Epigenetic Changes Associated with the Expression of Amyotrophic Lateral Sclerosis (ALS) Causing Genes

Masala, Alessandra; Sanna, Simona; Esposito, Salvatore; Rassu, Mariella; Galioto, Manuela; Zinellu, Angelo; Carru, Ciriaco; Carrı̀, Maria Teresa; Iaccarino, Ciro; Crosio, Claudia

doi:10.1016/j.neuroscience.2018.08.009

Cited by 25 publications

(23 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, the analysis and the interpretation of the data obtained by IFA and FCAs led us to hypothesize that VAPB aggregates may be a direct consequence of epigenetic modifications that result in an incorrect/different protein spatial conformation in sALS from those in HCs and PD patients. These results reinforce the idea that epigenetic studies can represent an attractive approach to giving a correct meaning to VAPB aggregates in pathogenic mechanisms of ALS [54].…”

Section: Discussionsupporting

confidence: 83%

VAPB ER-Aggregates, A Possible New Biomarker in ALS Pathology

Cadoni

Biggio

Arru

et al. 2020

Cells

View full text Add to dashboard Cite

A point mutation (P56S) in the gene-encoding vesicle-associated membrane-protein-associated protein B (VAPB) leads to an autosomal-dominant form of amyotrophic lateral sclerosis (ALS), classified as ALS-8. The mutant VAPB is characterized by ER-associated aggregates that lead to a complete reorganization of ER structures. Growing evidences suggest VAPB involvement in ALS pathomechanisms. In fact, numerous studies demonstrated VAPB alteration also in sporadic ALS (sALS) and showed the presence of its aggregates when others ALS-related gene are mutant. Recently, the identification of new biomarkers in peripheral blood mononuclear cells (PBMCs) has been proposed as a good noninvasive option for studying ALS. Here, we evaluated VAPB as a possible ALS pathologic marker analyzing PBMCs of sALS patients. Immunofluorescence analysis (IFA) showed a peculiar pattern of VAPB aggregates in sALS, not evident in healthy control (HC) subjects and in Parkinson’s disease (PD) PBMCs. This specific pattern led us to suppose that VAPB could be misfolded in sALS. The data indirectly confirmed by flow cytometry assay (FCA) showed a reduction of VAPB fluorescent signals in sALS. However, our observations were not associated with the presence of a genetic mutation or altered gene expression of VAPB. Our study brings further evidences of the VAPB role in ALS as a diagnostic biomarker.

show abstract

Section: Discussionsupporting

confidence: 83%

VAPB ER-Aggregates, A Possible New Biomarker in ALS Pathology

Cadoni

Biggio

Arru

et al. 2020

Cells

View full text Add to dashboard Cite

show abstract

“…Interestingly, immunostaining analysis in poly-PR mice showed that GFP-conjugated PR protein (a 50 repeat PR protein) localized to the H3K9me3, H3K27me3, and H3K4me3 marks; the latter two marks were also increased in GFP-PR-positive cells [15]. Recent investigations using cell lines suggest that the expression of SOD1 and TDP43 could also contribute to global epigenome alterations [52]. These findings point to a need for further in-depth analysis of H3K9me3 alterations in brain cells expressing mutant C9orf72, SOD1, and TDP43.…”

Section: Discussionmentioning

confidence: 99%

Widespread loss of the silencing epigenetic mark H3K9me3 in astrocytes and neurons along with hippocampal-dependent cognitive impairment in C9orf72 BAC transgenic mice

et al. 2020

View full text Add to dashboard Cite

Background: Hexanucleotide repeat expansions of the G 4 C 2 motif in a non-coding region of the C9ORF72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Tissues from C9ALS/FTD patients and from mouse models of ALS show RNA foci, dipeptide-repeat proteins, and notably, widespread alterations in the transcriptome. Epigenetic processes regulate gene expression without changing DNA sequences and therefore could account for the altered transcriptome profiles in C9ALS/FTD; here, we explore whether the critical repressive marks H3K9me2 and H3K9me3 are altered in a recently developed C9ALS/FTD BAC mouse model (C9BAC). Results: Chromocenters that constitute pericentric constitutive heterochromatin were visualized as DAPI-or Nucblue-dense foci in nuclei. Cultured C9BAC astrocytes exhibited a reduced staining signal for H3K9me3 (but not for H3K9me2) at chromocenters that was accompanied by a marked decline in the global nuclear level of this mark. Similar depletion of H3K9me3 at chromocenters was detected in astrocytes and neurons of the spinal cord, motor cortex, and hippocampus of C9BAC mice. The alterations of H3K9me3 in the hippocampus of C9BAC mice led us to identify previously undetected neuronal loss in CA1, CA3, and dentate gyrus, as well as hippocampal-dependent cognitive deficits. Conclusions: Our data indicate that a loss of the repressive mark H3K9me3 in astrocytes and neurons in the central nervous system of C9BAC mice represents a signature during neurodegeneration and memory deficit of C9ALS/FTD.

show abstract

“…Even though epigenetic modifications are not genetically transmitted, they can be pharmacologically manipulated, making them potential marks for medical intervention (Hwang et al, 2017). In reality, several lines of evidence suggest that epigenetics might not only facilitate the identification of effective therapeutic targets, but also assist with ALS diagnosis and follow-up, since the expression of numerous genes can be modulated by epigenetic mechanisms (Chestnut et al, 2011;Jimenez-Pacheco et al, 2017;Young et al, 2017;Coppedè et al, 2018;Masala et al, 2018).…”

Section: Regulation Of Neurogenic Function In Als Through Epigenetic mentioning

confidence: 99%

Mitochondrial Dysfunction, Neurogenesis, and Epigenetics: Putative Implications for Amyotrophic Lateral Sclerosis Neurodegeneration and Treatment

et al. 2020

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a progressive and devastating multifactorial neurodegenerative disorder. Although the pathogenesis of ALS is still not completely understood, numerous studies suggest that mitochondrial deregulation may be implicated in its onset and progression. Interestingly, mitochondrial deregulation has also been associated with changes in neural stem cells (NSC) proliferation, differentiation, and migration. In this review, we highlight the importance of mitochondrial function for neurogenesis, and how both processes are correlated and may contribute to the pathogenesis of ALS; we have focused primarily on preclinical data from animal models of ALS, since to date no studies have evaluated this link using human samples. As there is currently no cure and no effective therapy to counteract ALS, we have also discussed how improving neurogenic function by epigenetic modulation could benefit ALS. In support of this hypothesis, changes in histone deacetylation can alter mitochondrial function, which in turn might ameliorate cellular proliferation as well as neuronal differentiation and migration. We propose that modulation of epigenetics, mitochondrial function, and neurogenesis might provide new hope for ALS patients, and studies exploring these new territories are warranted in the near future.

show abstract

Epigenetic Changes Associated with the Expression of Amyotrophic Lateral Sclerosis (ALS) Causing Genes

Cited by 25 publications

References 52 publications

VAPB ER-Aggregates, A Possible New Biomarker in ALS Pathology

VAPB ER-Aggregates, A Possible New Biomarker in ALS Pathology

Widespread loss of the silencing epigenetic mark H3K9me3 in astrocytes and neurons along with hippocampal-dependent cognitive impairment in C9orf72 BAC transgenic mice

Mitochondrial Dysfunction, Neurogenesis, and Epigenetics: Putative Implications for Amyotrophic Lateral Sclerosis Neurodegeneration and Treatment

Contact Info

Product

Resources

About