The role of IT and English education in shaping cognitive and behavioral responses to green economic volatility.

Variants of transmembrane protein 106B () were first found to be genetic modifiers of risk for frontotemporal lobar degeneration (FTLD) with TDP-43 pathology (FTLD-TDP) in a genome-wide association study in 2010 (). Similar results were replicated in another FTLD cohort from Flanders, Belgium (). Furthermore, the major allele of single nucleotide polymorphism (SNP) rs1990622 was also found to correlate with earlier age at onset (), faster decrease in cognitive function (), and higher risk of developing neuroastroglial tauopathy in FTLD patients (). In addition to its roles in FTLD, the major allele of SNP rs1990622 also increases the risk of developing Alzheimer’s disease (AD) (), the most common neurodegenerative diseases (NDs), whereas its minor allele decreases the risk of developing hippocampal sclerosis in AD (). Interestingly, another study reported that AD risk is remarkably influenced by the interaction of APOE with rs1595014, another SNP in (). Studies also revealed that multiple SNPs of were correlated with the clinical and pathological phenotypes of amyotrophic lateral sclerosis (ALS) (; ) and hippocampal sclerosis of aging (). However, the effects of genetic variations on Parkinson’s disease (PD), the second most common NDs after AD, were poorly investigated. Given the findings about the influences of variants on the risk and phenotypes of NDs, especially FTLD, from clinical studies, the physiological function of TMEM106B and its pathogenic mechanisms in FTLD have received considerable attention and have been well studied over the past decade. Studies suggest that TMEM106B is an integral type II transmembrane lysosomal protein and plays vital roles in lysosomal morphology, localization, acidification, anterograde and retrograde trafficking, and function (; ). The expression of TMEM106B mRNA and protein was dysregulated in FTLD, AD and ALS (; ; ). Both overexpression and knockdown/knockout of resulted in lysosomal dysfunctions which were proved to be a common and critical pathological process in the development and progression of NDs (; ). Therefore, TMEM106B was thought to participate in the pathogenesis of NDs through influencing lysosomal function. Notably, similar to other pathogenic amyloid proteins (such as amyloid , Tau, and -synuclein) in NDs, TMEM106B was found to form amyloid fibrils in brains of patients with NDs, including PD (; ; ). This surprising finding expands our perspective on the roles that TMEM106B plays in the pathogenesis of NDs. Moreover, unlike disease-associated conformational polymorphisms of -synuclein (-syn) in -synucleinopathies or Tau in tauopathies, the conformation of TMEM106B fibrils is not influenced by neurodegenerative disease conditions but is instead determined by the genotypes of rs3173615 (), the only one SNP located in exonal region, which results in the nonsynonymous mutation p.Thr185Ser in TMEM106B. The causal relationship between rs3173615 haplotype and TMEM106B fibrils structural polymorphism in NDs further suggests the involvement of TMEM106B in the pathogenesis of NDs. As mentioned above, previous explorations about TMEM106B involvement in NDs were mostly focused on FTLD, followed by AD, with PD sparsely studied. Taking the indiscriminate amyloid fibrils composed of TMEM106B formation in FTLD, AD and PD, it is plausible to speculate that TMEM106B roles in PD is also nonnegligible. Nonetheless, to our knowledge, only one longitudinal study to date has investigated the effect on PD clinical phenotypes, and found that the major allele of rs1990622 was associated with the accelerated cognition decline in PD patients (). However, this study only assessed the global cognitive function without elevating specific cognitive subdomains and other non-motor symptoms (NMS). Thus, in combination with the effects of rs3173615 haplotype on the clinicopathological phenotypes across multiple NDs and its deterministic role in TMEM106B fibril conformation polymorphisms (), this study aims to systematically investigate the effects of genetic variation, SNP rs3173615, on clinical phenotypes in PD patients, which will provide potential new clues for the participation of TMEM106B in PD.