ALS lymphoblastoid cell lines as a considerable model to understand disease mechanisms

Pansarasa, Orietta; Bordoni, Matteo; Drufuca, Lorenzo; Diamanti, Luca; Sproviero, Daisy; Trotti, R.; Bernuzzi, Stefano; Salvia, Sabrina La; Gagliardi, Stella; Ceroni, Mauro; Cereda, Cristina

doi:10.1242/dmm.031625

Cited by 38 publications

(38 citation statements)

References 49 publications

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“…On the other hand, ALS C9orf72-expansion carriers showed similar D-loop methylation levels to healthy controls and significantly higher than those observed in sporadic or SOD1-mutant ALS patients. Some investigations demonstrated that different ALS-linked genes have diverse effects on mitochondrial dynamics and function [24,25], and previous studies suggested that nuclear DNA methylation signatures too can differ among patients with a different ALS genetic etiology. Particularly, Ebbert and coworkers observed differential DNA methylation patterns in both the cerebellum and the frontal cortex of C9orf72-associated and sporadic ALS patients compared to those of control subjects [26].…”

Section: Discussionmentioning

confidence: 99%

Reduced mitochondrial D-loop methylation levels in sporadic amyotrophic lateral sclerosis

et al. 2020

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Background Mitochondrial dysregulation and aberrant epigenetic mechanisms have been frequently reported in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), and several researchers suggested that epigenetic dysregulation in mitochondrial DNA (mtDNA) could contribute to the neurodegenerative process. We recently screened families with mutations in the major ALS causative genes, namely C9orf72, SOD1, FUS, and TARDBP, observing reduced methylation levels of the mtDNA regulatory region (D-loop) only in peripheral lymphocytes of SOD1 carriers. However, until now no studies investigated the potential role of mtDNA methylation impairment in the sporadic form of ALS, which accounts for the majority of disease cases. The aim of the current study was to investigate the D-loop methylation levels and the mtDNA copy number in sporadic ALS patients and compare them to those observed in healthy controls and in familial ALS patients. Pyrosequencing analysis of D-loop methylation levels and quantitative analysis of mtDNA copy number were performed in peripheral white blood cells from 36 sporadic ALS patients, 51 age- and sex-matched controls, and 27 familial ALS patients with germinal mutations in SOD1 or C9orf72 that represent the major familial ALS forms. Results In the total sample, D-loop methylation levels were significantly lower in ALS patients compared to controls, and a significant inverse correlation between D-loop methylation levels and the mtDNA copy number was observed. Stratification of ALS patients into different subtypes revealed that both SOD1-mutant and sporadic ALS patients showed lower D-loop methylation levels compared to controls, while C9orf72-ALS patients showed similar D-loop methylation levels than controls. In healthy controls, but not in ALS patients, D-loop methylation levels decreased with increasing age at sampling and were higher in males compared to females. Conclusions Present data reveal altered D-loop methylation levels in sporadic ALS and confirm previous evidence of an inverse correlation between D-loop methylation levels and the mtDNA copy number, as well as differences among the major familial ALS subtypes. Overall, present results suggest that D-loop methylation and mitochondrial replication are strictly related to each other and could represent compensatory mechanisms to counteract mitochondrial impairment in sporadic and SOD1-related ALS forms.

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Section: Discussionmentioning

confidence: 99%

Reduced mitochondrial D-loop methylation levels in sporadic amyotrophic lateral sclerosis

et al. 2020

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“…Nevertheless, in addition to changes in cellular redox status, alterations in mitochondrial dynamics ( Magrane et al, 2012 ), size ( Liu et al, 2013 ; Wang et al, 2013 ; Deng et al, 2015 ; Pansarasa et al, 2018 ) and localization ( Williamson and Cleveland, 1999 ; Higgins et al, 2002 ; Magrane et al, 2009 , 2012 ; Zhou et al, 2010 ; Vande Velde et al, 2011 ) are also believed to contribute to the pathophysiology of ALS. Indeed, defects in mitochondrial dynamics and disruption of mitochondrial axonal transport have been described in ALS models ( De Vos et al, 2007 ; Shi et al, 2010 ; Gao et al, 2018 ).…”

Section: Mitochondrial Dysfunction In Alsmentioning

confidence: 99%

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

et al. 2020

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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.

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“…The disease is considered a proteinopathy, since spinal cord histology of ALS patients reveals abnormal accumulations of protein aggregates in motor neurons and neural accessory cells ( Polymenidou and Cleveland, 2011 ). These aggregates (especially SOD1, TDP-43, FUS) originate from the accumulation of non-natively folded proteins that can propagate in a way similar to prion proteins (self-seeding), although neuronal cells are not infected with prions ( Cereda et al, 2006 , 2013 ; Diaz-Espinoza and Soto, 2010 ; Polymenidou and Cleveland, 2011 ; Pansarasa et al, 2018 ). This process could be mediated through release and uptake of protein aggregates or via extracellular vesicles (EVs) ( Grad et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

Pathological Proteins Are Transported by Extracellular Vesicles of Sporadic Amyotrophic Lateral Sclerosis Patients

et al. 2018

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Amyotrophic lateral sclerosis (ALS) is a progressive adult-onset neurodegenerative disease, that affects cortical, bulbar and spinal motor neurons, and it is considered a proteinopathy, in which pathological proteins (SOD1, TDP-43, and FUS) may accumulate and interfere with neuronal functions eventually leading to cell death. These proteins can be released from cells and transported in the body fluids by extracellular vesicles (EVs). EVs are spherical vesicles, which are classified mainly in microvesicles (MVs) and exosomes (EXOs) based on their biogenesis, size and surface markers. In this study we characterized MVs and EXOs isolated from plasma of sporadic ALS patients and healthy controls and determined their number, size and SOD1, TDP-43, and FUS protein composition. No variation was found in the number of EVs between ALS patients and controls. However, the mean size both for MVs and for EXOs resulted increased in ALS patients compared to controls. MVs derived from ALS patients were enriched in SOD1, TDP-43, phospho-TDP-43, and FUS proteins compared to CTRLs. SOD1 was generally more concentrated in EXOs than in MVs, while TDP-43 and FUS protein levels were slightly higher in MVs than in EXOs. We demonstrated that MVs and EXOs size were increased in ALS patients compared to controls and that MVs of ALS patients were enriched with toxic proteins compared to CTRLs. EXOs did not show any protein changes. These data may suggest that MVs can transport toxic proteins and might play a role in prion-like propagation of ALS disease.

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ALS lymphoblastoid cell lines as a considerable model to understand disease mechanisms

Cited by 38 publications

References 49 publications

Reduced mitochondrial D-loop methylation levels in sporadic amyotrophic lateral sclerosis

Reduced mitochondrial D-loop methylation levels in sporadic amyotrophic lateral sclerosis

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

Pathological Proteins Are Transported by Extracellular Vesicles of Sporadic Amyotrophic Lateral Sclerosis Patients

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