Nerve Degeneration

Publication Title: 
EMBO molecular medicine

Sirtuins are NAD-dependent protein deacetylases known to have protective effects against age-related diseases such as cancer, diabetes, cardiovascular and neurodegenerative diseases. In mammals, there are seven sirtuins (SIRT1-7), which display diversity in subcellular localization and function. While SIRT1 has been extensively investigated due to its initial connection with lifespan extension and involvement in calorie restriction, important biological and therapeutic roles of other sirtuins have only recently been recognized.

Author(s): 
Donmez, Gizem
Outeiro, Tiago F.
Publication Title: 
Human Molecular Genetics

The CISD2 gene, which is an evolutionarily conserved novel gene, encodes a transmembrane protein primarily associated with the mitochondrial outer membrane. Significantly, the CISD2 gene is located within the candidate region on chromosome 4q where a genetic component for human longevity has been mapped. Previously, we have shown that Cisd2 deficiency shortens lifespan resulting in premature aging in mice. Additionally, an age-dependent decrease in Cisd2 expression has been detected during normal aging.

Author(s): 
Wu, Chia-Yu
Chen, Yi-Fan
Wang, Chih-Hao
Kao, Cheng-Heng
Zhuang, Hui-Wen
Chen, Chih-Cheng
Chen, Liang-Kung
Kirby, Ralph
Wei, Yau-Huei
Tsai, Shih-Feng
Tsai, Ting-Fen
Publication Title: 
Genetics

Neurodegeneration is a hallmark of the human disease ataxia-telangiectasia (A-T) that is caused by mutation of the A-T mutated (ATM) gene. We have analyzed Drosophila melanogaster ATM mutants to determine the molecular mechanisms underlying neurodegeneration in A-T. Previously, we found that ATM mutants upregulate the expression of innate immune response (IIR) genes and undergo neurodegeneration in the central nervous system. Here, we present evidence that activation of the IIR is a cause of neurodegeneration in ATM mutants.

Author(s): 
Petersen, Andrew J.
Katzenberger, Rebeccah J.
Wassarman, David A.
Publication Title: 
Molecular Neurodegeneration

Most neurons are born with the potential to live for the entire lifespan of the organism. In addition, neurons are highly polarized cells with often long axons, extensively branched dendritic trees and many synaptic contacts. Longevity together with morphological complexity results in a formidable challenge to maintain synapses healthy and functional. This challenge is often evoked to explain adult-onset degeneration in numerous neurodegenerative disorders that result from otherwise divergent causes.

Author(s): 
Bezprozvanny, Ilya
Hiesinger, Peter Robin
Publication Title: 
Trends in Molecular Medicine

Calorie restriction (CR) extends lifespan in a wide variety of species and mitigates diseases of aging in mammals. Here, we describe the evidence that the silent information regulator 2 (SIR2) gene, which encodes a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase, regulates lifespan and mediates CR in lower species such as Saccharomyces cerevisiae and Caenorhabditis elegans. We discuss the emerging roles of mammalian SIR2 homologs in regulating physiological changes triggered by CR and their potential connections to diseases of aging.

Author(s): 
Chen, Danica
Guarente, Leonard
Publication Title: 
The EMBO journal

A progressive loss of neurons with age underlies a variety of debilitating neurological disorders, including Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), yet few effective treatments are currently available. The SIR2 gene promotes longevity in a variety of organisms and may underlie the health benefits of caloric restriction, a diet that delays aging and neurodegeneration in mammals. Here, we report that a human homologue of SIR2, SIRT1, is upregulated in mouse models for AD, ALS and in primary neurons challenged with neurotoxic insults.

Author(s): 
Kim, Dohoon
Nguyen, Minh Dang
Dobbin, Matthew M.
Fischer, Andre
Sananbenesi, Farahnaz
Rodgers, Joseph T.
Delalle, Ivana
Baur, Joseph A.
Sui, Guangchao
Armour, Sean M.
Puigserver, Pere
Sinclair, David A.
Tsai, Li-Huei
Publication Title: 
Neurobiology of Disease

Huntington's disease (HD) is a lethal, neurodegenerative disorder caused by expansion of the polyglutamine repeat in the Huntingtin gene (HTT), leading to mutant protein misfolding, aggregation, and neuronal death. Feeding a Drosophila HD model cystamine, or expressing a transgene encoding the anti-htt intracellular antibody (intrabody) C4-scFv in the nervous system, demonstrated therapeutic potential, but suppression of pathology was incomplete.

Author(s): 
Bortvedt, S. F.
McLear, J. A.
Messer, A.
Ahern-Rindell, A. J.
Wolfgang, W. J.
Publication Title: 
Food & Function

Black rice is rich in anthocyanin antioxidants. The present study investigated the lifespan-prolonging activity of black rice extracts (BREs) and its effect on gene expressions of CuZnSOD (SOD1), MnSOD (SOD2), catalase (CAT), methuselah (Mth) and Rpn11 involved in the antioxidant system and ageing of fruit flies. The OR wild type fly was maintained on a control diet or two experimental diets containing 10 mg ml(-1) BRE (BRE10) or 30 mg ml(-1) BRE (BRE30).

Author(s): 
Zuo, Yuanyuan
Peng, Cheng
Liang, Yintong
Ma, Ka Ying
Yu, Hongjian
Edwin Chan, Ho Yin
Chen, Zhen-Yu
Publication Title: 
Cell Metabolism

Iron regulatory proteins (Irps) 1 and 2 posttranscriptionally control the expression of transcripts that contain iron-responsive element (IRE) sequences, including ferritin, ferroportin, transferrin receptor, and hypoxia-inducible factor 2? (HIF2?). We report here that mice with targeted deletion of Irp1 developed pulmonary hypertension and polycythemia that was exacerbated by a low-iron diet. Hematocrits increased to 65% in iron-starved mice, and many polycythemic mice died of abdominal hemorrhages. Irp1 deletion enhanced HIF2?

Author(s): 
Ghosh, Manik C.
Zhang, De-Liang
Jeong, Suh Young
Kovtunovych, Gennadiy
Ollivierre-Wilson, Hayden
Noguchi, Audrey
Tu, Tiffany
Senecal, Thomas
Robinson, Gabrielle
Crooks, Daniel R.
Tong, Wing-Hang
Ramaswamy, Kavitha
Singh, Anamika
Graham, Brian B.
Tuder, Rubin M.
Yu, Zu-Xi
Eckhaus, Michael
Lee, Jaekwon
Springer, Danielle A.
Rouault, Tracey A.
Publication Title: 
Progress in Neuro-Psychopharmacology & Biological Psychiatry

Several diseases are known to have a multifactorial origin, depending not only on genetic but also on environmental factors. They are called "complex disorders" and include cardiovascular disease, cancer, diabetes, and neuropsychiatric and neurodegenerative diseases. In the latter class, Alzheimer's (AD) and Parkinson's diseases (PD) are by far the most common in the elderly and constitute a tremendous social and economical problem.

Author(s): 
Marques, Sueli C. F.
Oliveira, Catarina R.
Pereira, Claudia M. F.
Outeiro, Tiago F.

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