Categories: Watchlist

Like a good neighbor, microglia are there?

clock February 3, 2012

 

On patrol.  Microglia, the watchdogs of the brain and spinal cord, on the lookout in the brain.  Video: Science Visuals, Switzerland.

Microglia produce toxic substances that contribute to the inflammation of the motor nerves.   But these watch dogs of the brain and spinal cord might not be bad to their cytoskeletal  'bones', according to a study published this week.   The research team led by the University of Freiburg’s Knut Biber PhD discovered that resting microglia might actually help keep neurodegeneration in check by protecting neurons from death by glutamate (a.k.a glutamate-induced excitotoxicity).  The study focused on cultured nerve cells derived from the hippocampal region of healthy mouse brain.

Looking towards the clinic, this study suggests that quieting these angry watchdogs may be better than putting them to sleep to combat inflammation in people with ALS.  Soothing strategies currently in the pipeline include Neuraltus Pharamaceuticals' NP001.

To learn more about therapies researchers are developing to combat cytotoxic microglia in ALS, listen to our recent podcast with Methodist Neurological Institute’s Stan Appel MD, Symphony in M.

Reference

Vinet, J., van Weering, H.R., Heinrich, A., Kalin, R.E., Wegner, A., Brouwer, N., Heppner, F.L., van Rooijen, N., Boddeke, H.W. and Biber K. (2012). Neuroprotective function for ramified microglia in hippocampal excitotoxicity. Journal of Neuroinflammation 9(1), 27Abstract Full Text  

Further Reading

Appel, S.H., Beers, D.R, and Henkel, J.S. (2008). T cell-microglial dialogue in Parkinson's disease and amyotrophic lateral sclerosis: are we listening? Trends In Immunology31(1), 7-17.  Abstract Full Text (Subscription Required)

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Categories: From The Bench , Watchlist

RAMPing down ALS

clock January 18, 2012

ALS AMP-activated protein kinase AMPK

 

Energy star. When ATP drops to critical levels in the brain and spinal cord, AMPK (above) fires up to help meet energy demands. Image: MRC National Institute for Medical Research,  PDB

ALS may occur, at least in part, due to the breakdown of mitochondria that supply power to the motor nerves.  But according to a new study, the ramping up of energy production to compensate for these power outages may actually do more harm than good - further aggravating the disease.

The study is published today in the Journal of Neuroscience.

The Children's Hospital of Philadelphia (CHOP) team found that the level of activated AMP-associated protein kinase (AMPK), an enzyme that helps maintain energy levels in tissues including the CNS, increased by 50% with respect to the inactive enzyme in a cellular mouse model of ALS. And, by reducing the levels of activated AMPK using the inhibitor compound C, the loss of these cultured motor neurons dropped from 50% to nearly 0%.

These results suggest that a spike in AMPK activity might contribute to neurodegeneration in ALS.  Therefore, by reducing these levels, researchers might be able to slow or stop the progression of the disease.

To put this theory to the test, the CHOP team genetically reduced levels of activated AMPK in a roundworm model of ALS. The researchers found that these so-called nematodes moved more easily.

The CHOP team now hopes to take a look at mouse models of ALS to determine whether levels of activated AMPK are indeed elevated and if so, whether dropping these levels delays the progression of the disease.

Looking ahead, scientists might be able to develop drugs that reduce levels of AMPK in the CNS to treat ALS. But, CHOP neurologist Robert Kalb MD, the leader of the study, cautions that there could be downsides to such a strategy such as the exacerbation of certain conditions such as hypermetabolism or type II diabetes.

"There are all sorts of potential complications,” says Kalb. “Nothing in life is simple."

Reference

Lim, M.A., Selak, M.A., Xiang, Z., Krainc, D., Neve, R.L., Kraemer, B.C., Watts, J.L. and Kalb, R.G. (2011) Reduced activity of AMP-activated protein kinase protects against genetic models of motor neuron disease. Journal of Neuroscience, 32(3), 1123-1141. Abstract Full Text

Further Reading

Carling, D., Mayer, F.V., Sanders, M.J. and Gamblin, S.J. (2011) AMP-activated protein kinase: nature's energy sensor. Nature Chemical Biology, 7(8), 1123-1141. Abstract Full Text

 


Updated 1/25/12:  ALS Today talked to CHOP neurologist Robert Kalb MD about the potential of modulating AMPK as a therapy for ALS.

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Categories: Watchlist

Antibodies for sALS

clock November 10, 2011

Antibodies against misfolded antioxidant enzyme superoxide dismutase 1 (SOD1) may help people with the sporadic form of ALS (sALS) live longer according to a new study published this month.  The study which included nearly 300 people with sALS found that participants that produced antibodies against a misfolded form of the enzyme lived nearly 2.5 years longer than those that did not.  These results suggest that immunization strategies directed against misfolded SOD1 may have the potential to slow the progression of the disease even in people without ALS-associated SOD1 mutations.

Superoxide Dismutase 1 (SOD1). Conformational changes in SOD1 may contribute to sALS according to recent results.  Mutations in SOD1 are associated with 15-20% of cases of familial ALS. Image: Emw, Wikimedia.

References

van Blitterswijk, M. et al. (2011) Anti-superoxide dismutase antibodies are associated with survival in patients with sporadic amyotrophic lateral sclerosis. Amyotrophic  Lateral  Sclerosis. doi 10.3109/17482968.2011.585163 Abstract Full Text (Subscription Required)

Further Reading

Bosco, D.A. et al. (2010) Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS. Nature Neuroscience, 13, 1396-1403. Abstract Full Text (Subscription Required)

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Categories: Watchlist

TAF15, Going On More Than 16?

clock November 8, 2011

FUS homolog TAF15 may be the fifteenth gene associated with ALS according to a new study published this week.  The international team, led by University of Pennsylvania's Aaron Gitler, PhD, found mutations in the gene in 5 out of 1,262 patients tested.  Recently implicated in ALS, TAF15 helps to produce proteins appropriately in many cell types including motor neurons.  Studies are still needed in larger groups of people with ALS to determine whether mutations in TAF15 are linked to the disease.

Keeping score. Researchers looked for RNA processing proteins that when produced in baker’s yeast, clumped up and turned lethal.  The team identified 13 proteins (green) that shared similiarities to ALS-linked FUS and TDP-43.  Adapted from Couthouis et al. (2011).  Courtesy of the National Academy of Sciences Press. All rights reserved.

References

Couthouis, J., et al. (2011) A yeast screen predicts new candidate genes for amyotrophic lateral sclerosis.  Proceedings of the National Academy of Sciences. doi 10.1073/pnas.1109434108  Abstract Full Text

Ticozzi, N., et al. (2011) Mutational analysis reveals the FUS homolog TAF15 as a candidate gene for familial amyotrophic lateral sclerosis.  American Journal of Medical Genetics Part B:  Neuropsychiatric Genetics, 156(3): 285-290. Abstract Full Text (Subscription Required)

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Categories: Watchlist

C9ORF72, Silence Is Not Golden

clock September 23, 2011

Repeat expansions in the gene C9ORF72 may be the most common cause of familial ALS (fALS) according to two studies published this week. Researchers identified these so-called expanded repeat sequences in the gene in nearly 25% of 229 familial cases. And in Finland, researchers identified these sequences in upwards of 50% of 402 cases. This is more than twice the number of people with ALS harboring mutations in the superoxide dismutase 1 (SOD1) gene. The C9ORF72 gene is the fourteenth to be linked to the disease. Repeat expansion underlies a growing number of neurological disorders including Huntington’s disease and Fragile X syndrome.

Don't repeat that. Researchers discovered expansions of GGGGCC repeat sequences in between two sections (blue) of the C9ORF72 gene in people with ALS. These expanded repeats, upwards of 1600 by one team’s rough estimates, may block the expression of the C9ORF72 gene resulting in the disease. 

 

References

DeJesus-Hernandez, M. et al. (2011) Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS.  Neuron 72(2), 245-256.  Abstract | Full Text (Subscription Required)

Renton, A.E. et al. (2011) A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD. Neuron 72(2), 257-268.  Abstract | Full Text (Subscription Required)

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Categories: Watchlist

Ubqln2, a new gene in the ALS fold

clock August 22, 2011



 

Reduce, reuse and recycle.  Ubqln2 may help reduce misfolded proteins in the CNS by delivering them to protein degrading machines called proteasomes.  The resulting amino acids are subsequently reused to make new proteins.  Image: Emw, Wikimedia Commons.

Alterations in the ubiquilin 2 (Ubqln2) gene may trigger a rare form of ALS and ALS-dementia according to a study published this week.  Ubiquilin 2 may help reduce misfolded proteins which typically buildup in the central nervous system in people with ALS.  Researchers estimate that mutations in the gene, the thirteenth ALS gene identified to date, explain less than 1% of inherited cases of the disease.  The discovery adds to growing evidence that accumulation of misfolded proteins contributes to ALS.

References

Deng, H.X et al. (2011) Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature, 477(7363), 211-215.  Abstract  |  Full Text (Subscription Required)

Further Reading

Daoud, H. and Rouleau, G.A. (2011) A role for ubiquilin 2 mutations in neurodegeneration. Nature Reviews Neurology 7, 599-600.  Full Text

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Categories: Watchlist

TDP-43 Targets Emerge

clock March 1, 2011



The splice of life. Researchers discovered that the protein TDP-43 (above) regulated the assembly or stability of more than 1000 RNAs in the center of the mouse brain. Image: Emw, Wikimedia Commons.

TDP-43 helps ensure proteins are produced appropriately by regulating the processing and translation of RNAs.  But in over 90% of people with ALS, TDP-43 builds up in the cytoplasm of cells of the brain and spinal cord.  The role of TDP-43 in ALS however remains controversial.

To try and figure out what role if any TDP-43 could play in the disease, researchers at the University of California at San Diego (UCSD) turned to crosslinking, immunoprecipitation and high-throughput sequencing (CLIP-seq) to obtain a comprehensive list of genes that may be regulated by TDP-43 in the brain. 

The team found that nearly one third of all genes in the mouse brain may be regulated at least in part by TDP-43.  And, within the center of the brain, more than 1000 RNAs required TDP-43 for appropriate assembly or stability.

The study is published this week in Nature Neuroscience.

In future, the UCSD scientists hope to identify a subset of these genes that may contribute to the onset or progression of ALS due to mislocalized TDP-43.  These discoveries could inspire new therapeutic strategies for the disease.

Reference

Polymenidou M et al. (2006) Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43 . Nature Neuroscience, 14(4), 459-468.  Abstract | Full Text

Further Reading

Tollervey, J.R. et al. (2011) Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nature Neuroscience, 14(4), 452-458. Abstract | Full Text

 

 

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Categories: Watchlist

ALS, a prion disease?

clock February 15, 2011



Soak up the SOD. Researchers discovered that cultured neurons build up SOD1 (red) upon taking up misfolded forms of the enzyme. Adapted from Münch et al. (2011).

The buildup of proteins in the brain and spinal cord is a hallmark of ALS.  But how these proteins accumulate within the cells of the central nervous system in people with ALS remains a mystery.

Now, researchers from the University of Cambridge in England report that familial ALS type 1-associated superoxide dismutase 1 (SOD1) can spread from neuron to neuron.  And once inside these neurons, these misfolded proteins can trigger the aggregation of the cells’ own copies of the enzyme.

These results suggest that ALS may be similar to prion diseases such as the brain disorder Creutzfeldt-Jakob disease.  And at the same time, these findings suggest new therapeutic strategies to reduce the buildup of proteins in people with the disease.

Reference

Münch, C., O'Brien, J. and Bertolotti, A. (2011) Prion-like propagation of mutant superoxide dismutase-1 misfolding in neuronal cells. Proceedings of the National Academy of Sciences 108(9), 3548-3553. Abstract | Full Text


 

 

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