amyloid fibrils in brains of NDs patients, including PD, which further suggests the critical roles of TMEM106B in the pathogenesis in NDs⁷. However, the roles of TMEM106B in PD are sparsely explored.

Method: We longitudinally followed 241 PD patients and genotyped their single nucleotide polymorphism (SNPs) of rs3173615, the only coding variant among SNPs of TMEM106B using Asian Screening Array technology. PD patients were classified into three groups, GG (major allele homozygotes), GC (heterozygotes) and CC (minor allele homozygotes) groups, according to the genotypes of rs3173615. All patients completed clinical evaluations and neuropsychological tests at baseline and every follow-up. Linear mixed-effects models were adopted to determine the effects of rs3173615 on disease progression of PD patients.

Results: At baseline, both the GG and GC groups presented slighter excessive daytime sleep than the CC group, and no association between the remaining demographic and clinical characteristics and the genotypes of rs3175613 among the three groups was observed (Table 1). Longitudinally, compared to the CC group, the GC group manifested with remarkable faster exacerbation of depression, visuospatial function and quality of life (QoL), and the GG group showed the same tendency with the GC group though without remarkable statistical significance (Table 2, Figure 1, 2).

Conclusion: TMEM106B rs3173615 is a genetic modifier for the trajectory of depression, visuospatial function and QoL in PD. Our findings suggest the involvement of TMEM106B in the pathogenesis of disease progression in PD, especially in the deterioration of depression, cognition and QoL.

Figure 1

Figure 2

References: 1. Van Deerlin VM, Sleiman PM, Martinez-Lage M, et al. Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions. Nature genetics 2010;42(3):234-9. doi: 10.1038/ng.536 [published Online First: 2010/02/16]
2. Feng T, Lacrampe A, Hu F. Physiological and pathological functions of TMEM106B: a gene associated with brain aging and multiple brain disorders. Acta neuropathologica 2021;141(3):327-39. doi: 10.1007/s00401-020-02246-3 [published Online First: 2021/01/03]
3. Fan Y, Zhao Q, Xia W, et al. Generic amyloid fibrillation of TMEM106B in patient with Parkinson’s disease dementia and normal elders. Cell research 2022;32(6):585-88. doi: 10.1038/s41422-022-00665-3 [published Online First: 2022/04/29]
4. Chang A, Xiang X, Wang J, et al. Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases. Cell 2022;185(8):1346-55.e15. doi: 10.1016/j.cell.2022.02.026 [published Online First: 2022/03/06]
5. Jiang YX, Cao Q, Sawaya MR, et al. Amyloid fibrils in FTLD-TDP are composed of TMEM106B and not TDP-43. Nature 2022;605(7909):304-09. doi: 10.1038/s41586-022-04670-9 [published Online First: 2022/03/29]
6. Schweighauser M, Arseni D, Bacioglu M, et al. Age-dependent formation of TMEM106B amyloid filaments in human brains. Nature 2022;605(7909):310-14. doi: 10.1038/s41586-022-04650-z [published Online First: 2022/03/29]
7. Fan Y, Zhao W, Ni Y, et al. Newly identified transmembrane protein 106B amyloid fibrils in the human brain: pathogens or by-products? Ageing and Neurodegenerative Diseases 2023;3(1):4. doi: 10.20517/and.2022.30

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MDS Abstracts - https://www.mdsabstracts.org/abstract/effects-of-transmembrane-protein-106b-genetic-variations-on-disease-progression-in-parkinsons-disease/