TMEM106B and Mitochondrial Dysfunction in FTLD and Other Dementia

Dementia affects millions worldwide, yet remains without a cure, highlighting the urgent need for research into its causes. Frontotemporal lobar degeneration (FTLD) is a significant contributor to middle-age-onset dementias, accounting for up to 10% of cases and adding to the challenges faced by patients and caregivers. Genetic variation at the TMEM106B locus has been identified as a risk factor for FTLD and other dementias, like Alzheimer’s disease (AD). However, the specific mechanisms by which TMEM106B variants increase the risk of developing these diseases remain unclear. The extensive documentation of mitochondrial dysfunction as a feature of neurodegenerative diseases underscores its critical role in neuropathogenesis. Dysregulation of mitochondria-associated endoplasmic reticulum membranes (MAMs), which play an important role in regulating mitochondrial function, has been implicated in various neurodegenerative disorders. This dysregulation can lead to impaired calcium signaling, disrupted lipid metabolism, and altered mitochondrial dynamics, ultimately resulting in neuronal loss. Our ongoing research has uncovered a potential link between TMEM106B and mitochondrial dysfunction. We have observed that elevated levels of TMEM106B are associated with changes in mitochondrial morphology, reduced mitochondrial membrane potential, and impaired mitochondrial respiration in HEK293 cells. Furthermore, we have found that TMEM106B is enriched in MAMs and interacts with Sigma 1 receptor (SigR1), a key protein involved in regulating MAM function. To further investigate the role of TMEM106B in mitochondrial dysfunction and neuronal damage, we aim to determine if increased TMEM106B expression leads to these outcomes in cultured cortical neurons. Additionally, we will explore the mechanisms underlying TMEM106B-mediated mitochondrial dysfunction, focusing on its interaction with SigR1 and its impact on MAM function. Understanding the relationship between TMEM106B and mitochondrial dysfunction could provide valuable insights into the pathogenesis of FTLD and other related dementias. This knowledge could pave the way for new therapeutic approaches aimed at addressing mitochondrial dysfunction in these debilitating conditions. Project Number: 1R03AG094840-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Ju Gao | Institution: UNIVERSITY OF ARIZONA, TUCSON, AZ | Award Amount: $310,083 | Activity Code: R03 | Study Section: Neural Oxidative Metabolism and Death Study Section[NOMD] View on NIH RePORTER: https://reporter.nih.gov/project-details/11200685