The PNAS paper from Clemens Scherzer et al. identifies GATA transcription factors that regulate genes that are important for an age-related disease—Parkinson's. Our Cell paper shows that GATA transcription factors change expression in old age. If GATA-1 were to increase expression with age in the brain, then SNCA expression may also increase, which could help explain Parkinson disease in the elderly. The key test would be to look at GATA-1 expression in young versus old brains.
This is an intriguing study which links regulation of expression of a gene causative for Parkinson disease (PD), α-synuclein, with several heme metabolism genes. Given that heme is the major iron-binding protein in the body and that brain iron deposition has been suggested to be involved in PD, this could provide a tantalizing novel mechanistic link between α-synuclein and iron homeostasis.
Controlled expression of α-synuclein is essential for neuronal health in the substantial nigra and other brain regions. Therefore, elucidating regulatory mechanisms for α-synuclein production is of great interest.
In an elegant series of experiments, Dr. Scherzer and colleagues now report that α-synuclein is regulated by GATA hematopoietic transcription factors.
They have given the field an important piece of the α-synuclein puzzle, and in the process, raised some exciting new questions.
An iron responsive element is found at the α-synuclein mRNA exon 1-2 splice junction. Its formation requires precise excision of intron-1 from the pre-mRNA. Thus, the findings of Dr. Scherzer and colleagues that GATA-1 and GATA-2 bind specifically to DNA at intron 1 is intriguing, and it will be of interest to know if these or related proteins also bind to intron 1 in the pre-mRNA, where they might modulate RNA splicing for production of the iron responsive element.
Given what we already know about Parkinson disease neuropathology and genetics, it should come as no surprise that iron and oxidative metabolism might coordinate α-synuclein expression through a multi-tiered network of transcriptional, post-transcriptional, and translational events.
References:
Friedlich AL, Tanzi RE, Rogers JT.
The 5'-untranslated region of Parkinson's disease alpha-synuclein messengerRNA contains a predicted iron responsive element.
Mol Psychiatry. 2007 Mar;12(3):222-3.
PubMed.
I do think this is an interesting study. The possibility that GATA-1 in peripheral tissues, and GATA-2 in the CNS, might regulate synuclein is intriguing and the data here look very convincing. One possibility is that one might be able to target GATA-2 in the CNS and limit expression of SNCA and, thus, the damaging effects of α-synuclein in the brain rather specifically. The proof of this would be to identify trans-acting factors in the brain—if the authors are right, then there ought to be a trans-acting association between GATA-2 and synuclein (as well as other heme metabolism genes) in the human brain. There are some large datasets available now (e.g., Myers et al., 2007) and some in development that might allow for this idea to be tested.
References:
Myers AJ, Gibbs JR, Webster JA, Rohrer K, Zhao A, Marlowe L, Kaleem M, Leung D, Bryden L, Nath P, Zismann VL, Joshipura K, Huentelman MJ, Hu-Lince D, Coon KD, Craig DW, Pearson JV, Holmans P, Heward CB, Reiman EM, Stephan D, Hardy J.
A survey of genetic human cortical gene expression.
Nat Genet. 2007 Dec;39(12):1494-9. Epub 2007 Nov 4
PubMed.
The above study opens up new research avenues in the area of Parkinson's disease. The need for a diagnostic tool and a biomarker in this area is appropriately approached in this paper. Though the mechanism still remains elusive for the threshold levels of alpha-synuclein expression in blood versus brain. Bresnick's work on chromatin immunoprecipitation assays, which revealed that GATA-1 protein possess a GATA recognition site in the first intron of the α-synuclein gene supports the above concept. The current paper gives impetus for understanding the targets of alpha-synuclein and for monitoring the neuropathology of PD.
The link between α-synuclein and inflammation may also be of relevance to the AD-related condition Lewy body dementia, which shows some correspondence of α-synuclein inclusions with neurofibrillary tangles. In this regard, readers might be interested in Griffin et al., 2006:
"IL-1β elevated the levels of α-synuclein.... Delivery of IL-1β by slow-release pellets [in vivo] elevated mRNAs encoding α-synuclein.... Finally, human cases of AD/LBD showed colocalization of IL-1-expressing microglia with neurons that...contained both Lewy bodies and neurofibrillary tangles."
References:
Griffin WS, Liu L, Li Y, Mrak RE, Barger SW.
Interleukin-1 mediates Alzheimer and Lewy body pathologies.
J Neuroinflammation. 2006;3:5.
PubMed.
Comments
The PNAS paper from Clemens Scherzer et al. identifies GATA transcription factors that regulate genes that are important for an age-related disease—Parkinson's. Our Cell paper shows that GATA transcription factors change expression in old age. If GATA-1 were to increase expression with age in the brain, then SNCA expression may also increase, which could help explain Parkinson disease in the elderly. The key test would be to look at GATA-1 expression in young versus old brains.
View all comments by Stuart KimBuck Institute for Age Res
This is an intriguing study which links regulation of expression of a gene causative for Parkinson disease (PD), α-synuclein, with several heme metabolism genes. Given that heme is the major iron-binding protein in the body and that brain iron deposition has been suggested to be involved in PD, this could provide a tantalizing novel mechanistic link between α-synuclein and iron homeostasis.
View all comments by Julie AndersenLos Alamos Therapeutics, Inc.
Controlled expression of α-synuclein is essential for neuronal health in the substantial nigra and other brain regions. Therefore, elucidating regulatory mechanisms for α-synuclein production is of great interest.
In an elegant series of experiments, Dr. Scherzer and colleagues now report that α-synuclein is regulated by GATA hematopoietic transcription factors.
They have given the field an important piece of the α-synuclein puzzle, and in the process, raised some exciting new questions.
An iron responsive element is found at the α-synuclein mRNA exon 1-2 splice junction. Its formation requires precise excision of intron-1 from the pre-mRNA. Thus, the findings of Dr. Scherzer and colleagues that GATA-1 and GATA-2 bind specifically to DNA at intron 1 is intriguing, and it will be of interest to know if these or related proteins also bind to intron 1 in the pre-mRNA, where they might modulate RNA splicing for production of the iron responsive element.
Given what we already know about Parkinson disease neuropathology and genetics, it should come as no surprise that iron and oxidative metabolism might coordinate α-synuclein expression through a multi-tiered network of transcriptional, post-transcriptional, and translational events.
References:
Friedlich AL, Tanzi RE, Rogers JT. The 5'-untranslated region of Parkinson's disease alpha-synuclein messengerRNA contains a predicted iron responsive element. Mol Psychiatry. 2007 Mar;12(3):222-3. PubMed.
View all comments by Avi FriedlichNational Institute on Aging
I do think this is an interesting study. The possibility that GATA-1 in peripheral tissues, and GATA-2 in the CNS, might regulate synuclein is intriguing and the data here look very convincing. One possibility is that one might be able to target GATA-2 in the CNS and limit expression of SNCA and, thus, the damaging effects of α-synuclein in the brain rather specifically. The proof of this would be to identify trans-acting factors in the brain—if the authors are right, then there ought to be a trans-acting association between GATA-2 and synuclein (as well as other heme metabolism genes) in the human brain. There are some large datasets available now (e.g., Myers et al., 2007) and some in development that might allow for this idea to be tested.
References:
Myers AJ, Gibbs JR, Webster JA, Rohrer K, Zhao A, Marlowe L, Kaleem M, Leung D, Bryden L, Nath P, Zismann VL, Joshipura K, Huentelman MJ, Hu-Lince D, Coon KD, Craig DW, Pearson JV, Holmans P, Heward CB, Reiman EM, Stephan D, Hardy J. A survey of genetic human cortical gene expression. Nat Genet. 2007 Dec;39(12):1494-9. Epub 2007 Nov 4 PubMed.
View all comments by Mark CooksonJohns Hopkins University School of Medicine
The above study opens up new research avenues in the area of Parkinson's disease. The need for a diagnostic tool and a biomarker in this area is appropriately approached in this paper. Though the mechanism still remains elusive for the threshold levels of alpha-synuclein expression in blood versus brain. Bresnick's work on chromatin immunoprecipitation assays, which revealed that GATA-1 protein possess a GATA recognition site in the first intron of the α-synuclein gene supports the above concept. The current paper gives impetus for understanding the targets of alpha-synuclein and for monitoring the neuropathology of PD.
View all comments by Bharathi GadadUniversity of Arkansas for Medical Sciences
The link between α-synuclein and inflammation may also be of relevance to the AD-related condition Lewy body dementia, which shows some correspondence of α-synuclein inclusions with neurofibrillary tangles. In this regard, readers might be interested in Griffin et al., 2006:
"IL-1β elevated the levels of α-synuclein.... Delivery of IL-1β by slow-release pellets [in vivo] elevated mRNAs encoding α-synuclein.... Finally, human cases of AD/LBD showed colocalization of IL-1-expressing microglia with neurons that...contained both Lewy bodies and neurofibrillary tangles."
References:
Griffin WS, Liu L, Li Y, Mrak RE, Barger SW. Interleukin-1 mediates Alzheimer and Lewy body pathologies. J Neuroinflammation. 2006;3:5. PubMed.
View all comments by Steve BargerMake a Comment
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