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International Journal of Molecular... May 2024Movement disorders such as bradykinesia, tremor, dystonia, chorea, and myoclonus most often arise in several neurodegenerative diseases with basal ganglia and white...
Movement disorders such as bradykinesia, tremor, dystonia, chorea, and myoclonus most often arise in several neurodegenerative diseases with basal ganglia and white matter involvement. While the pathophysiology of these disorders remains incompletely understood, dysfunction of the basal ganglia and related brain regions is often implicated. The gene, part of the family, has emerged as a crucial player in neurological pathology, implicated in diverse phenotypes ranging from movement disorders to Leigh syndrome. We present a clinical case of -associated disease with two variants in the gene in an adult female. This case contributes to our evolving understanding of -related diseases and underscores the importance of genetic screening in diagnosing and managing such conditions.
Topics: Humans; Female; Spinocerebellar Ataxias; Vesicular Transport Proteins; Adult; Phenotype; Mutation; Genes, Recessive; Pedigree; Proteins
PubMed: 38791166
DOI: 10.3390/ijms25105127 -
PLoS Genetics May 2024Ataxin-2 (ATXN2) is a gene implicated in spinocerebellar ataxia type II (SCA2), amyotrophic lateral sclerosis (ALS) and Parkinsonism. The encoded protein is a...
Ataxin-2 (ATXN2) is a gene implicated in spinocerebellar ataxia type II (SCA2), amyotrophic lateral sclerosis (ALS) and Parkinsonism. The encoded protein is a therapeutic target for ALS and related conditions. ATXN2 (or Atx2 in insects) can function in translational activation, translational repression, mRNA stability and in the assembly of mRNP-granules, a process mediated by intrinsically disordered regions (IDRs). Previous work has shown that the LSm (Like-Sm) domain of Atx2, which can help stimulate mRNA translation, antagonizes mRNP-granule assembly. Here we advance these findings through a series of experiments on Drosophila and human Ataxin-2 proteins. Results of Targets of RNA Binding Proteins Identified by Editing (TRIBE), co-localization and immunoprecipitation experiments indicate that a polyA-binding protein (PABP) interacting, PAM2 motif of Ataxin-2 may be a major determinant of the mRNA and protein content of Ataxin-2 mRNP granules. Experiments with transgenic Drosophila indicate that while the Atx2-LSm domain may protect against neurodegeneration, structured PAM2- and unstructured IDR- interactions both support Atx2-induced cytotoxicity. Taken together, the data lead to a proposal for how Ataxin-2 interactions are remodelled during translational control and how structured and non-structured interactions contribute differently to the specificity and efficiency of RNP granule condensation as well as to neurodegeneration.
Topics: Ataxin-2; Animals; Humans; Ribonucleoproteins; Drosophila Proteins; Drosophila melanogaster; RNA, Messenger; Poly(A)-Binding Proteins; Animals, Genetically Modified; Cytoplasmic Granules; Amyotrophic Lateral Sclerosis; Protein Biosynthesis; RNA-Binding Proteins; Intrinsically Disordered Proteins; Nerve Tissue Proteins; DNA-Binding Proteins
PubMed: 38768217
DOI: 10.1371/journal.pgen.1011251 -
Stem Cell Research Jun 2024Spinocerebellar ataxia type 12 (SCA12) is caused by a CAG expansion mutation in PPP2R2B, a gene encoding brain-specific regulatory units of protein phosphatase 2A...
Spinocerebellar ataxia type 12 (SCA12) is caused by a CAG expansion mutation in PPP2R2B, a gene encoding brain-specific regulatory units of protein phosphatase 2A (PP2A); while normal alleles carry 4 to 31 triplets, the disease alleles carry 43 to 78 triplets. Here, by CRISPR/Cas9n genome editing, we have generated a human heterozygous SCA12 iPSC line with 73 triplets for the mutant allele. The heterozygous SCA12 iPSCs have normal karyotype, express pluripotency markers and are able to differentiate into the three germ layers.
Topics: Humans; Induced Pluripotent Stem Cells; Gene Editing; Spinocerebellar Ataxias; Heterozygote; Mutation; Cell Line; CRISPR-Cas Systems; Protein Phosphatase 2; Nerve Tissue Proteins
PubMed: 38759410
DOI: 10.1016/j.scr.2024.103441 -
Gaceta Medica de Mexico 2024Protein interactions participate in many molecular mechanisms involved in cellular processes. The human TATA box binding protein (hTBP) interacts with Antennapedia...
BACKGROUND
Protein interactions participate in many molecular mechanisms involved in cellular processes. The human TATA box binding protein (hTBP) interacts with Antennapedia (Antp) through its N-terminal region, specifically via its glutamine homopeptides. This PolyQ region acts as a binding site for other transcription factors under normal conditions, but when it expands, it generates spinocerebellar ataxia 17 (SCA17), whose protein aggregates in the brain prevent its correct functioning.
OBJECTIVE
To determine whether the hTBP glutamine-rich region is involved in its interaction with homeoproteins and the role it plays in the formation of protein aggregates in SCA17.
MATERIAL AND METHODS
We characterized hTBP interaction with other homeoproteins using BiFC, and modeled SCA17 in Drosophila melanogaster by targeting hTBPQ80 to the fly brain using UAS/GAL4.
RESULTS
There was hTBP interaction with homeoproteins through its glutamine-rich region, and hTBP protein aggregates with expanded glutamines were found to affect the locomotor capacity of flies.
CONCLUSIONS
The study of hTBP interactions opens the possibility for the search for new therapeutic strategies in neurodegenerative pathologies such as SCA17.
Topics: Animals; Drosophila melanogaster; Disease Models, Animal; Spinocerebellar Ataxias; TATA-Box Binding Protein; Humans; Drosophila Proteins; Glutamine; Protein Aggregates; Peptides; Brain
PubMed: 38753562
DOI: 10.24875/GMM.M24000845 -
Neurobiology of Disease Jul 2024Heterogeneity is one of the key features of the healthy brain and selective vulnerability characterizes many, if not all, neurodegenerative diseases. While cerebellum...
Heterogeneity is one of the key features of the healthy brain and selective vulnerability characterizes many, if not all, neurodegenerative diseases. While cerebellum contains majority of brain cells, neither its heterogeneity nor selective vulnerability in disease are well understood. Here we describe molecular, cellular and functional heterogeneity in the context of healthy cerebellum as well as in cerebellar disease Spinocerebellar Ataxia Type 1 (SCA1). We first compared disease pathology in cerebellar vermis and hemispheres across anterior to posterior axis in a knock-in SCA1 mouse model. Using immunohistochemistry, we demonstrated earlier and more severe pathology of PCs and glia in the posterior cerebellar vermis of SCA1 mice. We also demonstrate heterogeneity of Bergmann glia in the unaffected, wild-type mice. Then, using RNA sequencing, we found both shared, as well as, posterior cerebellum-specific molecular mechanisms of pathogenesis that include exacerbated gene dysregulation, increased number of altered signaling pathways, and decreased pathway activity scores in the posterior cerebellum of SCA1 mice. We demonstrated unexpectedly large differences in the gene expression between posterior and anterior cerebellar vermis of wild-type mice, indicative of robust intraregional heterogeneity of gene expression in the healthy cerebellum. Additionally, we found that SCA1 disease profoundly reduces intracerebellar heterogeneity of gene expression. Further, using fiber photometry, we found that population level PC calcium activity was altered in the posterior lobules in SCA1 mice during walking. We also identified regional differences in the population level activity of Purkinje cells (PCs) in unrestrained wild-type mice that were diminished in SCA1 mice.
Topics: Animals; Cerebellum; Spinocerebellar Ataxias; Mice; Ataxin-1; Purkinje Cells; Neuroglia; Disease Models, Animal; Mice, Transgenic; Mice, Inbred C57BL; Male
PubMed: 38750673
DOI: 10.1016/j.nbd.2024.106530 -
BioRxiv : the Preprint Server For... May 2024Mutations in , which encodes intracellular fibroblast growth factor 14 (iFGF14), have been linked to spinocerebellar ataxia type 27 (SCA27), a multisystem disorder...
Mutations in , which encodes intracellular fibroblast growth factor 14 (iFGF14), have been linked to spinocerebellar ataxia type 27 (SCA27), a multisystem disorder associated with progressive deficits in motor coordination and cognitive function. Mice ( ) lacking iFGF14 display similar phenotypes, and we have previously shown that the deficits in motor coordination reflect excitability of cerebellar Purkinje neurons, owing to the loss of iFGF14-mediated regulation of the voltage-dependence of inactivation of the fast transient component of the voltage-gated Na (Nav) current, I . Here, we present the results of experiments designed to test the hypothesis that loss of iFGF14 also attenuates the intrinsic excitability of mature hippocampal and cortical pyramidal neurons. Current-clamp recordings from adult mouse hippocampal CA1 pyramidal neurons in acute slices, however, revealed that repetitive firing rates were in , than in wild type (WT), cells. In addition, the waveforms of individual action potentials were altered in hippocampal CA1 pyramidal neurons, and the loss of iFGF14 reduced the time delay between the initiation of axonal and somal action potentials. Voltage-clamp recordings revealed that the loss of iFGF14 altered the voltage-dependence of activation, but not inactivation, of I in CA1 pyramidal neurons. Similar effects of the loss of iFGF14 on firing properties were evident in current-clamp recordings from layer 5 visual cortical pyramidal neurons. Additional experiments demonstrated that the loss of iFGF14 alter the distribution of anti-Nav1.6 or anti-ankyrin G immunofluorescence labeling intensity along the axon initial segments (AIS) of mature hippocampal CA1 or layer 5 visual cortical pyramidal neurons . Taken together, the results demonstrate that, in contrast with results reported for neonatal (rat) hippocampal pyramidal neurons in dissociated cell culture, the loss of iFGF14 does disrupt AIS architecture or Nav1.6 localization/distribution along the AIS of mature hippocampal (or cortical) pyramidal neurons .
PubMed: 38746081
DOI: 10.1101/2024.05.04.592532 -
Osong Public Health and Research... Apr 2024Rare diseases are predominantly genetic or inherited, and patients with these conditions frequently exhibit neurological symptoms. Diagnosing and treating many rare...
Rare diseases are predominantly genetic or inherited, and patients with these conditions frequently exhibit neurological symptoms. Diagnosing and treating many rare diseases is a complex challenge, and their low prevalence complicates the performance of research, which in turn hinders the advancement of therapeutic options. One strategy to address this issue is the creation of national or international registries for rare diseases, which can help researchers monitor and investigate their natural progression. In the Republic of Korea, we established a registry across 5 centers that focuses on 3 rare diseases, all of which are characterized by gait disturbances resulting from motor system dysfunction. The registry will collect clinical information and human bioresources from patients with amyotrophic lateral sclerosis, spinocerebellar ataxia, and hereditary spastic paraplegia. These resources will be stored at ICreaT and the National Biobank of Korea. Once the registry is complete, the data will be made publicly available for further research. Through this registry, our research team is dedicated to identifying genetic variants that are specific to Korean patients, uncovering biomarkers that show a strong correlation with clinical symptoms, and leveraging this information for early diagnosis and the development of treatments.
PubMed: 38725125
DOI: 10.24171/j.phrp.2023.0353 -
Neurology. Genetics Apr 2024Micro-RNAs (miRNAs) are critical for regulating the expression of genes in multiple neurodegenerative diseases, but miRNAs have not been investigated in spinocerebellar...
BACKGROUND AND OBJECTIVES
Micro-RNAs (miRNAs) are critical for regulating the expression of genes in multiple neurodegenerative diseases, but miRNAs have not been investigated in spinocerebellar ataxia type 2 (SCA2). SCA2, a dominantly inherited progressive neurodegenerative polyglutamine (polyQ) disease, is caused by a CAG repeat expansion in the ataxin-2 () gene. In this study, we determined miRNA transcriptomes in SCA2-BAC- transgenic mice.
METHODS
We assessed the expression of miRNAs in SCA2 transgenic mouse cerebella using the HiSeq Illumina sequencer. We used the miRNA target filter tool in Qiagen Ingenuity Pathway Analysis (IPA) to identify target genes of differentially expressed miRNAs (DEmiRs) within in the SCA2 mouse transcriptomes and then performed pathway analyses.
RESULTS
Our analysis revealed significant changes in the expression levels of multiple miRNAs in mice with SCA2. We identified 81 DEmiRs in mice with SCA2, with 52 miRNAs upregulated and 29 miRNAs downregulated after onset of rotarod deficit. Subsequent IPA processing enabled us to establish connections between these DEmiRs and specific biological regulatory functions. Furthermore, by using the IPA miRNA target filter, we identified target genes of DEmiRs in the SCA2-BAC- transcriptome data set and demonstrated their significant impact on several biological functional and disease pathways.
DISCUSSION
Our study establishes the role of both DEmiRs and their targets in SCA2 pathogenesis. By expressing mutant ATXN2 under the control of its endogenous regulatory elements in the SCA2-BAC- mouse model we identified a set of DEmiRs that are shared across multiple neurodegenerative diseases including other SCAs, Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS). There was a significant overlap of both DEmiRs and their targets of BAC- transcriptomes in dysregulated pathways that characterize SCA2. This observation also extended to dysregulated pathways in ALS, AD, and PD. DEmiRs identified in this study may represent therapeutic targets for neurodegeneration or lead to biomarkers for characterizing various neurodegenerative diseases.
PubMed: 38715656
DOI: 10.1212/NXG.0000000000200144 -
Journal of Clinical Neurology (Seoul,... May 2024
PubMed: 38713080
DOI: 10.3988/jcn.2023.0397 -
IScience May 2024Spinocerebellar Ataxia type-12 (SCA12) is a neurodegenerative disease caused by tandem CAG repeat expansion in the 5'-UTR/non-coding region of . Molecular pathology of...
Spinocerebellar Ataxia type-12 (SCA12) is a neurodegenerative disease caused by tandem CAG repeat expansion in the 5'-UTR/non-coding region of . Molecular pathology of SCA12 has not been studied in the context of CAG repeats, and no appropriate models exist. We found in human SCA12-iPSC-derived neuronal lineage that expanded CAG in transcript forms nuclear RNA foci and were found to sequester variety of proteins. Further, the ectopic expression of transcript containing varying length of CAG repeats exhibits non-canonical repeat-associated non-AUG (RAN) translation in multiple frames in HEK293T cells, which was further validated in patient-derived neural stem cells using specific antibodies. mRNA sequencing of the SCA12 and control neurons have shown a network of crucial transcription factors affecting neural fate, in addition to alteration of various signaling pathways involved in neurodevelopment. Altogether, this study identifies the molecular signatures of SCA12 disorder using patient-derived neuronal cell lines.
PubMed: 38711441
DOI: 10.1016/j.isci.2024.109768