Muscling In on PGC-1α for Improved Quality of Life in ALS

Impaired activity of peroxisome proliferator-activated receptor (PPAR)-γ coactivator (PGC)-1α has been implicated in the pathophysiology of several neurodegenerative disorders. In this issue, Da Cruz et al. (2012) show improved muscle function, but not survival, with increased PGC-1α activity in muscle in a mouse model of amyotrophic lateral sclerosis

Concordant Signaling Pathways Produced by Pesticide Exposure in Mice Correspond to Pathways Identified in Human Parkinson's Disease

Parkinson's disease (PD) is a neurodegenerative disease in which the etiology of 90 percent of the patients is unknown. Pesticide exposure is a major risk factor for PD, and paraquat (PQ), pyridaben (PY) and maneb (MN) are amongst the most widely used pesticides. We studied mRNA expression using transcriptome sequencing (RNA-Seq) in the ventral midbrain (VMB) and striatum (STR) of PQ, PY and paraquat+maneb (MNPQ) treated mice, followed by pathway analysis. We found concordance of signaling pathways between the three pesticide models in both the VMB and STR as well as concordance in these two brain areas. The concordant signaling pathways with relevance to PD pathogenesis were e.g. axonal guidance signaling, Wnt/β-catenin signaling, as well as pathways not previously linked to PD, e.g. basal cell carcinoma, human embryonic stem cell pluripotency and role of macrophages, fibroblasts and endothelial cells in rheumatoid arthritis. Human PD pathways previously identified by expression analysis, concordant with VMB pathways identified in our study were axonal guidance signaling, Wnt/β-catenin signaling, IL-6 signaling, ephrin receptor signaling, TGF-β signaling, PPAR signaling and G-protein coupled receptor signaling. Human PD pathways concordant with the STR pathways in our study were Wnt/β-catenin signaling, axonal guidance signaling and G-protein coupled receptor signaling. Peroxisome proliferator activated receptor delta (Ppard) and G-Protein Coupled Receptors (GPCRs) were common genes in VMB and STR identified by network analysis. In conclusion, the pesticides PQ, PY and MNPQ elicit common signaling pathways in the VMB and STR in mice, which are concordant with known signaling pathways identified in human PD, suggesting that these pathways contribute to the pathogenesis of idiopathic PD. The analysis of these networks and pathways may therefore lead to improved understanding of disease pathogenesis, and potential novel therapeutic targets

Disentangling Mitochondria in Alzheimer’s Disease

Alzheimer’s disease (AD) is a major cause of dementia in older adults and is fast becoming a major societal and economic burden due to an increase in life expectancy. Age seems to be the major factor driving AD, and currently, only symptomatic treatments are available. AD has a complex etiology, although mitochondrial dysfunction, oxidative stress, inflammation, and metabolic abnormalities have been widely and deeply investigated as plausible mechanisms for its neuropathology. Aβ plaques and hyperphosphorylated tau aggregates, along with cognitive deficits and behavioral problems, are the hallmarks of the disease. Restoration of mitochondrial bioenergetics, prevention of oxidative stress, and diet and exercise seem to be effective in reducing Aβ and in ameliorating learning and memory problems. Many mitochondria-targeted antioxidants have been tested in AD and are currently in development. However, larger streamlined clinical studies are needed to provide hard evidence of benefits in AD. This review discusses the causative factors, as well as potential therapeutics employed in the treatment of AD

Connection Lost, MAM: Errors in ER–Mitochondria Connections in Neurodegenerative Diseases

Mitochondria associated membranes (MAMs), as the name suggests, are the membranes that physically and biochemically connect mitochondria with endoplasmic reticulum. MAMs not only structurally but also functionally connect these two important organelles within the cell which were previously thought to exist independently. There are multiple points of communication between ER–mitochondria and MAMs play an important role in both ER and mitochondria functions such as Ca2+ homeostasis, proteostasis, mitochondrial bioenergetics, movement, and mitophagy. The number of disease-related proteins and genes being associated with MAMs has been continually on the rise since its discovery. There is an overwhelming overlap between the biochemical functions of MAMs and processes affected in neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD). Thus, MAMs have received well-deserving and much delayed attention as modulators for ER–mitochondria communication and function. This review briefly discusses the recent progress made in this now fast developing field full of promise for very exciting future therapeutic discoveries

PGC-1α, mitochondrial dysfunction, and Huntington's disease

Here is my submission for Beatles Day. I thought that since the boys tried making music with every instrument they could get their creative hands on, I\u27d continue that creativity and imagined their music in electronic fashion. So here is my Twist & Shout remix. :)https://scholarlycommons.pacific.edu/beatles-day/1008/thumbnail.jp

Transducer Of Regulated Creb-Binding Proteins (Torcs) Transcription And Function Is Impaired In Huntington\u27S Disease

Huntington\u27s disease (HD) is an incurable neurological disorder caused by an abnormal glutamine repeat expansion in the huntingtin (Htt) protein. In the present studies, we investigated the role of Transducers of Regulated cAMP response element-binding (CREB) protein activity (TORCs) in HD, since TORCs play an important role in the expression of the transcriptional co-regulator peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α), whose expression is impaired in HD. We found significantly decreased TORC1 expression levels in STHdhQ111 cells expressing mutant Htt, in the striatum of NLS-N171-82Q, R6/2 and HdhQ111 HD transgenic mice and in postmortem striatal tissue from HD patients. TORC1 overexpression in wild-type (WT) and Htt striatal cells increased CREB mRNA and protein levels, PGC-1α promoter activity, mRNA expression of the PGC-1α, NRF-1, Tfam and CytC genes, mitochondrial DNA content, mitochondrial activity and mitochondrial membrane potential. TORC1 overexpression also increased the resistance of striatal cells to 3-nitropropionic (3-NP) acid-mediated toxicity. In cultured WT and mutant Htt striatal cells, small hairpin RNA-mediated TORC1 knockdown resulted in decreased PGC-1α expression and increased susceptibility to 3-NP-induced toxicity. Overexpression of PGC-1α partially prevented TORC1 knockdown-mediated increased susceptibility of Htt striatal cells to 3-NP. Specific knockdown of TORC1 in the striatum of NLS-N171-82Q HD transgenic mice induced neurodegeneration. Lastly, knockdown of Htt prevents transcriptional repression of TORC1 and CREB in Htt striatal cells. These findings show that impaired expression and function of TORC1, which results in a reduction in PGC-1α, plays an important role in mitochondrial dysfunction in HD. © The Author 2012. Published by Oxford University Press. All rights reserved

Venn diagram of top ten signaling pathways in PQ, PY and MNPQ models of PD.

<p>A) Signaling pathways in VMB. B) Signaling pathways in STR. C) Common overlapping pathways in VMB and STR are underlined. Considering the top ten canonical pathways there are six pathways common in VMB of PQ, PY and MNPQ mouse models. There are three pathways common in STR of PQ, PY and MNPQ mouse models. All the three common canonical pathways in STR overlap with pathways common in the VMB between the three pesticide models.</p