Spinal and bulbar muscular atrophy is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor gene,which encodes a ligand-dependent transcription facto r.The mutant androgen r...Spinal and bulbar muscular atrophy is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor gene,which encodes a ligand-dependent transcription facto r.The mutant androgen receptor protein,characterized by polyglutamine expansion,is prone to misfolding and forms aggregates in both the nucleus and cytoplasm in the brain in spinal and bulbar muscular atrophy patients.These aggregates alter protein-protein interactions and compromise transcriptional activity.In this study,we reported that in both cultured N2a cells and mouse brain,mutant androgen receptor with polyglutamine expansion causes reduced expression of mesencephalic astrocyte-de rived neurotrophic factor.Overexpressio n of mesencephalic astrocyte-derived neurotrophic factor amelio rated the neurotoxicity of mutant androgen receptor through the inhibition of mutant androgen receptor aggregation.Conversely.knocking down endogenous mesencephalic astrocyte-derived neurotrophic factor in the mouse brain exacerbated neuronal damage and mutant androgen receptor aggregation.Our findings suggest that inhibition of mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor is a potential mechanism underlying neurodegeneration in spinal and bulbar muscular atrophy.展开更多
<div style="text-align:justify;"> <span style="font-family:Verdana;">Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease (MJD), is an autosomal dominant neurodege...<div style="text-align:justify;"> <span style="font-family:Verdana;">Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease (MJD), is an autosomal dominant neurodegenerative disorder that predominantly involves the cerebellar, pyramidal, extrapyramidal, motor neuron and oculomotor systems. SCA3 presents strong phenotypic heterogeneity and its causative mutation of SCA3 consists of an expansion of a CAG tract in exon 10 of the <em>ATXN3</em> gene, situated at 14q32.1. The <em>ATXN3</em> gene is ubiquitously expressed in neuronal and non-neuronal tissues, and also participates in cellular protein quality control pathways. Mutated <em>ATXN3</em> alleles present about 45 to 87CAG repeats, which result in an expanded polyglutamine tract in ataxin-3. After mutation, the polyQ tract reaches the pathological threshold (about 50 glutamine residues);the protein is considered that it might gain a neurotoxic function through some unclear mechanisms. We reviewed the literature on the pathogenesis and therapeutic strategies of spinocerebellar ataxia type 3 patients. Conversion of the expanded protein is possible by enhancing protein refolding and degradation or preventing proteolytic cleavage and prevents the protein to reach the site of toxicity by altering its ability to translocate between the nucleus and cytoplasm. Proteasomal degradation and enhancing autophagic aggregate clearance are currently proposed remarkable therapy. In spite of extensive research, the molecular mechanisms of cellular toxicity resulting from mutant ataxin-3 remain no preventive treatment is currently available. These therapeutic strategies might be able to improve sign symptoms of SCA3 as well as slow the disease progression.</span> </div>展开更多
Transgenic animal models have revealed much about the pathogenesis of age-dependent neurodegenerative diseases and proved to be a useful tool for uncovering therapeutic targets. Huntington＇s disease is a well-charact...Transgenic animal models have revealed much about the pathogenesis of age-dependent neurodegenerative diseases and proved to be a useful tool for uncovering therapeutic targets. Huntington＇s disease is a well-characterized neurodegenerative disorder that is caused by expansion of a CAG repeat, which results in expansion of a polyglutamine tract in the N-terminal region of huntingtin （HTT）. Similar CAG/glutamine expansions are also found to cause eight other neurodegenerative diseases that affect distinct brain regions in an age- dependent manner. Identification of this CAG/glutamine expansion has led to the generation of a variety of transgenic animal models. Of these different animal models, transgenic mice have been investigated extensively, and they show similar neuropathology and phenotypes as seen in their respective diseases. The common pathological hallmark of age-dependent neurodegeneration is the formation of aggregates or inclusions consisting of misfolded proteins in the affected brain regions; however, overt or striking neurodegeneration and apoptosis have not been reported in most transgenic mouse models for age-dependent diseases, including HD. By comparing the neuropathology of transgenic HD mouse, pig, and monkey models, we found that mutant HTT is more toxic to larger animals than mice, and larger animals also show neuropathology that has not been uncovered by transgenic mouse models. This review will discuss the importance of transgenic large animal models for analyzing the treatments. pathogenesis of neurodegenerative diseases and developing effective展开更多
The neurodegenerative polyglutamine diseases are caused various disease proteins. Although these mutant proteins are by an expansion of unstable polyglutamine repeats in expressed ubiquitously in neuronal and non-neur...The neurodegenerative polyglutamine diseases are caused various disease proteins. Although these mutant proteins are by an expansion of unstable polyglutamine repeats in expressed ubiquitously in neuronal and non-neuronal cells, they cause selective degeneration of specific neuronal populations. Recently, increasing evidence shows that polyglutamine disease proteins also affect non-neuronal cells. However, it remains unclear how the expression of polyglutamine proteins in non-neuronal cells contributes to the course of the polyglutamine diseases. Here, we discuss recent findings about the expression of mutant polyglutamine proteins in non-neuronal cells and their influence on neurological symptoms. Understanding the contribution of non-neuronal polyglutamine proteins to disease progres- sion will help elucidate disease mechanisms and also help in the development of new treatment options.展开更多
基金supported by the National Key R&D Program of China,No.2021YFA0805200(to SY)the National Natural Science Foundation of China,No.31970954(to SY)two grants from the Department of Science and Technology of Guangdong Province,Nos.2021ZT09Y007,2020B121201006(both to XJL)。
文摘Spinal and bulbar muscular atrophy is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor gene,which encodes a ligand-dependent transcription facto r.The mutant androgen receptor protein,characterized by polyglutamine expansion,is prone to misfolding and forms aggregates in both the nucleus and cytoplasm in the brain in spinal and bulbar muscular atrophy patients.These aggregates alter protein-protein interactions and compromise transcriptional activity.In this study,we reported that in both cultured N2a cells and mouse brain,mutant androgen receptor with polyglutamine expansion causes reduced expression of mesencephalic astrocyte-de rived neurotrophic factor.Overexpressio n of mesencephalic astrocyte-derived neurotrophic factor amelio rated the neurotoxicity of mutant androgen receptor through the inhibition of mutant androgen receptor aggregation.Conversely.knocking down endogenous mesencephalic astrocyte-derived neurotrophic factor in the mouse brain exacerbated neuronal damage and mutant androgen receptor aggregation.Our findings suggest that inhibition of mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor is a potential mechanism underlying neurodegeneration in spinal and bulbar muscular atrophy.
文摘<div style="text-align:justify;"> <span style="font-family:Verdana;">Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease (MJD), is an autosomal dominant neurodegenerative disorder that predominantly involves the cerebellar, pyramidal, extrapyramidal, motor neuron and oculomotor systems. SCA3 presents strong phenotypic heterogeneity and its causative mutation of SCA3 consists of an expansion of a CAG tract in exon 10 of the <em>ATXN3</em> gene, situated at 14q32.1. The <em>ATXN3</em> gene is ubiquitously expressed in neuronal and non-neuronal tissues, and also participates in cellular protein quality control pathways. Mutated <em>ATXN3</em> alleles present about 45 to 87CAG repeats, which result in an expanded polyglutamine tract in ataxin-3. After mutation, the polyQ tract reaches the pathological threshold (about 50 glutamine residues);the protein is considered that it might gain a neurotoxic function through some unclear mechanisms. We reviewed the literature on the pathogenesis and therapeutic strategies of spinocerebellar ataxia type 3 patients. Conversion of the expanded protein is possible by enhancing protein refolding and degradation or preventing proteolytic cleavage and prevents the protein to reach the site of toxicity by altering its ability to translocate between the nucleus and cytoplasm. Proteasomal degradation and enhancing autophagic aggregate clearance are currently proposed remarkable therapy. In spite of extensive research, the molecular mechanisms of cellular toxicity resulting from mutant ataxin-3 remain no preventive treatment is currently available. These therapeutic strategies might be able to improve sign symptoms of SCA3 as well as slow the disease progression.</span> </div>
基金supported by NIH grants NS036232, AG019206,NS041669 for X.J.L. and AG031153 for S.H.L.
文摘Transgenic animal models have revealed much about the pathogenesis of age-dependent neurodegenerative diseases and proved to be a useful tool for uncovering therapeutic targets. Huntington＇s disease is a well-characterized neurodegenerative disorder that is caused by expansion of a CAG repeat, which results in expansion of a polyglutamine tract in the N-terminal region of huntingtin （HTT）. Similar CAG/glutamine expansions are also found to cause eight other neurodegenerative diseases that affect distinct brain regions in an age- dependent manner. Identification of this CAG/glutamine expansion has led to the generation of a variety of transgenic animal models. Of these different animal models, transgenic mice have been investigated extensively, and they show similar neuropathology and phenotypes as seen in their respective diseases. The common pathological hallmark of age-dependent neurodegeneration is the formation of aggregates or inclusions consisting of misfolded proteins in the affected brain regions; however, overt or striking neurodegeneration and apoptosis have not been reported in most transgenic mouse models for age-dependent diseases, including HD. By comparing the neuropathology of transgenic HD mouse, pig, and monkey models, we found that mutant HTT is more toxic to larger animals than mice, and larger animals also show neuropathology that has not been uncovered by transgenic mouse models. This review will discuss the importance of transgenic large animal models for analyzing the treatments. pathogenesis of neurodegenerative diseases and developing effective
文摘The neurodegenerative polyglutamine diseases are caused various disease proteins. Although these mutant proteins are by an expansion of unstable polyglutamine repeats in expressed ubiquitously in neuronal and non-neuronal cells, they cause selective degeneration of specific neuronal populations. Recently, increasing evidence shows that polyglutamine disease proteins also affect non-neuronal cells. However, it remains unclear how the expression of polyglutamine proteins in non-neuronal cells contributes to the course of the polyglutamine diseases. Here, we discuss recent findings about the expression of mutant polyglutamine proteins in non-neuronal cells and their influence on neurological symptoms. Understanding the contribution of non-neuronal polyglutamine proteins to disease progres- sion will help elucidate disease mechanisms and also help in the development of new treatment options.
