Abnormalities in brain glucose metabolism and accumulation of abnormal protein deposits called plaques and tangles are neuropathological hallmarks of Alzheimer’s disease (AD), but their relationship to disease pathogenesis and to each other remains unclear. Here we show that succinylation, a metabolism-associated post-translational protein modification (PTM), provides a potential link between abnormal metabolism and AD pathology. We quantified the lysine succinylomes and proteomes from brains of individuals with AD, and healthy controls. In AD, succinylation of multiple mitochondrial proteins declined, and succinylation of small number of cytosolic proteins increased. The largest increases occurred at critical sites of amyloid precursor protein (APP) and microtubule-associated tau. We show that in vitro, succinylation of APP disrupted its normal proteolytic processing thereby promoting Aβ accumulation and plaque formation and that succinylation of tau promoted its aggregation to tangles and impaired microtubule assembly. In transgenic mouse models of AD, elevated succinylation associated with soluble and insoluble APP derivatives and tau. These findings indicate that a metabolism-linked PTM may be associated with AD.

To promote new thinking of the pathogenesis of Alzheimer's disease (AD), we examine the central role of mitochondrial dysfunction in AD. Pathologically, AD is characterized by progressive neuronal loss and biochemical abnormalities including mitochondrial dysfunction. Conventional thinking has dictated that AD is driven by amyloid beta pathology, per the Amyloid Cascade Hypothesis. However, the underlying mechanism of how amyloid beta leads to cognitive decline remains unclear. A model correctly identifying the pathogenesis of AD is critical and needed for the development of effective therapeutics. Mitochondrial dysfunction is closely linked to the core pathological feature of AD: neuronal dysfunction. Targeting mitochondria and associated proteins may hold promise for new strategies for the development of disease-modifying therapies. According to the Mitochondrial Cascade Hypothesis, mitochondrial dysfunction drives the pathogenesis of AD, as baseline mitochondrial function and mitochondrial change rates influence the progression of cognitive decline. HIGHLIGHTS: The Amyloid Cascade Model does not readily account for various parameters associated with Alzheimer's disease (AD). A unified model correctly identifying the pathogenesis of AD is greatly needed to inform the development of successful therapeutics. Mitochondria play a key and central role in the maintenance of optimal neuronal and synaptic function, the core pathological feature of AD. Mitochondrial dysfunction may be the primary cause of AD, and is a promising target for new therapeutic strategies.

AIMS:Mitochondrial dysfunction and inflammation are at the core of axonal degeneration in several multifactorial neurodegenerative diseases, including multiple sclerosis, Alzheimer's disease, and Parkinson's disease. The transcriptional coregulator RIP140/NRIP1 (receptor-interacting protein 140) modulates these functions in liver and adipose tissue, but its role in the nervous system remains unexplored. Here, we investigated the impact of RIP140 in the Abcd1- mouse model of X-linked adrenoleukodystrophy (X-ALD), a genetic model of chronic axonopathy involving the convergence of redox imbalance, bioenergetic failure, and chronic inflammation. METHODS AND RESULTS:We provide evidence that RIP140 is modulated through a redox-dependent mechanism driven by very long-chain fatty acids (VLCFAs), the levels of which are increased in X-ALD. Genetic inactivation of RIP140 prevented mitochondrial depletion and dysfunction, bioenergetic failure, inflammatory dysregulation, axonal degeneration and associated locomotor disabilities in vivo in X-ALD mouse models. CONCLUSIONS:Together, these findings show that aberrant overactivation of RIP140 promotes neurodegeneration in X-ALD, underscoring its potential as a therapeutic target for X-ALD and other neurodegenerative disorders that present with metabolic and inflammatory dyshomeostasis.

This chapter reviews the current evidence supporting the involvement of mitochondria in amyotrophic lateral sclerosis (ALS) and discusses the potential implications in the pathogenesis of this neurodegenerative disease. Morphologic and ultrastructural abnormalities of mitochondria have been observed in autopsies of patients with sporadic disorder (SALS). In eukaryotic cells, superoxide is a normal byproduct of aerobic respiration and it is produced by oxidative phosphorylation in the mitochondria. A development in the field that has helped in shedding some light on the mechanisms of mitochondrial dysfunction caused by mutant SOD1 is the finding that a proportion of SOD1 is localized in the mitochondria. A number of toxic effects of mutated SOD1 have been proposed, including impairment of mitochondrial energy metabolism and apoptosis. Mitochondria are the site of initiation of the intrinsic apoptotic pathway, which is activated by the release of pro-apoptotic factors from mitochondria and can be either caspase-dependent or caspase-independent.

Small biomolecules, such as coenzyme A (CoA) and acetyl coenzyme A (acetyl-CoA), play vital roles in the regulation of cellular energy metabolism. In this paper, we evaluated the delayed effect of the potent hepatotoxin thioacetamide (TAA) on the concentrations of CoA and acetyl-CoA in plasma and in different rat tissues. Administration of TAA negatively affects liver function and leads to the development of hepatic encephalopathy (HE). In our experiments, rats were administered a single intraperitoneal injection of TAA at doses of 200, 400, or 600 mg/kg. Plasma, liver, kidney, and brain samples were collected six days after the TAA administration, a period that has been suggested to allow for restoration of liver function. The concentrations of CoA and acetyl-CoA in the group of rats exposed to different doses of TAA were compared to those observed in healthy rats. The results obtained indicate that even a single administration of TAA to rats is sufficient to alter the physiological balance of CoA and acetyl-CoA in the plasma and tissues of rats for an extended period of time. The initial concentrations of CoA and acetyl-CoA were not restored even after the completion of the liver regeneration process.

Biotin is an essential cofactor for carboxylases that regulates the energy metabolism. Recently, high-dose pharmaceutical-grade biotin (MD1003) was shown to improve clinical parameters in a subset of patients with chronic progressive multiple sclerosis. To gain insight into the mechanisms of action, we investigated the efficacy of high-dose biotin in a genetic model of chronic axonopathy caused by oxidative damage and bioenergetic failure, theAbcd1(-)mouse model of adrenomyeloneuropathy. High-dose biotin restored redox homeostasis driven by NRF-2, mitochondria biogenesis and ATP levels, and reversed axonal demise and locomotor impairment. Moreover, we uncovered a concerted dysregulation of the transcriptional program for lipid synthesis and degradation in the spinal cord likely driven by aberrant SREBP-1c/mTORC1signaling. This resulted in increased triglyceride levels and lipid droplets in motor neurons. High-dose biotin normalized the hyperactivation of mTORC1, thus restoring lipid homeostasis. These results shed light into the mechanism of action of high-dose biotin of relevance for neurodegenerative and metabolic disorders.

Lipid peroxidation is a key to a portfolio of neurodegenerative diseases and plays a central role in α-synuclein (α-syn) toxicity, mitochondrial dysfunction and neuronal death, all key processes in the pathogenesis of Parkinson’s disease (PD). Polyunsaturated fatty acids (PUFAs) are important constituents of the synaptic and mitochondrial membranes and are often the first molecular targets attacked by reactive oxygen species (ROS). The rate-limiting step of the chain reaction of ROS-initiated PUFAs autoxidation involves hydrogen abstraction at bis-allylic sites, which can be slowed down if hydrogens are replaced with deuteriums. In this study, we show that targeted overexpression of human A53T α-syn using an AAV vector unilaterally in the rat substantia nigra reproduces some of pathological features seen in PD patients. Chronic dietary supplementation with deuterated PUFAs (D-PUFAs), specifically 0.8% D-linoleic and 0.3% H-linolenic, produced significant disease-modifying beneficial effects against α-syn-induced motor deficits, synaptic pathology, oxidative damage, mitochondrial dysfunction, disrupted trafficking along axons, inflammation and DA neuronal loss. These findings support the clinical evaluation of D-PUFAs as a neuroprotective therapy for PD.

The brain requires a continuous supply of energy in the form of ATP, most of which is produced from glucose by oxidative phosphorylation in mitochondria, complemented by aerobic glycolysis in the cytoplasm. When glucose levels are limited, ketone bodies generated in the liver and lactate derived from exercising skeletal muscle can also become important energy substrates for the brain. In neurodegenerative disorders of ageing, brain glucose metabolism deteriorates in a progressive, region-specific and disease-specific manner - a problem that is best characterized in Alzheimer disease, where it begins presymptomatically. This Review discusses the status and prospects of therapeutic strategies for countering neurodegenerative disorders of ageing by improving, preserving or rescuing brain energetics. The approaches described include restoring oxidative phosphorylation and glycolysis, increasing insulin sensitivity, correcting mitochondrial dysfunction, ketone-based interventions, acting via hormones that modulate cerebral energetics, RNA therapeutics and complementary multimodal lifestyle changes.

Animal models of human diseases are crucial experimental tools to investigate the mechanisms involved in disease pathogenesis and to develop new therapies. In spite of the numerous animal models currently available that reproduce several neuropathological features of Parkinson disease (PD), it is challenging to have one that consistently recapitulates human PD conditions in both motor behaviors and biochemical pathological outcomes. Given that, we have implemented a new paradigm to expose rats to a chronic low dose of paraquat (PQ), using osmotic minipumps and characterized the developed pathologic features over time. The PQ exposure paradigm used lead to a rodent model of PD depicting progressive nigrostriatal dopaminergic neurodegeneration, characterized by a 41% significant loss of dopaminergic neuron in the substantia nigra pars compacta (SNpc), a significant decrease of 18% and 40% of dopamine levels in striatum at week 5 and 8, respectively, and a significant 1.5-fold decrease in motor performance. We observed a significant increase of microglia activation state, sustained levels of α-synucleinopathy and increased oxidative stress markers in the SNpc. In summary, this is an explorative study that allowed to characterize an improved PQ-based rat model that recapitulates cardinal features of PD and may represent an attractive tool to investigate several mechanisms underlying the various aspects of PD pathogenesis as well as for the validation of the efficacy of new therapeutic approaches that targets different mechanisms involved in PD neurodegeneration.

Abnormalities in glucose metabolism and misfolded protein deposits composed of the amyloid-β peptide (Aβ) and tau are the three most common neuropathological hallmarks of Alzheimer’s disease (AD), but their relationship(s) to the disease process or to each other largely remains unclear. In this report, the first human brain quantitative lysine succinylome together with a global proteome analysis from controls and patients reveals that lysine succinylation contributes to these three key AD-related pathologies. Succinylation, a newly discovered protein post-translational modification (PTM), of multiple proteins, particularly mitochondrial proteins, declines with the progression of AD. In contrast, amyloid precursor protein (APP) and tau consistently exhibit the largest AD-related increases in succinylation, occurring at specific sites in AD brains but never in controls. Transgenic mouse studies demonstrate that succinylated APP and succinylated tau are detectable in the hippocampus concurrent with Aβ assemblies in the oligomer and insoluble fiber assembly states. Multiple biochemical approaches revealed that succinylation of APP alters APP processing so as to promote Aβ accumulation, while succinylation of tau promotes its aggregation and impairs its microtubule binding ability. Succinylation, therefore, is the first single PTM that can be added in parallel to multiple substrates, thereby promoting amyloidosis, tauopathy, and glucose hypometabolism. These data raise the possibility that, in order to show meaningful clinical benefit, any therapeutic and/or preventative measures destined for success must have an activity to either prevent or reverse the molecular pathologies attributable to excess succinylation.

May 5, 2019April 9, 2019Free AccessNeuroprotection of HP-beta-CD in the adult transgenic mice of Alzheimer disease (P1.1-003)Jiaqi Yao, Noel Calingasan, Paisith Piriyawat, Flint Beal, and Salvador Cruz-FloresAuthors Info & AffiliationsApril 9, 2019 issue92 (15_supplement)https://doi.org/10.1212/WNL.92.15_supplement.P1.1-003 Letters to the Editor

A Mu A Rolf Aalto Duur K. Aanen Maria Abascal Adam R. Abate Cory Abate-Shen Abul K. Abbas Jon Abbatt Patrick Abbot Karen C. Abbott Larry Abbott Nicholas L. Abbott Zakia Abdelhamed Mohamed H. Abdel-Rahman Omar Abdel-Wahab Ikuro Abe Guy J. Abel Laurent Abel Rachel E. Abercrombie Andrea Ablasser Clara Abraham Jonatas S. Abrahao Nerilie Abram Peter A. Abrams Jeff Abramson S. Abrignani Héctor D. Abruña Arhat Abzhanov Domenico Accili Sergio P. Acebron Hans Acha-Orbea Christopher Achen Eric P. Achterberg Mark Achtman David D. Ackerly Susan L. Ackerman Martin Ackermann Alicia T. R. Acosta Ivan Acosta Victor M. Acosta Diego Acosta-Alvear Ted Acott Oreste Acuto Emma K. Adam Ángel F. Adames Igor Adameyko Christoph Adami Wiktor Adamowicz Charles Adams Dean C. Adams Michael W. W. Adams Michael Adams Philip Adams Russell Adams Mokhtar Adda-Bedia Louigi Addario-Berry Donna Rose Addis Zach N. Adelman Hillel Adesnik William Neil Adger Achyuta Adhvaryu Claire L. Adida Jess F. Adkins Frederick R. Adler Nancy E. Adler Ralph Adolphs Tobias Adrian Markus Aebi Shuchin Aeron Andrey Afanasev Markus Affolter Pavel V. Afonine Dritan Agalliu Theodor Agapie Athos Agapiou Nathalie Y. R. Agar David A. Agard Sapan Agarwal Deepa Agashe Ann Ager Joel W. Ager III Amir AghaKouchak Anders Ågmo Rajesh Agnihotri Anurag A. Agrawal Hans Ågren Andrew J. Aguirre Christopher A. Ahern Merav Ahissar Margaret Ahmad Rafi Ahmed Saleh Ahmed Zubair Ahmed Natalie G. Ahn Jorge Ahumada Elena Aikawa Elizabeth A. Ainsworth Edoardo Airoldi Sally N. Aitken Joanna Aizenberg Bahareh Ajami Michael Akam Masaki Akaogi Schahram Akbarian Erol Akçay Seun Akeju Mark Akeson Huda Akil Modupe Akinola Masashi Akiyama Takahiko Akiyama Michael Aklin Georgiy Akopov Klaus Aktories Alessandro Alabastri Petri Ala-Laurila Richard Alba Joseph Albanesi Umberto Albarella Jawdat Al-Bassam Cristina M. Alberini H. Elliott Albers Kathryn M. Albers Barbara Albert Dustin Albert Frank W. Albert Victor A. Albert Filipe Alberto Paul Albertus Jordi Albo-Canals Steve D. Albon Torsten Albrecht Elizabeth Albright Michaeline B. N. Albright Antonio Alcami Courtney C. Aldrich Richard W. Aldrich Bree B. Aldridge Ricard Alert Accardi Alessio Becky Alexander Clark Alexander Conel M. O’D. Alexander Gareth P. Alexander Ian E. Alexander Matthew S. Alexander R. Todd Alexander Chloe Alexandre Michael E. Alfaro Juan D. Alfonzo Hashim M. Al-Hashimi Karen Alim Dan Alistarh Kari Alitalo Jennifer M. Alix-Garcia Saed Alizamir Richard Alkire Eric Allan David Alland Hunt Allcott Benjamin L. Allen David T. Allen Eric E. Allen Jenny Allen Karen N. Allen Micah Allen Nicola J. Allen Paul M. Allen Stefano Allesina Heidi Alleway David B. Allison Kyle R. Allison Steven D. Allison Ted Allison Marco A. Allodi Robin Allshire Maria Almeida Osborne F. X. Almeida Genevieve Almouzni Emad S. Alnemri Ronen Alon Uri Alon Maria J. Alonso Carlos Alonso-Blanco Francis Alonzo III Hal S. Alper Luke Alphey Jean Alric Frederick W. Alt Grégoire Altan-Bonnet Lee Altenberg Eckart Altenmüller Marcus Altfeld Christian L. Althaus Benjamin M. Althouse John D. Altman Philipp M. Altrock Daniel L. Altschuler Res Altwegg Andrea Alu N. R. Aluru Lihini I. Aluwihare Jorge Alvarez-Solas James C. Alwine Teresa Amabile Rudolf Amann Katrin Amann-Winkel Susan G. Amara Luis A. Nunes Amaral Gaya K. Amarasinghe Kapil Amarnath Richard Ambinder Sandro Ambuehl Ken-ichi Amemori Jan Amend Seth A. Ament Stefano Amente Manuel R. Amieva Sebastian Amigorena Ariel Amir Ido Amit Katrin Amunts Marc Amyot Florin Amzica Weihua An Kevin J. Anchukaitis Niels Andela William R. L. Anderegg John M. Anderies Strom M. Anders Gary L. Andersen Ana Anderson Charles T. Anderson Christopher B. Anderson Clark L. Anderson Craig A. Anderson G. Brooke Anderson James M. Anderson Jill T. Anderson Mark E. Anderson Marti J. Anderson Mary P. Anderson Michael G. Anderson Sarah E. Anderson Stephen K. Anderson Stephen R. Anderson David Andersson Leif Andersson Ove Andersson M. Andiappan Raul Andino Anuska Andjelkovic Tadashi Ando

Parkinson's disease (PD) is the second most common neurodegenerative disease. Two percent of the population above the age of 60 is affected by the disease. The pathological hallmarks of PD include loss of dopaminergic neurons and the presence of Lewy bodies. Mitochondrial dysfunction and oxidative stress are thought to play a pivotal role in both sporadic and familial forms of the disease. In this review we focus on the role of mitochondrial dysfunction and oxidative stress in induced pluripotent stem cell (IPSC) models of PD.We also provide an overview of therapeutics that have been tested and some possible new therapeutics that can be tested in IPSC models of PD.

Using molecular, biochemical, and untargeted stable isotope tracing approaches, we identify a previously unappreciated glutamine-derived α-ketoglutarate (αKG) energy-generating anaplerotic flux to be critical in mitochondrial DNA (mtDNA) mutant cells that harbor human disease-associated oxidative phosphorylation defects. Stimulating this flux with αKG supplementation enables the survival of diverse mtDNA mutant cells under otherwise lethal obligatory oxidative conditions. Strikingly, we demonstrate that when residual mitochondrial respiration in mtDNA mutant cells exceeds 45% of control levels, αKG oxidative flux prevails over reductive carboxylation. Furthermore, in a mouse model of mitochondrial myopathy, we show that increased oxidative αKG flux in muscle arises from enhanced alanine synthesis and release into blood, concomitant with accelerated amino acid catabolism from protein breakdown. Importantly, in this mouse model of mitochondriopathy, muscle amino acid imbalance is normalized by αKG supplementation. Taken together, our findings provide a rationale for αKG supplementation as a therapeutic strategy for mitochondrial myopathies.

Impaired glucose metabolism, decreased levels of thiamine and its phosphate esters, and reduced activity of thiamine-dependent enzymes, such as pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase and transketolase occur in Alzheimer's disease (AD). Thiamine deficiency exacerbates amyloid beta (Aβ) deposition, tau hyperphosphorylation and oxidative stress. Benfotiamine (BFT) rescued cognitive deficits and reduced Aβ burden in amyloid precursor protein (APP)/PS1 mice. In this study, we examined whether BFT confers neuroprotection against tau phosphorylation and the generation of neurofibrillary tangles (NFTs) in the P301S mouse model of tauopathy. Chronic dietary treatment with BFT increased lifespan, improved behavior, reduced glycated tau, decreased NFTs and prevented death of motor neurons. BFT administration significantly ameliorated mitochondrial dysfunction and attenuated oxidative damage and inflammation. We found that BFT and its metabolites (but not thiamine) trigger the expression of Nrf2/antioxidant response element (ARE)-dependent genes in mouse brain as well as in wild-type but not Nrf2-deficient fibroblasts. Active metabolites were more potent in activating the Nrf2 target genes than the parent molecule BFT. Docking studies showed that BFT and its metabolites (but not thiamine) bind to Keap1 with high affinity. These findings demonstrate that BFT activates the Nrf2/ARE pathway and is a promising therapeutic agent for the treatment of diseases with tau pathology, such as AD, frontotemporal dementia and progressive supranuclear palsy.

The recent identification of profilin1 mutations in 25 familial ALS cases has linked altered function of this cytoskeleton-regulating protein to the pathogenesis of motor neuron disease. To investigate the pathological role of mutant profilin1 in motor neuron disease, we generated transgenic lines of mice expressing human profilin1 with a mutation at position 118 (hPFN1(G118V)). One of the mouse lines expressing high levels of mutant human PFN1 protein in the brain and spinal cord exhibited many key clinical and pathological features consistent with human ALS disease. These include loss of lower (ventral horn) and upper motor neurons ( corticospinal motor neurons in layer V), mutant profilin1 aggregation, abnormally ubiquitinated proteins, reduced choline acetyltransferase (ChAT) enzyme expression, fragmented mitochondria, glial cell activation, muscle atrophy, weight loss, and reduced survival. Our investigations of actin dynamics and axonal integrity suggest that mutant PFN1 protein is associated with an abnormally low filamentous/globular (F/G)-actin ratio that may be the underlying cause of severe damage to ventral root axons resulting in a Wallerian-like degeneration. These observations indicate that our novel profilin1 mutant mouse line may provide a new ALS model with the opportunity to gain unique perspectives into mechanisms of neurodegeneration that contribute to ALS pathogenesis.