Calcium Dyshomeostasis Research Articles

Chronic inhibition of the mitochondrial ATP synthase in skeletal muscle triggers sarcoplasmic reticulum distress and tubular aggregates

Tubular aggregates (TA) are honeycomb-like arrays of sarcoplasmic-reticulum (SR) tubules affecting aged glycolytic fibers of male individuals and inducing severe sarcomere disorganization and muscular pain. TA develop in skeletal muscle from Tubular Aggregate Myopathy (TAM) patients as well as in other disorders including endocrine syndromes, diabetes, and ageing, being their primary cause unknown. Nowadays, there is no cure for TA. Intriguingly, both hypoxia and calcium dyshomeostasis prompt TA formation, pointing to a possible role for mitochondria in their setting. However, a functional link between mitochondrial dysfunctions and TA remains unknown. Herein, we investigate the alteration in muscle-proteome of TAM patients, the molecular mechanism of TA onset and a potential therapy in a preclinical mouse model of the disease. We show that in vivo chronic inhibition of the mitochondrial ATP synthase in muscle causes TA. Upon long-term restrained oxidative phosphorylation (OXPHOS), oxidative soleus experiments a metabolic and structural switch towards glycolytic fibers, increases mitochondrial fission, and activates mitophagy to recycle damaged mitochondria. TA result from the overresponse of the fission controller DRP1, that upregulates the Store-Operate-Calcium-Entry and increases the mitochondria-SR interaction in a futile attempt to buffer calcium overloads upon prolonged OXPHOS inhibition. Accordingly, hypoxic muscles cultured ex vivo show an increase in mitochondria/SR contact sites and autophagic/mitophagic zones, where TA clusters grow around defective mitochondria. Moreover, hypoxia triggered a stronger TA formation upon ATP synthase inhibition, and this effect was reduced by the DRP1 inhibitor mDIVI. Remarkably, the muscle proteome of TAM patients displays similar alterations in mitochondrial dynamics and in ATP synthase contents. In vivo edaravone treatment in mice with restrained OXPHOS restored a healthy phenotype by prompting mitogenesis and mitochondrial fusion. Altogether, our data provide a functional link between the ATP synthase/DRP1 axis and the setting of TA, and repurpose edaravone as a possible treatment for TA-associated disorders.

The Common Cellular Events in the Neurodegenerative Diseases and the Associated Role of Endoplasmic Reticulum Stress.

Neurodegenerative diseases are inseparably linked with aging and increase as life expectancy extends. There are common dysfunctions in various cellular events shared among neurogenerative diseases, such as calcium dyshomeostasis, neuroinflammation, and age-associated decline in the autophagy-lysosome system. However, most of all, the prominent pathological feature of neurodegenerative diseases is the toxic buildup of misfolded protein aggregates and inclusion bodies accompanied by an impairment in proteostasis. Recent studies have suggested a close association between endoplasmic reticulum (ER) stress and neurodegenerative pathology in cellular and animal models as well as in human patients. The contribution of mutant or misfolded protein-triggered ER stress and its associated signaling events, such as unfolded protein response (UPR), to the pathophysiology of various neurodegenerative disorders, including Alzheimer’s, Parkinson’s, and Huntington’s disease, amyotrophic lateral sclerosis, and prion disease, is described here. Impaired UPR action is commonly attributed to exacerbated ER stress, pathogenic protein aggregate accumulation, and deteriorating neurodegenerative pathologies. Thus, activating certain UPR components has been shown to alleviate ER stress and its associated neurodegeneration. However, uncontrolled activation of some UPR factors has also been demonstrated to worsen neurodegenerative phenotypes, suggesting that detailed molecular mechanisms around ER stress and its related neurodegenerations should be understood to develop effective therapeutics against aging-associated neurological syndromes. We also discuss current therapeutic endeavors, such as the development of small molecules that selectively target individual UPR components and address ER stress in general.

The Plasma Membrane Ca2+-ATPase, a Molecular Target for Tau-induced Cytosolic Calcium Dysregulation

Disruption of calcium (Ca2+) homeostasis is emerging as a prevalent feature of aging and aging-associated neurodegenerative diseases, including Alzheimer’s disease (AD), the most common type of tauopathy. This disease is characterized by the combined presence of extracellular neuritic plaques composed by amyloid β-peptides (Aβ) and neurofibrillary tangles of tau. The association of calcium dyshomeostasis with Aβ has been extensively studied, however its link with tau has been less investigated. Thus, this review will concentrate on the functional link between tau and the plasma membrane Ca2+ pump (PMCA) and other membrane proteins involved in the regulation of intracellular calcium and/or its association with neurodegeneration.

Aberrant miR-339-5p/neuronatin signaling causes prodromal neuronal calcium dyshomeostasis in mutant presenilin mice.

Mushroom spine loss and calcium dyshomeostasis are early hallmark events of age-related neurodegeneration, such as Alzheimer’s disease (AD), that are connected with neuronal hyperactivity in early pathology of cognitive brain areas. However, it remains elusive how these key events are triggered at the molecular level for the neuronal abnormality that occurs at the initial stage of disease. Here, we identify downregulated miR-339-5p and its upregulated target protein, neuronatin (Nnat), in cortex neurons from the presenilin-1 M146V knockin (PSEN1-M146V KI) mouse model of familial AD (FAD). Inhibition of miR-339-5p or overexpression of Nnat recapitulates spine loss and endoplasmic reticulum calcium overload in cortical neurons with the PSEN1 mutation. Conversely, either overexpression of miR-339-5p or knockdown of Nnat restores spine morphogenesis and calcium homeostasis. We used fiber photometry recording during the object-cognitive process to further demonstrate that the PSEN1 mutant causes defective habituation in neuronal reaction in the retrosplenial cortex and that this can be rescued by restoring the miR-339-5p/Nnat pathway. Our findings thus reveal crucial roles of the miR-339-5p/Nnat pathway in FAD that may serve as potential diagnostic and therapeutic targets for early pathogenesis.

Oral nimodipine treatment has no effect on amyloid pathology or neuritic dystrophy in the 5XFAD mouse model of amyloidosis.

Dysregulation of calcium homeostasis has been hypothesized to play a role in Alzheimer’s disease (AD) pathogenesis. Increased calcium levels can impair axonal transport, disrupt synaptic transmission, and ultimately lead to cell death. Given the potential role of calcium dyshomeostasis in AD, there is interest in testing the ability of already approved drugs targeting various calcium channels to affect amyloid pathology and other aspects of disease. The objective of this study was to test the effects of FDA-approved L-type calcium channel antagonist nimodipine on amyloid accumulation and dystrophic neurite formation in 5XFAD mice, a mouse model of amyloid pathology. 5XFAD transgenic mice and non-transgenic littermates were treated with vehicle or nimodipine-containing chow from two to eight months of age, then brains were harvested and amyloid pathology assessed by immunoblot and immunofluorescence microscopy analyses. Nimodipine was well tolerated and crossed the blood brain barrier, as expected, but there was no effect on Aβ accumulation or on the relative amount of neuritic dystrophy, as assessed by either immunoblot, dot blot or immunofluorescence imaging of Aβ42 and dystrophic neurite marker LAMP1. While we conclude that nimodipine treatment is not likely to improve amyloid pathology or decrease neuritic dystrophy in AD, it is worth noting that nimodipine did not worsen the phenotype suggesting its use is safe in AD patients.

Azoramide ameliorated tachypacing-induced injury of atrial myocytes differentiated from human induced pluripotent stem cell by regulating endoplasmic reticulum stress

Hypoglycemicagents have been shown to reduce the incidence of atrial fibrillation (AF) in patients with diabetes mellitus. Azoramide is a novel anti-diabetic agent which protects cells against endoplasmic reticulum (ER) stress; however, the cardioprotective effect of azoramide against AF is not clear. In this study, we aimed to investigate the protective effect of azoramide in human iPS-derived atrial myocytes (a-iCMs) against injury induced by high-frequency electrical stimulation. Human-induced pluripotent stem cells were differentiated into a-iCMs by treatment of retinoic acid. The tachypacing group was subjected to 7 Hz tachypacing for 48 h. Azoramide was preconditioned 2-hours before tachypacing. a-iCMs expressed atria-specific genes and the characteristics of the action potential were analogous to those of human atrial myocytes. Tachypacing induced disorder of intracellular calcium homeostasis, apoptosis, depressed ATP level, and severer myofilament dissolution. MetaboAnalysis revealed that tachypacing induced remarkable changes in metabolites involved in energy, amino acid, and glucose metabolism, whereas there was no significant effect on lipid metabolism. Azoramide pretreatment partly alleviated tachypacing-induced calcium dyshomeostasis, ATP consumption, and accelerated apoptosis, which was likely achieved by regulating the PERK/CHOP/CaMKII pathway. Azoramide protected atrial myocytes against injury induced by high-frequency electrical stimulation by regulating ER stress, which may inhibit cell apoptosis and calcium dyshomeostasis via the PERK/CHOP/CaMKII pathway.

Role of endothelial TRPA1 expression in blood‐brain barrier dysfunction

AbstractBackgroundTransient Receptor Potential Ankyrin 1 (TRPA1) is a cation channel receptor that regulate calcium homeostasis among other cations. Calcium dyshomeostasis known to disrupt the blood‐brain barrier (BBB). In the brains of Alzheimer's disease (AD) transgenic mice, increased levels of TRPA1 was associated with increased levels of amyloid‐β (Aβ) and neuroinflammation. TRPA1 expressed in the endothelial cells of the BBB. The objective of this work is to investigate the effect of BBB‐endothelium TRPA1 activation on the BBB tightness and function.MethodWe performed in vitro and in vivo studies, Western blot, calcium assay, immunostaining.ResultWe performed in vitro studies using the mouse brain endothelial cell line bEnd3. First, we determined the expression of TRPA1 in bEnd3 by western blot and immunocytochemistry. Results confirmed TRPA1 expression in bEnd3. In addition, TRPA1 function was evaluated by monitoring calcium influx; the addition of the TRPA1 antagonist A‐967079 significantly reduced calcium influx in bEnd3, while the addition of Aβ42 oligomers to the cells increased intracellular calcium levels, which was blocked by the co‐addition of the TRPA1 antagonist suggesting that Aβ induces calcium influx via TRPA1. When tested in vivo in 5XFAD mouse model for AD by western blot, we found that TRPA1 levels were significantly higher in brain homogenates when compared to wild‐type (WT) mouse brains. Furthermore, the cerebrovascular levels of TRPA1 were significantly higher in 5XFAD compared to WT, which were also associated with BBB disruption as determined by increased IgG extravasation.ConclusionOur data suggests that endothelium‐TRPA1 could contribute to BBB disruption by increasing calcium influx.

Neuropathological signaling in AD human induced neurons

Neurons and other CNS-based cells derived from human AD patients are increasingly used for investigating cellular and molecular mechanisms of AD, and as a translational tool between animal models and human patients.We generated human induced neurons (HiN) from AD patients and age-matched controls using direct (fibroblast - neuron) and indirect methods (fibroblasts - iPSCs - neuron) and investigated a range of known and suspected pathogenic pathways using whole cell patch clamp electrophysiological recordings of membrane properties and synaptic signaling, live-cell fluorescent imaging of calcium signals and of organelle functions, and immunoassays to measure aberrant protein species.We identified a range of AD phenotypes in the AD HiN, including pathogenic beta amyloid peptides and phospho-tau species, and revealed new cellular signaling cascades that generate key physiological deficits associated with AD. These include altered synaptic transmission properties, defects in lysosome-autophagosome processing, altered mitochondrial bioenergetics, and intracellular calcium dyshomeostasis. Notably, we found that the common underlying feature of these altered functions was dysregulated calcium stemming from intracellular stores.Identifying and characterizing pathogenic processes at the cellular level from HiN offers powerful and novel insights into upstream drivers of AD mechanisms, and thus, may reveal novel therapeutic targets that can directly prevent disease progression and preserve cognitive functions in patients.

Endoplasmic Reticulum-Based Calcium Dysfunctions in Synucleinopathies.

Neuronal calcium dyshomeostasis has been associated to Parkinson's disease (PD) development based on epidemiological studies on users of calcium channel antagonists and clinical trials are currently conducted exploring the hypothesis of increased calcium influx into neuronal cytosol as basic premise. We reported in 2018 an opposite hypothesis based on the demonstration that α-synuclein aggregates stimulate the endoplasmic reticulum (ER) calcium pump SERCA and demonstrated in cell models the existence of an α-synuclein-aggregate dependent neuronal state wherein cytosolic calcium is decreased due to an increased pumping of calcium into the ER. Inhibiting the SERCA pump protected both neurons and an α-synuclein transgenic C. elegans model. This models two cellular states that could contribute to development of PD. First the prolonged state with reduced cytosolic calcium that could deregulate multiple signaling pathways. Second the disease ER state with increased calcium concentration. We will discuss our hypothesis in the light of recent papers. First, a mechanistic study describing how variation in the Inositol-1,4,5-triphosphate (IP3) kinase B (ITPKB) may explain GWAS studies identifying the ITPKB gene as a protective factor toward PD. Here it was demonstrated that how increased ITPKB activity reduces influx of ER calcium to mitochondria via contact between IP3-receptors and the mitochondrial calcium uniporter complex in ER-mitochondria contact, known as mitochondria-associated membranes (MAMs). Secondly, it was demonstrated that astrocytes derived from PD patients contain α-synuclein accumulations. A recent study has demonstrated how human astrocytes derived from a few PD patients carrying the LRRK2-2019S mutation express more α-synuclein than control astrocytes, release more calcium from ER upon ryanodine receptor (RyR) stimulation, show changes in ER calcium channels and exhibit a decreased maximal and spare respiration indicating altered mitochondrial function in PD astrocytes. Here, we summarize the previous findings focusing the effect of α-synuclein to SERCA, RyR, IP3R, MCU subunits and other MAM-related channels. We also consider how the SOCE-related events could contribute to the development of PD.

Mitochondrial Abnormalities and Synaptic Damage in Huntington's Disease: a Focus on Defective Mitophagy and Mitochondria-Targeted Therapeutics.

Huntington's disease (HD) is a fatal and pure genetic disease with a progressive loss of medium spiny neurons (MSN). HD is caused by expanded polyglutamine repeats in the exon 1 of HD gene. Clinically, HD is characterized by chorea, seizures, involuntary movements, dystonia, cognitive decline, intellectual impairment, and emotional disturbances. Several years of intense research revealed that multiple cellular changes, including defective axonal transport, protein-protein interactions, defective bioenergetics, calcium dyshomeostasis, NMDAR activation, synaptic damage, mitochondrial abnormalities, and selective loss of medium spiny neurons are implicated in HD. Recent research on mutant huntingtin (mHtt) and mitochondria has found that mHtt interacts with the mitochondrial division protein, dynamin-related protein 1 (DRP1), enhances GTPase DRP1 enzymatic activity, and causes excessive mitochondrial fragmentation and abnormal distribution, leading to defective axonal transport of mitochondria and selective synaptic degeneration. Recent research also revealed that failure to remove dead and/or dying mitochondria is an early event in the disease progression. Currently, efforts are being made to reduce abnormal protein interactions and enhance synaptic mitophagy as therapeutic strategies for HD. The purpose of this article is to discuss recent research in HD progression. This article also discusses recent developments of cell and mouse models, cellular changes, mitochondrial abnormalities, DNA damage, bioenergetics, oxidative stress, mitophagy, and therapeutics strategies in HD.

Distinct types of amyloid-β oligomers displaying diverse neurotoxicity mechanisms in Alzheimer's disease.

Soluble oligomers of amyloid-β (Aβ) are recognized as key pernicious species in Alzheimer's disease (AD) that cause synaptic dysfunction and memory impairments. Numerous studies have identified various types of Aβ oligomers having heterogeneous peptide length, size distribution, structure, appearance, and toxicity. Here, we review the characteristics of soluble Aβ oligomers based on their morphology, size, and structural reactivity toward the conformation-specific antibodies and then describe their formation, localization, and cellular effects in AD brains, in vivo and in vitro. We also summarize the mechanistic pathways by which these soluble Aβ oligomers cause proteasomal impairment, calcium dyshomeostasis, inhibition of long-term potentiation, apoptosis, mitochondrial damage, and cognitive decline. These cellular events include three distinct molecular mechanisms: (i) high-affinity binding with the receptors for Aβ oligomers such as N-methyl- d-aspartate receptors, cellular prion protein, nerve growth factor, insulin receptors, and frizzled receptors; (ii) the interaction of Aβ oligomers with the lipid membranes; (iii) intraneuronal accumulation of Aβ by α7-nicotinic acetylcholine receptors, apolipoprotein E, and receptor for advanced glycation end products. These studies indicate that there is a pressing need to carefully examine the role of size, appearance, and the conformation of oligomers in identifying the specific mechanism of neurotoxicity that may uncoverpotential targets for designing AD therapeutics.

Sources and triggers of oxidative damage in neurodegeneration

Neurodegeneration describes a group of more than 300 neurological diseases, characterised by neuronal loss and intra- or extracellular protein depositions, as key neuropathological features. Multiple factors play role in the pathogenesis of these group of disorders: mitochondrial dysfunction, membrane damage, calcium dyshomeostasis, metallostasis, defect clearance and renewal mechanisms, to name a few. All these factors, without exceptions, have in common the involvement of immensely increased generation of free radicals and occurrence of oxidative stress, and as a result - exhaustion of the scavenging potency of the cellular redox defence mechanisms. Besides genetic predisposition and environmental exposure to toxins, the main risk factor for developing neurodegeneration is age. And although the “Free radical theory of ageing” was declared dead, it is undisputable that accumulation of damage occurs with age, especially in systems that are regulated by free radical messengers and those that oppose oxidative stress, protein oxidation and the accuracy in protein synthesis and degradation machinery has difficulties to be maintained.This brief review provides a comprehensive summary on the main sources of free radical damage, occurring in the setting of neurodegeneration.

Amelioration of circadian disruption and calcium-handling protein defects by choline alleviates cardiac remodeling in abdominal aorta coarctation rats

The key pathophysiological process leading to heart failure is cardiac remodeling, a term referring to cardiac hypertrophy, fibrosis, and apoptosis. We explored circadian rhythm disruption and calcium dyshomeostasis in cardiac remodeling and investigated the cardioprotective effect of choline. The experiments were conducted using a model of cardiac remodeling by abdominal aorta coarctation (AAC) in Sprague–Dawley rats. In vitro cardiomyocyte remodeling was induced by exposing neonatal rat cardiomyocytes to angiotensin II. The circadian rhythms of the transcript levels of the seven major components of the mammalian clock (Bmal1, Clock, Rev-erbα, Per1/2, and Cry1/2) were altered in AAC rat hearts during a normal 24 h light/dark cycle. AAC also upregulated the levels of proteins that mediate store-operated Ca2+ entry/receptor-operated Ca2+ entry (stromal interaction molecule 1 [STIM1], Orai1, and transient receptor potential canonical 6 [TRPC6]) in rat hearts. Moreover, choline ameliorated circadian rhythm disruption, reduced the upregulated protein levels of STIM1, Orai1, and TRPC6, and alleviated cardiac dysfunction and remodeling (evidenced by attenuated cardiac hypertrophy, fibrosis, and apoptosis) in AAC rats. In vitro analyses showed that choline ameliorated calcium overload, downregulated STIM1, Orai1, and TRPC6, and inhibited thapsigargin-induced store-operated Ca2+ entry and 1-oleoyl-2-acetyl-sn-glycerol-induced receptor-operated Ca2+ entry in angiotensin II-treated cardiomyocytes. In conclusion, choline attenuated AAC-induced cardiac remodeling and cardiac dysfunction, which was related to amelioration of circadian rhythm disruption and attenuation of calcium-handling protein defects. Modulation of vagal activity by choline targeting the circadian rhythm and calcium homeostasis may have therapeutic potential for cardiac remodeling and heart failure.Choline attenuates abdominal aortic coarctation-induced cardiac remodeling and cardiac dysfunction, by amelioration of circadian rhythm disruption and attenuation of calcium-handling protein defects. Modulation of vagal activity by choline may have therapeutic potential for cardiac remodeling and heart failure.

Iron overload induces apoptosis of osteoblast cells via eliciting ER stress-mediated mitochondrial dysfunction and p-eIF2α/ATF4/CHOP pathway in vitro

Iron is an essential element for crucial biological function; whereas excess iron sedimentation impairs the main functions of tissues or organs. Cumulative researches have shown that the disturbances in iron metabolism, especially iron overload is closely concatenating with bone loss. Nevertheless, the specific process of iron overload-induced apoptosis in osteoblasts has not been thoroughly studied. In this study, our purpose is to elucidate the mechanism of osteoblast apoptosis induced by iron overload via the MC3T3-E1 cell line. Ferric ammonium citrate (FAC) was utilized to simulate iron overload conditions in vitro. These results showed that treatment with FAC dose-dependently induced the apoptosis of MC3T3-E1 cells at 48 h, dysfunction of iron metabolism, and increased intracellular reactive oxygen species (ROS) levels. Following, FAC does-dependently caused the calcium dyshomeostasis, decreased the calcium concentration in endoplasmic reticulum (ER), but increased the crosstalk between ER and mitochondria, and calcium concentration in the mitochondria. Moreover, FAC dose-dependently decreased mitochondrial membrane potential (MMP) and enhanced the expression of apoptosis related proteins (Bax, Cyto-C and C-caspase3). We furthermore revealed that FAC treatment activated the ER-mediated cell apoptosis via p-eIF2α/ATF4/CHOP pathway in MC3T3-E1 osteoblasts cells. In addition, pretreatment with the N-acetylcysteine (NAC) or Tauroursodeoxycholate Sodium (TUDC) attenuated cell apoptosis, ROS levels, mitochondria fragmentation and ER stress-related protein expression, and recovered the protein expression related to iron metabolism. In conclusion, our finding suggested that iron overload induced apoptosis via eliciting ER stress, which resulted in mitochondrial dysfunction and activated p-eIF2α/ATF4/CHOP pathway.

Роль дисфункції мітохондрій у розвитку хвороби Альцгеймера

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by memory loss and multiple cognitive impairments. Several decades of intensive research have shown that multicellular changes are involved in AD’s development and progression, including mitochondrial damage, synaptic dysfunction, formation and accumulation of beta-amyloid (Aβ), formation and accumulation of hyperphosphorylated tau protein, and loss of neurons in patients with this disease. Among them, mitochondrial dysfunction and synaptic damage are the primary manifestations in the disease process. Recent studies have also shown that defective mitophagy caused by Aβ and tau protein are the main indicators in AD’s pathogenesis. This review includes an overview of recent researches on the role of mitochondria in AD development. The review summarizes several aspects of mitochondrial dysfunction, including abnormal mitochondrial dynamics, changes in mitochondrial DNA, and calcium dyshomeostasis in AD pathogenesis

Rectifying Attenuated Store-Operated Calcium Entry as a Therapeutic Approach for Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder. Although the pathological hallmarks of AD have been identified, the derived therapies cannot effectively slow down or stop disease progression; hence, it is likely that other pathogenic mechanisms are involved in AD pathogenesis. Intracellular calcium (Ca2+) dyshomeostasis has been consistently observed in AD patients and numerous AD models and may emerge prior to the development of amyloid plaques and neurofibrillary tangles. Thus, intracellular Ca2+ disruptions are believed to play an important role in AD development and could serve as promising therapeutic intervention targets. One of the disrupted intracellular Ca2+ signaling pathways manifested in AD is attenuated storeoperated Ca2+ entry (SOCE). SOCE is an extracellular Ca2+ entry mechanism mainly triggered by intracellular Ca2+ store depletion. Maintaining normal SOCE function not only provides a means for the cell to replenish ER Ca2+ stores but also serves as a cellular signal that maintains normal neuronal functions, including excitability, neurogenesis, neurotransmission, synaptic plasticity, and gene expression. However, normal SOCE function is diminished in AD, resulting in disrupted neuronal spine stability and synaptic plasticity and the promotion of amyloidogenesis. Mounting evidence suggests that rectifying diminished SOCE in neurons may intervene with the progression of AD. In this review, the mechanisms of SOCE disruption and the associated pathogenic impacts on AD will be discussed. We will also highlight the potential therapeutic targets or approaches that may help ameliorate SOCE deficits for AD treatment.

Pluripotent Stem Cell Derived Neurons as In Vitro Models for Studying Autosomal Recessive Parkinson's Disease (ARPD): PLA2G6 and Other Gene Loci.

Parkinson's disease (PD) is a neurodegenerative motor disorder which is largely sporadic; however, some familial forms have been identified. Genetic PD can be inherited by autosomal, dominant or recessive mutations. While the dominant mutations mirror the prototype of PD with adult-onset and L-dopa-responsive cases, autosomal recessive PD (ARPD) exhibit atypical phenotypes with additional clinical manifestations. Young-onset PD is also very common with mutations in recessive gene loci. The main genes associated with ARPD are Parkin, PINK1, DJ-1, ATP13A2, FBXO7 and PLA2G6. Calcium dyshomeostasis is a mainstay in all types of PD, be it genetic or sporadic. Intriguingly, calcium imbalances manifesting as altered Store-Operated Calcium Entry (SOCE) is suggested in PLA2G6-linked PARK 14 PD. The common pathways underlying ARPD pathology, including mitochondrial abnormalities and autophagic dysfunction, can be investigated ex vivo using induced pluripotent stem cell (iPSC) technology and are discussed here. PD pathophysiology is not faithfully replicated by animal models, and, therefore, nigral dopaminergic neurons generated from iPSC serve as improved human cellular models. With no cure to date and treatments aiming at symptomatic relief, these in vitro models derived through midbrain floor-plate induction provide a platform to understand the molecular and biochemical pathways underlying PD etiology in a patient-specific manner.

Synaptic Loss in Alzheimer's Disease: Mechanistic Insights Provided by Two-Photon in vivo Imaging of Transgenic Mouse Models.

Synapse loss is the strongest correlate for cognitive decline in Alzheimer's disease. The mechanisms underlying synapse loss have been extensively investigated using mouse models expressing genes with human familial Alzheimer's disease mutations. In this review, we summarize how multiphoton in vivo imaging has improved our understanding of synapse loss mechanisms associated with excessive amyloid in the living animal brain. We also discuss evidence obtained from these imaging studies for the role of cell-intrinsic calcium dyshomeostasis and cell-extrinsic activities of microglia, which are the immune cells of the brain, in mediating synapse loss.

The Role of Mitochondrial Calcium Homeostasis in Alzheimer's and Related Diseases.

Calcium signaling is essential for neuronal function, and its dysregulation has been implicated across neurodegenerative diseases, including Alzheimer’s disease (AD). A close reciprocal relationship exists between calcium signaling and mitochondrial function. Growing evidence in a variety of AD models indicates that calcium dyshomeostasis drastically alters mitochondrial activity which, in turn, drives neurodegeneration. This review discusses the potential pathogenic mechanisms by which calcium impairs mitochondrial function in AD, focusing on the impact of calcium in endoplasmic reticulum (ER)–mitochondrial communication, mitochondrial transport, oxidative stress, and protein homeostasis. This review also summarizes recent data that highlight the need for exploring the mechanisms underlying calcium-mediated mitochondrial dysfunction while suggesting potential targets for modulating mitochondrial calcium levels to treat neurodegenerative diseases such as AD.

PPAR gamma agonist leriglitazone improves frataxin-loss impairments in cellular and animal models of Friedreich Ataxia

Friedreich ataxia (FRDA), the most common autosomal recessive ataxia, is characterized by degeneration of the large sensory neurons and spinocerebellar tracts, cardiomyopathy, and increased incidence in diabetes. The underlying pathophysiological mechanism of FRDA, driven by a significantly decreased expression of frataxin (FXN), involves increased oxidative stress, reduced activity of enzymes containing iron‑sulfur clusters (ISC), defective energy production, calcium dyshomeostasis, and impaired mitochondrial biogenesis, leading to mitochondrial dysfunction. The peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcriptional factor playing a key role in mitochondrial function and biogenesis, fatty acid storage, energy metabolism, and antioxidant defence. It has been previously shown that the PPARγ/PPARγ coactivator 1 alpha (PGC-1α) pathway is dysregulated when there is frataxin deficiency, thus contributing to FRDA pathogenesis and supporting the PPARγ pathway as a potential therapeutic target. Here we assess whether MIN-102 (INN: leriglitazone), a novel brain penetrant and orally bioavailable PPARγ agonist with an improved profile for central nervous system (CNS) diseases, rescues phenotypic features in cellular and animal models of FRDA. In frataxin-deficient dorsal root ganglia (DRG) neurons, leriglitazone increased frataxin protein levels, reduced neurite degeneration and α-fodrin cleavage mediated by calpain and caspase 3, and increased survival. Leriglitazone also restored mitochondrial membrane potential and partially reversed decreased levels of mitochondrial Na+/Ca2+ exchanger (NCLX), resulting in an improvement of mitochondrial functions and calcium homeostasis. In frataxin-deficient primary neonatal cardiomyocytes, leriglitazone prevented lipid droplet accumulation without increases in frataxin levels. Furthermore, leriglitazone improved motor function deficit in YG8sR mice, a FRDA mouse model. In agreement with the role of PPARγ in mitochondrial biogenesis, leriglitazone significantly increased markers of mitochondrial biogenesis in FRDA patient cells. Overall, these results suggest that targeting the PPARγ pathway by leriglitazone may provide an efficacious therapy for FRDA increasing the mitochondrial function and biogenesis that could increase frataxin levels in compromised frataxin-deficient DRG neurons. Alternately, leriglitazone improved the energy metabolism by increasing the fatty acid β-oxidation in frataxin-deficient cardiomyocytes without elevation of frataxin levels. This could be linked to a lack of significant mitochondrial biogenesis and cardiac hypertrophy. The results reinforced the different tissue requirement in FRDA and the pleiotropic effects of leriglitazone that could be a promising therapy for FRDA.