Metabolic Dysfunctions in Amyotrophic Lateral Sclerosis Pathogenesis and Potential Metabolic Treatments

Tefera, Tesfaye Wolde; Borges, Karin

doi:10.3389/fnins.2016.00611

Cited by 81 publications

(97 citation statements)

References 197 publications

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“…This organelle is mainly responsible for energy production and transfer, crucial for cellular redox and calcium homeostasis, and have a central role in apoptosis (Nicholls and Ferguson, 2013). Disturbed mitochondrial functions have been associated with encephalopathy of common neurological disorders (Farshbaf and Ghaedi, 2017;Guo et al, 2017;Tefera and Borges, 2017;Angelova and Abramov, 2018;Zhou et al, 2018), as well as in brain injury of GA I (Strauss and Morton, 2003;Kölker et al, 2004;Wajner and Goodman, 2011).…”

Section: Bioenergetics Dysfunction In Gcdh −/− Micementioning

confidence: 99%

Pathogenesis of brain damage in glutaric acidemia type I: Lessons from the genetic mice model

Wajner

Amaral

Leipnitz

2019

Intl J of Devlp Neuroscience

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Glutaric acidemia type I (GA I) is an inherited neurometabolic disease caused by deficient activity of the mitochondrial enzyme glutaryl‐CoA dehydrogenase (GCDH), resulting in predominant accumulation of glutaric and 3‐hydroxyglutaric acids derived from lysine (Lys), hydroxylysine, and tryptophan catabolism. GA I patients usually present progressive cortical leukodystrophy and frequently develop acute striatal degeneration during encephalopathic crises during the first three years of life. The pathophysiology of the neurodegeneration observed in GA I is still partly known, although the development of the genetic mice model of GA I (Gcdh−/−) has contributed to clarify potential underlying mechanisms involved in brain damage in this disease. In this review we will summarize the knowledge acquired from studies using this animal model indicating that disruption of redox homeostasis, glutamatergic neurotransmission and bioenergetics, as well as vascular alterations, blood‐brain barrier breakage and altered myelination underlie the cortical and striatum abnormalities and white matter changes observed in GA I patients. Elucidation of these pathomechanisms potentially offers new standpoints for the development of novel therapeutic strategies for this disease.

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Section: Bioenergetics Dysfunction In Gcdh −/− Micementioning

confidence: 99%

Pathogenesis of brain damage in glutaric acidemia type I: Lessons from the genetic mice model

Wajner

Amaral

Leipnitz

2019

Intl J of Devlp Neuroscience

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“…Unlike other studies of the whole plasma proteome in ALS, here we show that the protein composition of plasma CPA from ALS individuals reproduces most of the extensively described pathological hallmarks of ALS, including pathways involved in protein degradation through the proteasome and energy metabolism ( 52-55 ). The same approach applied to the TMT-proteomic datasets reveals regulated features also known to be involved in ALS pathology and in protein aggregates homeostasis including lysosome as well as lipoprotein and glycosaminoglycan metabolisms ( 33,34,45,48,49,(52)(53)(54)(55) ) (Table S4). All disease-related alterations in proteasome activity in ALS have so far been shown in such detail only in brain, spinal cord and in neuronal cell lines, but not systemically or more specifically in blood, as in our study ( 52,53 ).…”

Section: Discussionmentioning

confidence: 99%

“…Within the top ten regulated pathways, five were involved in metabolism of lipoproteins (Table S4). The significant representation of these pathways in our brain/CPA proteomes reflects known changes of the ALS pathophysiology, where metabolism is thought to be switched from sugars and carbohydrates to lipids use ( [33][34][35] ). To identify potential protein candidates for biomarkers analysis, we looked at highly regulated protein (unique peptides ≥ 2, LogFC < -0.693 or > 0.693, p-value < 0.05; 48 proteins in total) within the 69 pathways highlighted by FAT.…”

Section: Functional Analysismentioning

confidence: 99%

Analysis of circulating protein aggregates reveals pathological hallmarks of amyotrophic lateral sclerosis

Adiutori

Puentes

Bremang

et al. 2020

Preprint

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Blood-based biomarkers can be informative of brain disorders where protein aggregation play a major role. The proteome of plasma and circulating protein aggregates (CPA) reflect the inflammatory and metabolic state of the organism and can be predictive of system-level and/or organ-specific pathologies. CPA are enriched with heavy chain neurofilaments (NfH), key axonal constituents involved in brain aggregates formation and biomarkers of the fatal neurodegenerative disorder amyotrophic lateral sclerosis (ALS). Here we show that CPA and brain protein aggregates (BPA) from ALS differ in protein composition and appear as a combination of electron-dense large globular and small filamentous formations on transmission electron microscopy. CPA are highly enriched with proteins involved in the proteasome and energy metabolism. Compared to the human proteome, proteins within aggregates show distinct and tissue-dependent chemical features of aggregation propensity. The use of a TMTcalibrator™ proteomics workflow with ALS brain as calibrant reveals 4973 brain-derived low-abundance proteins in CPA, including the products of translation of 24 ALS risk genes. 285 of these (5.7%) are regulated in ALS CPA including FUS (p<0.05). CPA from both ALS and healthy controls affect cell viability when testing endothelial and PC12 neuronal cell lines, while CPA from ALS exert a more toxic effect at lower concentrations. The analysis of resistance to protease enzymes hydrolysis indicates an ALS-specific digestion pattern for NfH using enterokinase. This study reveals how peripheral protein aggregates are significantly enriched with brain proteins which are highly representative of ALS pathology and a potential alternative source of biomarkers and therapeutic targets for this incurable disorder.Significance StatementMolecular mechanism of neurodegeneration like protein aggregation are important brain-specific alterations which need to be addressed therapeutically. Recently described fluid biomarkers of neurodegenerative disorders provide means for stratification and monitoring of disease progression. Here we show that circulating protein aggregates are easily accessible in blood and reproduce important features of brain pathology for an incurable disorder like amyotrophic lateral sclerosis. They represent a source of biomarkers and of novel therapeutics for ALS.

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“…Based on published studies, we treated cortical PNs with the cell-permeant mitochondria modulator L-Carnitine (Dickey and Strack, 2011;Sainath et al, 2017), a cell-permeant, lysine-derived quaternary amine that acts by promoting the metabolism of long-chain fatty acids by the mitochondria. It has been shown to be neuroprotective in a wide variety of metabolic stresses (Tefera and Borges, 2016;Zanelli et al, 2005) and has clinical interest in the treatment of depression and anxiety (Chiechio et al, 2017;Filiou and Sandi, 2019). We achieved single-cell knockout of NUAK1 through EVCE of CRE-coding plasmid in NUAK1 F/F cortical PNs and quantified axon morphology at 5DIV.…”

Section: Upregulation Of Mitochondria Function Rescues Collateral Bramentioning

confidence: 99%

The AMPK-related kinase NUAK1 controls cortical axons branching though a local modulation of mitochondrial metabolic functions

Lanfranchi

Meyer-Dilhet

Reis

et al. 2020

Preprint

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The precise regulation of the cellular mechanisms underlying axonal morphogenesis is essential to the formation of functional neuronal networks. We previously identified the autism-candidate kinase NUAK1 as a central regulator of axon branching in mouse cortical neurons through the control of mitochondria trafficking. How does local mitochondrial position or function regulate axon branching during development? Here, we characterized the metabolic regulation in the developing axon and report a marked metabolic decorrelation between axon elongation and collateral branching. We next solved the cascade of event leading to presynaptic clustering and mitochondria recruitment during spontaneous branch formation. Interestingly and contrary to peripheral neurons, mitochondria are recruited after but not prior to branch formation in cortical neurons. Using flux metabolomics and fluorescent biosensors, we observed that NUAK1 deficiency significantly impairs mitochondrial metabolism and axonal ATP concentration. Upregulation of mitochondrial function is sufficient to rescue axonal branching in NUAK1 null neurons in vitro and in vivo. Altogether, our results indicate that NUAK1 exerts a dual function during axon branching through its ability to control mitochondria distribution and activity, and suggest that a mitochondrial-dependent remodeling of local metabolic homeostasis plays a critical role during axon morphogenesis. RESULTS Cortical axon elongation and collateral branching rely on distinct metabolic pathways

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Metabolic Dysfunctions in Amyotrophic Lateral Sclerosis Pathogenesis and Potential Metabolic Treatments

Cited by 81 publications

References 197 publications

Pathogenesis of brain damage in glutaric acidemia type I: Lessons from the genetic mice model

Pathogenesis of brain damage in glutaric acidemia type I: Lessons from the genetic mice model

Analysis of circulating protein aggregates reveals pathological hallmarks of amyotrophic lateral sclerosis

The AMPK-related kinase NUAK1 controls cortical axons branching though a local modulation of mitochondrial metabolic functions

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