Metabolic alterations precede neurofilament changes in presymptomatic ALS gene carriers

Dorst, Johannes; Weydt, Patrick; Brenner, Dávid; Witzel, Simon; Kandler, Katharina; Huss, André; Herrmann, Christine; Wiesenfarth, Maximilian; Knehr, Antje; Günther, Klaus Peter; Müller, Kathrin; Weishaupt, Jochen H.; Prudlo, Johannes; Forsberg, Karin; Andersen, Peter M.; Rosenbohm, Angela; Schuster, Joachim; Roselli, Francesco; Dupuis, Luc; Mayer, Benjamin; Tumani, Hayrettin; Kassubek, Jan; Ludolph, Albert C.

doi:10.1016/j.ebiom.2023.104521

Cited by 19 publications

(8 citation statements)

References 30 publications

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“…Strikingly, the authors showed that presymptomatic ALS gene carriers display abnormal body composition, indicating elevated catabolism and loss of metabolically active cells compared to metabolically active tissue. Surprisingly, resting energy expenditure was reduced in ALS gene carriers but increased when approaching the expected age of onset [45 ▪▪ ]. According to the authors, these observations could reflect a presymptomatic reduction of physical activity, which was previously reported in ALS patients [48].…”

Section: Early Involvement Of Metabolic Abnormalities In Amyotrophic ...mentioning

confidence: 52%

“…Although some contradictory results emerged for mutant SOD1 -ALS patients, they could be explained by the differences in patient cohorts and, notably, the distribution of SOD1 variants. Furthermore, metabolic profiling of presymptomatic ALS gene carriers revealed prevalent alterations in all mutations, but SOD1 and C9ORF72 gene carriers have each distinct profile compared to other ALS gene carriers [45 ▪▪ ,56 ▪▪ ]. C9ORF72 -ALS patients have a lower cardiovascular risk profile, characterized by lower BMI, lower fasting serum glucose, and higher HDL, while SOD1 -ALS patients have an opposite profile [45 ▪▪ ,56 ▪▪ ].…”

Section: The Complex Link Between Amyotrophic Lateral Sclerosis Genet...mentioning

confidence: 99%

“…A long-lasting question is whether metabolic dysfunctions precede motor symptoms in ALS patients. Recently, Dorst and collaborators tackled this question with a cohort of 60 presymptomatic ALS gene mutation carriers [45 ▪▪ ]. These patients did not present any clinical signs or changes in neurofilament light chain (NfL) blood levels.…”

Section: Early Involvement Of Metabolic Abnormalities In Amyotrophic ...mentioning

confidence: 99%

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Abnormal energy metabolism in ALS: a key player?

Burg

Bosch

2023

Current Opinion in Neurology

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Purpose of the review Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease of the motor system due to the selective and progressive degeneration of both upper and lower motor neurons. Disturbances in energy homeostasis were repeatedly associated with the ALS pathogenesis and appear early during the disease process. In this review, we highlight recent work demonstrating the crucial role of energy metabolism in ALS and discuss its potential clinical relevance. Recent findings The alteration of various metabolic pathways contributes to the heterogeneity of the clinical phenotype of ALS. Recent work showed that different ALS mutations selectively impact these pathways and translate to the disease phenotypes in patients and disease models. Strikingly, a growing number of studies point towards an early, even presymptomatic, contribution of abnormal energy homeostasis to the ALS pathogenesis. Advances in metabolomics generated valuable tools to study altered metabolic pathways, to test their therapeutic potential, and to develop personalized medicine. Importantly, recent preclinical studies and clinical trials demonstrated that targeting energy metabolism is a promising therapeutic approach. Summary Abnormal energy metabolism is a key player in ALS pathogenesis, emerging as a source of potential disease biomarkers and therapeutic targets.

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Section: Early Involvement Of Metabolic Abnormalities In Amyotrophic ...mentioning

confidence: 52%

Section: The Complex Link Between Amyotrophic Lateral Sclerosis Genet...mentioning

confidence: 99%

Section: Early Involvement Of Metabolic Abnormalities In Amyotrophic ...mentioning

confidence: 99%

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Abnormal energy metabolism in ALS: a key player?

Burg

Bosch

2023

Current Opinion in Neurology

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“…One of the most consistent observations is the association between lower premorbid BMI and a higher risk of ALS, an effect particularly pronounced among C9ORF72 expansion carriers [21]. In another more nuanced view, lower lean body mass and a higher ratio of metabolically active/inactive cells was reported among presymptomatic carriers, with all tissue types affected among C9ORF72 expansion carriers, but only metabolically active tissue in the SOD1 population [22 ▪▪ ]. It has been suggested that these changes precede rises in NfL, but the data were cross-sectional; it is therefore impossible to disentangle what might represent an endophenotype from an early presymptomatic stage of disease.…”

Section: Biomarkersmentioning

confidence: 91%

Presymptomatic amyotrophic lateral sclerosis: from characterization to prevention

Benatar

Turner

Wuu

2023

Current Opinion in Neurology

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Purpose of review Significant progress in characterizing presymptomatic amyotrophic lateral sclerosis (ALS) is ushering in an era of potential disease prevention. Although these advances have largely been based on cohorts of deep-phenotyped mutation carriers at an elevated risk for ALS, there are increasing opportunities to apply principles and insights gleaned, to the broader population at risk for ALS [and frontotemporal dementia (FTD)]. Recent findings The discovery that blood neurofilament light chain (NfL) level increases presymptomatically and may serve as a susceptibility biomarker, predicting timing of phenoconversion in some mutation carriers, has empowered the first-ever prevention trial in SOD1-ALS. Moreover, there is emerging evidence that presymptomatic disease is not uniformly clinically silent, with mild motor impairment (MMI), mild cognitive impairment (MCI), and/or mild behavioral impairment (MBI) representing a prodromal stage of disease. Structural and functional brain abnormalities, as well as systemic markers of metabolic dysfunction, have emerged as potentially even earlier markers of presymptomatic disease. Ongoing longitudinal studies will determine the extent to which these reflect an endophenotype of genetic risk. Summary The discovery of presymptomatic biomarkers and the delineation of prodromal states is yielding unprecedented opportunities for earlier diagnosis, treatment, and perhaps even prevention of genetic and apparently sporadic forms of disease.

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“…Even though ALS is considered the prototype of motor neuron diseases, systemic metabolic dysregulation has also been described in ALS patients, as well as in animal models of the disease [ 6 , 7 ]. Hypermetabolism, leading to a rapid depletion of energy stores, is observed in about one third of patients, who show a decrease in body mass index, often during a premorbid state [ 8 , 9 , 10 , 11 ]. Moreover, metabolic dysfunction in ALS patients correlates with a poor prognosis and a faster decline in locomotor performances [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Trimetazidine Improves Mitochondrial Dysfunction in SOD1G93A Cellular Models of Amyotrophic Lateral Sclerosis through Autophagy Activation

Salvatori,

Nesci,

Spalloni

et al. 2024

IJMS

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Amyotrophic Lateral Sclerosis (ALS) is considered the prototype of motor neuron disease, characterized by motor neuron loss and muscle waste. A well-established pathogenic hallmark of ALS is mitochondrial failure, leading to bioenergetic deficits. So far, pharmacological interventions for the disease have proven ineffective. Trimetazidine (TMZ) is described as a metabolic modulator acting on different cellular pathways. Its efficacy in enhancing muscular and cardiovascular performance has been widely described, although its molecular target remains elusive. We addressed the molecular mechanisms underlying TMZ action on neuronal experimental paradigms. To this aim, we treated murine SOD1G93A-model-derived primary cultures of cortical and spinal enriched motor neurons, as well as a murine motor-neuron-like cell line overexpressing SOD1G93A, with TMZ. We first characterized the bioenergetic profile of the cell cultures, demonstrating significant mitochondrial dysfunction that is reversed by acute TMZ treatments. We then investigated the effect of TMZ in promoting autophagy processes and its impact on mitochondrial morphology. Finally, we demonstrated the effectiveness of TMZ in terms of the mitochondrial functionality of ALS-rpatient-derived peripheral blood mononuclear cells (PBMCs). In summary, our results emphasize the concept that targeting mitochondrial dysfunction may represent an effective therapeutic strategy for ALS. The findings demonstrate that TMZ enhances mitochondrial performance in motor neuron cells by activating autophagy processes, particularly mitophagy. Although further investigations are needed to elucidate the precise molecular pathways involved, these results hold critical implications for the development of more effective and specific derivatives of TMZ for ALS treatment.

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Metabolic alterations precede neurofilament changes in presymptomatic ALS gene carriers

Cited by 19 publications

References 30 publications

Abnormal energy metabolism in ALS: a key player?

Abnormal energy metabolism in ALS: a key player?

Presymptomatic amyotrophic lateral sclerosis: from characterization to prevention

Trimetazidine Improves Mitochondrial Dysfunction in SOD1G93A Cellular Models of Amyotrophic Lateral Sclerosis through Autophagy Activation

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