Background:Acute-onset neurodegenerative diseases in older patients are rare clinical cases,especially when the degeneration only affects specific regions of the nervous system.Several neurological disorders have been...Background:Acute-onset neurodegenerative diseases in older patients are rare clinical cases,especially when the degeneration only affects specific regions of the nervous system.Several neurological disorders have been described in which the degeneration of brain parenchyma originates from and/or primarily affects the brain stem.Clinical diagnosis in these patients,however,is often complicated due to a poor understanding of these diseases and their underlying mechanisms.Case presentation:In this manuscript we report on a 73-year-old female who had experienced a sudden onset of complex neurological symptoms that progressively worsened over a period of 2 years.Original evaluation had suggested a MRI-negative stroke as underlying pathogenesis.The combination of patient’s medical history,clinical examination and exceptional pattern of brain stem degeneration presenting as“kissing swan sign”in MR imaging was strongly suggestive of acute onset of Alexander’s disease.This leukoencephalopathy is caused by GFAP(glial fibrilary acidic protein)gene mutations and may present with brain stem atrophy and stroke-like onset of symptoms in elderly individuals.However,a pathognomonic GFAP gene mutation could not be identified by Sanger sequencing.Conclusions:After an extended differential diagnosis and exclusion of other diseases,a definite diagnosis of the patient’s condition presently remains elusive.However,whole-exome sequencing performed from patient’s blood revealed 12 potentially disease-causative heterozygous variants,amongst which several have been associated with neurological disorders in vitro and in vivo–in particular the axon degeneration-related NMNAT2 gene.展开更多
Pathological cardiac hypertrophy is a maladaptive response in a variety of organic heart disease(OHD),which is characterized by mitochondrial dysfunction that results from disturbed energy metabolism.SIRT3,a mitochond...Pathological cardiac hypertrophy is a maladaptive response in a variety of organic heart disease(OHD),which is characterized by mitochondrial dysfunction that results from disturbed energy metabolism.SIRT3,a mitochondria-localized sirtuin,regulates global mitochondrial lysine acetylation and preserves mitochondrial function.However,the mechanisms by which SIRT3 regulates cardiac hypertrophy remains to be further elucidated.In this study,we firstly demonstrated that expression of SIRT3 was decreased in AngiotensionⅡ(AngⅡ)-treated cardiomyocytes and in hearts of AngⅡ-induced cardiac hypertrophic mice.In addition,SIRT3 overexpression protected myocytes from hypertrophy,whereas SIRT3 silencing exacerbated AngⅡ-induced cardiomyocyte hypertrophy.In particular,SIRT3-KO mice exhibited significant cardiac hypertrophy.Mechanistically,we identified NMNAT3(nicotinamide mononucleotide adenylyltransferase 3),the rate-limiting enzyme for mitochondrial NAD biosynthesis,as a new target and binding partner of SIRT3.Specifically,SIRT3 physically interacts with and deacetylates NMNAT3,thereby enhancing the enzyme activity of NMNAT3 and contributing to SIRT3-mediated anti-hypertrophic effects.Moreover,NMNAT3 regulates the activity of SIRT3 via synthesis of mitochondria NAD.Taken together,these findings provide mechanistic insights into the negative regulatory role of SIRT3 in cardiac hypertrophy.Sirtuin 3(SIRT3),a mitochondrial deacetylase that may play an important role in regulating cardiac function and a potential target for CHF.展开更多
Although the nicotinamide nucleotides NAD（H） and NADP（H） are essential for various metabolic reactions that play major roles in maintenance of cellular homeostasis, the significance of NAD biosynthesis is not well...Although the nicotinamide nucleotides NAD（H） and NADP（H） are essential for various metabolic reactions that play major roles in maintenance of cellular homeostasis, the significance of NAD biosynthesis is not well under- stood. Here, we investigated the dynamics of pollen nicotinamide nucleotides in response to imbibition, a representative germination cue. Metabolic analysis with capillary electrophoresis electrospray ionization mass spectrometry revealed that excess amount of NAD＊ is accumulated in freshly harvested dry pollen, whereas it dramatically decreased immedi- ately after contact with water, importantly, excess of NAD~ impaired pollen tube growth. Moreover, NAD~ accumulation was retained after pollen was imbibed in the presence of NAD^-consuming reaction inhibitors and pollen germination was greatly retarded. Pollen deficient in the nicotinate/nicotinamide mononucleotide adenyltransferase （NMNAT） gene, encoding a key enzyme in NAD biosynthesis, and a lack of NAD＊ accumulation in the gametophyte, showed precocious pollen tube germination inside the anther Iocule and vigorous tube growth under high-humidity conditions. Hence, the accumulation of excess NAD＊ is not essential for pollen germination, but instead participates in regulating the timing of germination onset. These results indicate that NAD＋ accumulation acts to negatively regulate germination and a decrease in NAD＋ plays an important role in metabolic state transition.展开更多
文摘Background:Acute-onset neurodegenerative diseases in older patients are rare clinical cases,especially when the degeneration only affects specific regions of the nervous system.Several neurological disorders have been described in which the degeneration of brain parenchyma originates from and/or primarily affects the brain stem.Clinical diagnosis in these patients,however,is often complicated due to a poor understanding of these diseases and their underlying mechanisms.Case presentation:In this manuscript we report on a 73-year-old female who had experienced a sudden onset of complex neurological symptoms that progressively worsened over a period of 2 years.Original evaluation had suggested a MRI-negative stroke as underlying pathogenesis.The combination of patient’s medical history,clinical examination and exceptional pattern of brain stem degeneration presenting as“kissing swan sign”in MR imaging was strongly suggestive of acute onset of Alexander’s disease.This leukoencephalopathy is caused by GFAP(glial fibrilary acidic protein)gene mutations and may present with brain stem atrophy and stroke-like onset of symptoms in elderly individuals.However,a pathognomonic GFAP gene mutation could not be identified by Sanger sequencing.Conclusions:After an extended differential diagnosis and exclusion of other diseases,a definite diagnosis of the patient’s condition presently remains elusive.However,whole-exome sequencing performed from patient’s blood revealed 12 potentially disease-causative heterozygous variants,amongst which several have been associated with neurological disorders in vitro and in vivo–in particular the axon degeneration-related NMNAT2 gene.
基金This work was supported by grants from the National Natural Science Foundation of China(No.81673433,No.81026548 and No.81273499),Team item of the Natural Science Foundation of Guangdong Province(No.S2011030003190).
文摘Pathological cardiac hypertrophy is a maladaptive response in a variety of organic heart disease(OHD),which is characterized by mitochondrial dysfunction that results from disturbed energy metabolism.SIRT3,a mitochondria-localized sirtuin,regulates global mitochondrial lysine acetylation and preserves mitochondrial function.However,the mechanisms by which SIRT3 regulates cardiac hypertrophy remains to be further elucidated.In this study,we firstly demonstrated that expression of SIRT3 was decreased in AngiotensionⅡ(AngⅡ)-treated cardiomyocytes and in hearts of AngⅡ-induced cardiac hypertrophic mice.In addition,SIRT3 overexpression protected myocytes from hypertrophy,whereas SIRT3 silencing exacerbated AngⅡ-induced cardiomyocyte hypertrophy.In particular,SIRT3-KO mice exhibited significant cardiac hypertrophy.Mechanistically,we identified NMNAT3(nicotinamide mononucleotide adenylyltransferase 3),the rate-limiting enzyme for mitochondrial NAD biosynthesis,as a new target and binding partner of SIRT3.Specifically,SIRT3 physically interacts with and deacetylates NMNAT3,thereby enhancing the enzyme activity of NMNAT3 and contributing to SIRT3-mediated anti-hypertrophic effects.Moreover,NMNAT3 regulates the activity of SIRT3 via synthesis of mitochondria NAD.Taken together,these findings provide mechanistic insights into the negative regulatory role of SIRT3 in cardiac hypertrophy.Sirtuin 3(SIRT3),a mitochondrial deacetylase that may play an important role in regulating cardiac function and a potential target for CHF.
文摘Although the nicotinamide nucleotides NAD（H） and NADP（H） are essential for various metabolic reactions that play major roles in maintenance of cellular homeostasis, the significance of NAD biosynthesis is not well under- stood. Here, we investigated the dynamics of pollen nicotinamide nucleotides in response to imbibition, a representative germination cue. Metabolic analysis with capillary electrophoresis electrospray ionization mass spectrometry revealed that excess amount of NAD＊ is accumulated in freshly harvested dry pollen, whereas it dramatically decreased immedi- ately after contact with water, importantly, excess of NAD~ impaired pollen tube growth. Moreover, NAD~ accumulation was retained after pollen was imbibed in the presence of NAD^-consuming reaction inhibitors and pollen germination was greatly retarded. Pollen deficient in the nicotinate/nicotinamide mononucleotide adenyltransferase （NMNAT） gene, encoding a key enzyme in NAD biosynthesis, and a lack of NAD＊ accumulation in the gametophyte, showed precocious pollen tube germination inside the anther Iocule and vigorous tube growth under high-humidity conditions. Hence, the accumulation of excess NAD＊ is not essential for pollen germination, but instead participates in regulating the timing of germination onset. These results indicate that NAD＋ accumulation acts to negatively regulate germination and a decrease in NAD＋ plays an important role in metabolic state transition.
