Mitochondrial transcription factor A (TFAM) polymorphisms and risk of late-onset Alzheimer's disease in Han Chinese

Qun, Zhang; Yu, Jin‐Tai; Wang, Ping; Chen, Wei; Wu, Zhong-Chen; Jiang, Hong; Tan, Lan

doi:10.1016/j.brainres.2010.10.074

Cited by 30 publications

(23 citation statements)

References 41 publications

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“…Increased TFAM enhances mt stability and reduces oxidative stress. A patient based study analyzing single nucleotide polymorphisms within the TFAM gene (rs1937 and rs2306604) showed that mutations in the TFAM gene contribute to declining mitochondria biogenesis leading to disease [161]. The Aguirre-Reuda group found that overexpression of PGC-1alpha and TFAM protect against oxidative stress [162].…”

Section: Tfam Directed Therapeuticsmentioning

confidence: 99%

Mitochondrial pathways to cardiac recovery: TFAM

2016

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Mitochondrial dysfunction underlines a multitude of pathologies; however, studies are scarce that rescue the mitochondria for cellular resuscitation. Exploration into the protective role of mitochondrial Transcription factor A (TFAM) and its mitochondrial functions respective to cardiomyocyte death are in need of further investigation. TFAM is a gene regulator that acts to mitigate calcium mishandling and ROS production by wrapping around mitochondrial DNA (mtDNA) complexes. TFAM’s regulatory functions over serca2a, NFAT and Lon protease contribute to cardiomyocyte stability. Calcium and ROS dependent proteases, calpains and matrix metallo-proteinases (MMP’s) are abundantly found upregulated in the failing heart. TFAM’s regulatory role over ROS production and calcium mishandling leads to further investigation into the cardioprotective role of exogenous TFAM. In an effort to restabilize physiological and contractile activity of cardiomyocytes in HF models, we propose that TFAM-packed exosomes (TFAM-PE) will act therapeutically by mitigating mitochondrial dysfunction. Notably, this is the first mention of exosomal delivery of transcription factors in the literature. Here we elucidate the role of TFAM in mitochondrial rescue and focus on its therapeutic potential.

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Section: Tfam Directed Therapeuticsmentioning

confidence: 99%

Mitochondrial pathways to cardiac recovery: TFAM

2016

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“…The mtDNA damage in AD patients increases the production of ROS (Swerdlow et al, 1997) resulting in production of more mtDNA damage, and this combined with deficient mtBER may create an increasing cycle of destruction culminating in neuronal death. Polymorphisms in TFAM, a modulator of mtBER (see above), can influence the risk of sporadic late-onset AD (Zhang et al, 2011). …”

Section: Mitochondrial Dysfunction and Dna Repairmentioning

confidence: 99%

DNA repair deficiency in neurodegeneration

Jeppesen

Bohr

Stevnsner

2011

Progress in Neurobiology

301

268

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Deficiency in repair of nuclear and mitochondrial DNA damage has been linked to several neurodegenerative disorders. Many recent experimental results indicate that the post-mitotic neurons are particularly prone to accumulation of unrepaired DNA lesions potentially leading to progressive neurodegeneration. Nucleotide excision repair is the cellular pathway responsible for removing helix-distorting DNA damage and deficiency in such repair is found in a number of diseases with neurodegenerative phenotypes, including Xeroderma Pigmentosum and Cockayne syndrome. The main pathway for repairing oxidative base lesions is base excision repair, and such repair is crucial for neurons given their high rates of oxygen metabolism. Mismatch repair corrects base mispairs generated during replication and evidence indicates that oxidative DNA damage can cause this pathway to expand trinucleotide repeats, thereby causing Huntington’s disease. Single-strand breaks are common DNA lesions and are associated with the neurodegenerative diseases, ataxia-oculomotor apraxia-1 and spinocerebellar ataxia with axonal neuropathy-1. DNA double-strand breaks are toxic lesions and two main pathways exist for their repair: homologous recombination and non-homologous end-joining. Ataxia telangiectasia and related disorders with defects in these pathways illustrate that such defects can lead to early childhood neurodegeneration. Aging is a risk factor for neurodegeneration and accumulation of oxidative mitochondrial DNA damage may be linked with the age-associated neurodegenerative disorders Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Mutation in the WRN protein leads to the premature aging disease Werner syndrome, a disorder that features neurodegeneration. In this article we review the evidence linking deficiencies in the DNA repair pathways with neurodegeneration.

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“…Recent studies suggest particular TOMM40 polymorphisms may affect the age of AD onset more stringently than APOE polymorphisms, leading some to speculate this mitochondrial protein is potentially more relevant to AD than apolipoprotein E (223). Several studies have also associated variation in the TFAM gene with AD risk (5,14,102,303). The TFAM gene encodes transcription factor A of the mitochondria, which plays a major role in mtDNA replication and expression (50, 82,134,200).…”

Section: Synthesizing the Data: The Mitochondrial Cascade Hypothesismentioning

confidence: 99%