TMEM106B is a gene that codes for the transmembrane protein 106B. This protein is present in cells throughout the body, particularly in neurons and oligodendrocytes within the central nervous system. It plays a part in fundamental cellular processes, contributing to overall cellular health.
The Role of the TMEM106B Protein
The TMEM106B protein primarily resides within the membranes of lysosomes, the cell’s recycling and waste disposal centers. These cellular components are responsible for breaking down and clearing out cellular debris, damaged proteins, and other waste products. The protein’s presence ensures these “recycling centers” operate efficiently.
TMEM106B helps regulate several aspects of lysosomal function, including maintaining the correct pH balance inside lysosomes. It also influences lysosome movement and their release of contents outside the cell, a process called exocytosis. Both an increase and a decrease in the levels of TMEM106B can lead to abnormalities in these lysosomal functions.
The protein interacts with other cellular components, such as microtubule-associated protein 6 (MAP6), to influence the transport of lysosomes within neurons. This interaction helps to regulate the movement of lysosomes, particularly inhibiting their retrograde transport in neuronal dendrites. This control over lysosome positioning is important for the health and structure of nerve cells.
Genetic Variants and Their Impact
Everyone possesses the TMEM106B gene, but slight differences in its genetic code, known as genetic variants, can alter how the protein functions. These variants can change the protein’s efficiency or expression levels, affecting the lysosomal system it supports. Some variants are considered “risk,” while others are “protective.”
One well-studied variant is rs1990622, where the major allele (A) is associated with increased risk for certain conditions, while the minor allele (G) offers a protective effect. For instance, a protective variant known as p.T185S (rs3173615) has been linked to an increased proportion of neurons.
Risk variants can lead to impaired protein function, contributing to less efficient lysosomal waste clearance. Research indicates that the major allele of TMEM106B is associated with a higher accumulation of TMEM106B-derived filaments in the brain. This buildup is linked to more aggressive disease progression and enhanced dysfunction of cellular proteins.
Connection to Neurodegenerative Diseases
Impaired TMEM106B function, often influenced by genetic variants, is linked to several neurodegenerative diseases, acting as a risk modifier. Its strongest association is with Frontotemporal Lobar Degeneration (FTLD), particularly the subtype characterized by TDP-43 protein pathology. Risk variants of TMEM106B significantly increase disease susceptibility, especially in individuals who also carry mutations in the GRN gene.
Faulty cellular waste clearance due to TMEM106B dysfunction contributes to the toxic protein buildups that characterize these brain disorders. The presence of the TMEM106B risk allele (rs1990622T or A) influences cognitive decline and brain volume changes in FTLD patients. Increased deposition of TMEM106B filaments in the brain is specifically associated with worsened TDP-43 pathology.
Beyond FTLD, TMEM106B variants are also recognized as risk factors in Alzheimer’s disease (AD). The protective minor allele of rs1990622 has been observed to offer some protection against hippocampal sclerosis and TDP-43 pathology in AD patients. TMEM106B fibrillar aggregates have also been detected in the brains of individuals with AD.
The protein also plays a role in Parkinson’s disease (PD), affecting cognitive progression. Studies show that individuals carrying the TMEM106B risk allele (rs1990622T) experience more rapid cognitive decline. The presence of TMEM106B fibril aggregates is higher in the brains of Parkinson’s disease patients with dementia compared to age-matched healthy individuals. This suggests that lysosomal dysfunction mediated by TMEM106B contributes to the development of cognitive issues in PD.
The Link to Healthy Aging
Research also highlights the positive influence of certain TMEM106B variants on healthy aging and cognitive resilience. “Protective” variants of TMEM106B are associated with a lower likelihood of developing dementia in older age. The protective TMEM106B haplotype, a specific combination of genetic variants, is found more frequently in cognitively healthy centenarians.
Individuals who carry two copies of the protective rs1990622 variant show less brain shrinkage, reduced signs of neurodegeneration, and a slower rate of cognitive decline. This protective effect is particularly noticeable in people who also have GRN gene mutations, where the TMEM106B variant appears to lessen the impact of the GRN mutation. An underlying theory suggests that a highly efficient TMEM106B protein helps brain cells better withstand aging stresses by continuously and effectively clearing cellular waste, thereby maintaining neuronal health. The major risk allele, in contrast, is linked to smaller brain volumes in specific regions like the superior temporal gyrus and worse cognitive function in elderly individuals.