Showing papers on "Neurodegeneration published in 2021"

Neurotoxic reactive astrocytes induce cell death via saturated lipids

Abstract: Astrocytes regulate the response of the central nervous system to disease and injury and have been hypothesized to actively kill neurons in neurodegenerative disease1–6. Here we report an approach to isolate one component of the long-sought astrocyte-derived toxic factor5,6. Notably, instead of a protein, saturated lipids contained in APOE and APOJ lipoparticles mediate astrocyte-induced toxicity. Eliminating the formation of long-chain saturated lipids by astrocyte-specific knockout of the saturated lipid synthesis enzyme ELOVL1 mitigates astrocyte-mediated toxicity in vitro as well as in a model of acute axonal injury in vivo. These results suggest a mechanism by which astrocytes kill cells in the central nervous system. Astrocytes can respond to diseases and injuries of the central nervous system by driving the death of neurons and mature oligodendrocytes through the delivery of long-chain saturated fatty acids contained in lipoparticles.

A lymphocyte-microglia-astrocyte axis in chronic active multiple sclerosis.

Abstract: Multiple sclerosis (MS) lesions that do not resolve in the months after they form harbour ongoing demyelination and axon degeneration, and are identifiable in vivo by their paramagnetic rims on MRI scans1-3. Here, to define mechanisms underlying this disabling, progressive neurodegenerative state4-6 and foster development of new therapeutic agents, we used MRI-informed single-nucleus RNA sequencing to profile the edge of demyelinated white matter lesions at various stages of inflammation. We uncovered notable glial and immune cell diversity, especially at the chronically inflamed lesion edge. We define 'microglia inflamed in MS' (MIMS) and 'astrocytes inflamed in MS', glial phenotypes that demonstrate neurodegenerative programming. The MIMS transcriptional profile overlaps with that of microglia in other neurodegenerative diseases, suggesting that primary and secondary neurodegeneration share common mechanisms and could benefit from similar therapeutic approaches. We identify complement component 1q (C1q) as a critical mediator of MIMS activation, validated immunohistochemically in MS tissue, genetically by microglia-specific C1q ablation in mice with experimental autoimmune encephalomyelitis, and therapeutically by treating chronic experimental autoimmune encephalomyelitis with C1q blockade. C1q inhibition is a potential therapeutic avenue to address chronic white matter inflammation, which could be monitored by longitudinal assessment of its dynamic biomarker, paramagnetic rim lesions, using advanced MRI methods.

TDP-43 proteinopathies: a new wave of neurodegenerative diseases.

Abstract: Inclusions of pathogenic deposits containing TAR DNA-binding protein 43 (TDP-43) are evident in the brain and spinal cord of patients that present across a spectrum of neurodegenerative diseases. For instance, the majority of patients with sporadic amyotrophic lateral sclerosis (up to 97%) and a substantial proportion of patients with frontotemporal lobar degeneration (~45%) exhibit TDP-43 positive neuronal inclusions, suggesting a role for this protein in disease pathogenesis. In addition, TDP-43 inclusions are evident in familial ALS phenotypes linked to multiple gene mutations including the TDP-43 gene coding (TARDBP) and unrelated genes (eg, C9orf72). While TDP-43 is an essential RNA/DNA binding protein critical for RNA-related metabolism, determining the pathophysiological mechanisms through which TDP-43 mediates neurodegeneration appears complex, and unravelling these molecular processes seems critical for the development of effective therapies. This review highlights the key physiological functions of the TDP-43 protein, while considering an expanding spectrum of neurodegenerative diseases associated with pathogenic TDP-43 deposition, and dissecting key molecular pathways through which TDP-43 may mediate neurodegeneration.

Ubiquitin signalling in neurodegeneration: mechanisms and therapeutic opportunities.

Abstract: Neurodegenerative diseases are characterised by progressive damage to the nervous system including the selective loss of vulnerable populations of neurons leading to motor symptoms and cognitive decline. Despite millions of people being affected worldwide, there are still no drugs that block the neurodegenerative process to stop or slow disease progression. Neuronal death in these diseases is often linked to the misfolded proteins that aggregate within the brain (proteinopathies) as a result of disease-related gene mutations or abnormal protein homoeostasis. There are two major degradation pathways to rid a cell of unwanted or misfolded proteins to prevent their accumulation and to maintain the health of a cell: the ubiquitin-proteasome system and the autophagy-lysosomal pathway. Both of these degradative pathways depend on the modification of targets with ubiquitin. Aging is the primary risk factor of most neurodegenerative diseases including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. With aging there is a general reduction in proteasomal degradation and autophagy, and a consequent increase of potentially neurotoxic protein aggregates of β-amyloid, tau, α-synuclein, SOD1 and TDP-43. An often over-looked yet major component of these aggregates is ubiquitin, implicating these protein aggregates as either an adaptive response to toxic misfolded proteins or as evidence of dysregulated ubiquitin-mediated degradation driving toxic aggregation. In addition, non-degradative ubiquitin signalling is critical for homoeostatic mechanisms fundamental for neuronal function and survival, including mitochondrial homoeostasis, receptor trafficking and DNA damage responses, whilst also playing a role in inflammatory processes. This review will discuss the current understanding of the role of ubiquitin-dependent processes in the progressive loss of neurons and the emergence of ubiquitin signalling as a target for the development of much needed new drugs to treat neurodegenerative disease.

Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol.

Abstract: Alzheimer’s disease (AD) is characterized by the presence of amyloid β (Aβ) plaques, tau tangles, inflammation, and loss of cognitive function. Genetic variation in a cholesterol transport protein, apolipoprotein E (apoE), is the most common genetic risk factor for sporadic AD. In vitro evidence suggests that apoE links to Aβ production through nanoscale lipid compartments (lipid clusters), but its regulation in vivo is unclear. Here, we use superresolution imaging in the mouse brain to show that apoE utilizes astrocyte-derived cholesterol to specifically traffic neuronal amyloid precursor protein (APP) in and out of lipid clusters, where it interacts with β- and γ-secretases to generate Aβ-peptide. We find that the targeted deletion of astrocyte cholesterol synthesis robustly reduces amyloid and tau burden in a mouse model of AD. Treatment with cholesterol-free apoE or knockdown of cholesterol synthesis in astrocytes decreases cholesterol levels in cultured neurons and causes APP to traffic out of lipid clusters, where it interacts with α-secretase and gives rise to soluble APP-α (sAPP-α), a neuronal protective product of APP. Changes in cellular cholesterol have no effect on α-, β-, and γ-secretase trafficking, suggesting that the ratio of Aβ to sAPP-α is regulated by the trafficking of the substrate, not the enzymes. We conclude that cholesterol is kept low in neurons, which inhibits Aβ accumulation and enables the astrocyte regulation of Aβ accumulation by cholesterol signaling.

Microglial gene signature reveals loss of homeostatic microglia associated with neurodegeneration of Alzheimer's disease.

Abstract: Microglia-mediated neuroinflammation has been implicated in the pathogenesis of Alzheimer’s disease (AD). Although microglia in aging and neurodegenerative disease model mice show a loss of homeostatic phenotype and activation of disease-associated microglia (DAM), a correlation between those phenotypes and the degree of neuronal cell loss has not been clarified. In this study, we performed RNA sequencing of microglia isolated from three representative neurodegenerative mouse models, AppNL-G-F/NL-G-F with amyloid pathology, rTg4510 with tauopathy, and SOD1G93A with motor neuron disease by magnetic activated cell sorting. In parallel, gene expression patterns of the human precuneus with early Alzheimer’s change (n = 11) and control brain (n = 14) were also analyzed by RNA sequencing. We found that a substantial reduction of homeostatic microglial genes in rTg4510 and SOD1G93A microglia, whereas DAM genes were uniformly upregulated in all mouse models. The reduction of homeostatic microglial genes was correlated with the degree of neuronal cell loss. In human precuneus with early AD pathology, reduced expression of genes related to microglia- and oligodendrocyte-specific markers was observed, although the expression of DAM genes was not upregulated. Our results implicate a loss of homeostatic microglial function in the progression of AD and other neurodegenerative diseases. Moreover, analyses of human precuneus also suggest loss of microglia and oligodendrocyte functions induced by early amyloid pathology in human.

Astrocytic interleukin-3 programs microglia and limits Alzheimer’s disease

Abstract: Communication within the glial cell ecosystem is essential for neuronal and brain health1–3. The influence of glial cells on the accumulation and clearance of β-amyloid (Aβ) and neurofibrillary tau in the brains of individuals with Alzheimer’s disease (AD) is poorly understood, despite growing awareness that these are therapeutically important interactions4,5. Here we show, in humans and mice, that astrocyte-sourced interleukin-3 (IL-3) programs microglia to ameliorate the pathology of AD. Upon recognition of Aβ deposits, microglia increase their expression of IL-3Rα—the specific receptor for IL-3 (also known as CD123)—making them responsive to IL-3. Astrocytes constitutively produce IL-3, which elicits transcriptional, morphological, and functional programming of microglia to endow them with an acute immune response program, enhanced motility, and the capacity to cluster and clear aggregates of Aβ and tau. These changes restrict AD pathology and cognitive decline. Our findings identify IL-3 as a key mediator of astrocyte–microglia cross-talk and a node for therapeutic intervention in AD. Interleukin-3 signalling from astrocytes to microglia readies microglia to defend against Alzheimer’s disease.

Mitochondria and lipid peroxidation in the mechanism of neurodegeneration: Finding ways for prevention.

Abstract: The world's population aging progression renders age-related neurodegenerative diseases to be one of the biggest unsolved problems of modern society. Despite the progress in studying the development of pathology, finding ways for modifying neurodegenerative disorders remains a high priority. One common feature of neurodegenerative diseases is mitochondrial dysfunction and overproduction of reactive oxygen species, resulting in oxidative stress. Although lipid peroxidation is one of the markers for oxidative stress, it also plays an important role in cell physiology, including activation of phospholipases and stimulation of signaling cascades. Excessive lipid peroxidation is a hallmark for most neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and many other neurological conditions. The products of lipid peroxidation have been shown to be the trigger for necrotic, apoptotic, and more specifically for oxidative stress-related, that is, ferroptosis and neuronal cell death. Here we discuss the involvement of lipid peroxidation in the mechanism of neuronal loss and some novel therapeutic directions to oppose it.

Phospholipase iPLA2β Averts Ferroptosis By Eliminating A Redox Lipid Death Signal

Abstract: Ferroptosis, triggered by discoordination of iron, thiols and lipids, leads to the accumulation of 15-hydroperoxy (Hp)-arachidonoyl-phosphatidylethanolamine (15-HpETE-PE), generated by complexes of 15-lipoxygenase (15-LOX) and a scaffold protein, phosphatidylethanolamine (PE)-binding protein (PEBP)1 As the Ca2+-independent phospholipase A2β (iPLA2β, PLA2G6 or PNPLA9 gene) can preferentially hydrolyze peroxidized phospholipids, it may eliminate the ferroptotic 15-HpETE-PE death signal Here, we demonstrate that by hydrolyzing 15-HpETE-PE, iPLA2β averts ferroptosis, whereas its genetic or pharmacological inactivation sensitizes cells to ferroptosis Given that PLA2G6 mutations relate to neurodegeneration, we examined fibroblasts from a patient with a Parkinson's disease (PD)-associated mutation (fPDR747W) and found selectively decreased 15-HpETE-PE-hydrolyzing activity, 15-HpETE-PE accumulation and elevated sensitivity to ferroptosis CRISPR-Cas9-engineered Pnpla9R748W/R748W mice exhibited progressive parkinsonian motor deficits and 15-HpETE-PE accumulation Elevated 15-HpETE-PE levels were also detected in midbrains of rotenone-infused parkinsonian rats and α-synuclein-mutant SncaA53T mice, with decreased iPLA2β expression and a PD-relevant phenotype Thus, iPLA2β is a new ferroptosis regulator, and its mutations may be implicated in PD pathogenesis

NAD+ supplementation reduces neuroinflammation and cell senescence in a transgenic mouse model of Alzheimer's disease via cGAS-STING.

Abstract: Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disorder. Impaired neuronal bioenergetics and neuroinflammation are thought to play key roles in the progression of AD, but their interplay is not clear. Nicotinamide adenine dinucleotide (NAD+) is an important metabolite in all human cells in which it is pivotal for multiple processes including DNA repair and mitophagy, both of which are impaired in AD neurons. Here, we report that levels of NAD+ are reduced and markers of inflammation increased in the brains of APP/PS1 mutant transgenic mice with beta-amyloid pathology. Treatment of APP/PS1 mutant mice with the NAD+ precursor nicotinamide riboside (NR) for 5 mo increased brain NAD+ levels, reduced expression of proinflammatory cytokines, and decreased activation of microglia and astrocytes. NR treatment also reduced NLRP3 inflammasome expression, DNA damage, apoptosis, and cellular senescence in the AD mouse brains. Activation of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) are associated with DNA damage and senescence. cGAS-STING elevation was observed in the AD mice and normalized by NR treatment. Cell culture experiments using microglia suggested that the beneficial effects of NR are, in part, through a cGAS-STING-dependent pathway. Levels of ectopic (cytoplasmic) DNA were increased in APP/PS1 mutant mice and human AD fibroblasts and down-regulated by NR. NR treatment induced mitophagy and improved cognitive and synaptic functions in APP/PS1 mutant mice. Our findings suggest a role for NAD+ depletion-mediated activation of cGAS-STING in neuroinflammation and cellular senescence in AD.

Targeting Mitochondrial Biogenesis with Polyphenol Compounds

Abstract: Appropriate mitochondrial physiology is an essential for health and survival. Cells have developed unique mechanisms to adapt to stress circumstances and changes in metabolic demands, by meditating mitochondrial function and number. In this context, sufficient mitochondrial biogenesis is necessary for efficient cell function and haemostasis, which is dependent on the regulation of ATP generation and maintenance of mitochondrial DNA (mtDNA). These procedures play a primary role in the processes of inflammation, aging, cancer, metabolic diseases, and neurodegeneration. Polyphenols have been considered as the main components of plants, fruits, and natural extracts with proven therapeutic effects during the time. These components regulate the intracellular pathways of mitochondrial biogenesis. Therefore, the current review is aimed at representing an updated review which determines the effects of different natural polyphenol compounds from various plant kingdoms on modulating signaling pathways of mitochondrial biogenesis that could be a promising alternative for the treatment of several disorders.

Microglia in Alzheimer's disease at single-cell level. Are there common patterns in humans and mice?

Abstract: Alzheimer's disease (AD) is characterized by extracellular aggregates of amyloid β peptides, intraneuronal tau aggregates, and neuronal death. This pathology triggers activation of microglia. Because variants of genes expressed in microglia correlate with AD risk, microglial response to pathology plausibly impacts disease course. In mouse AD models, single-cell RNA sequencing (scRNA-seq) analyses delineated this response as progressive conversion of homeostatic microglia into disease-associated microglia (DAM); additional reactive microglial populations have been reported in other models of neurodegeneration and neuroinflammation. We review all of these microglial signatures, highlighting four fundamental patterns: DAM, IFN-microglia, MHC-II microglia, and proliferating microglia. We propose that all reported microglia populations are either just one or a combination, depending on the clustering strategy applied and the disease model. We further review single-nucleus RNA sequencing (snRNA-seq) data from human AD specimens and discuss reasons for parallels and discrepancies between human and mouse transcriptional profiles. Finally, we outline future directions for delineating the microglial impact in AD pathogenesis.

Microglia in Neuroinflammation and Neurodegeneration: From Understanding to Therapy

Abstract: Microglia are the resident macrophages of the central nervous system (CNS) acting as the first line of defense in the brain by phagocytosing harmful pathogens and cellular debris. Microglia emerge from early erythromyeloid progenitors of the yolk sac and enter the developing brain before the establishment of a fully mature blood-brain barrier. In physiological conditions, during brain development, microglia contribute to CNS homeostasis by supporting cell proliferation of neural precursors. In post-natal life, such cells contribute to preserving the integrity of neuronal circuits by sculpting synapses. After a CNS injury, microglia change their morphology and down-regulate those genes supporting homeostatic functions. However, it is still unclear whether such changes are accompanied by molecular and functional modifications that might contribute to the pathological process. While comprehensive transcriptome analyses at the single-cell level have identified specific gene perturbations occurring in the "pathological" microglia, still the precise protective/detrimental role of microglia in neurological disorders is far from being fully elucidated. In this review, the results so far obtained regarding the role of microglia in neurodegenerative disorders will be discussed. There is solid and sound evidence suggesting that regulating microglia functions during disease pathology might represent a strategy to develop future therapies aimed at counteracting brain degeneration in multiple sclerosis, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.

Hydrogen sulfide is neuroprotective in Alzheimer's disease by sulfhydrating GSK3β and inhibiting Tau hyperphosphorylation.

Abstract: Alzheimer’s disease (AD), the most common cause of dementia and neurodegeneration in the elderly, is characterized by deterioration of memory and executive and motor functions. Neuropathologic hallmarks of AD include neurofibrillary tangles (NFTs), paired helical filaments, and amyloid plaques. Mutations in the microtubule-associated protein Tau, a major component of the NFTs, cause its hyperphosphorylation in AD. We have shown that signaling by the gaseous molecule hydrogen sulfide (H2S) is dysregulated during aging. H2S signals via a posttranslational modification termed sulfhydration/persulfidation, which participates in diverse cellular processes. Here we show that cystathionine γ-lyase (CSE), the biosynthetic enzyme for H2S, binds wild type Tau, which enhances its catalytic activity. By contrast, CSE fails to bind Tau P301L, a mutant that is present in the 3xTg-AD mouse model of AD. We further show that CSE is depleted in 3xTg-AD mice as well as in human AD brains, and that H2S prevents hyperphosphorylation of Tau by sulfhydrating its kinase, glycogen synthase kinase 3β (GSK3β). Finally, we demonstrate that sulfhydration is diminished in AD, while administering the H2S donor sodium GYY4137 (NaGYY) to 3xTg-AD mice ameliorates motor and cognitive deficits in AD.

Glutathione in the Brain.

Abstract: Glutathione (GSH) is the most abundant non-protein thiol, and plays crucial roles in the antioxidant defense system and the maintenance of redox homeostasis in neurons. GSH depletion in the brain is a common finding in patients with neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, and can cause neurodegeneration prior to disease onset. Excitatory amino acid carrier 1 (EAAC1), a sodium-dependent glutamate/cysteine transporter that is selectively present in neurons, plays a central role in the regulation of neuronal GSH production. The expression of EAAC1 is posttranslationally controlled by the glutamate transporter-associated protein 3–18 (GTRAP3-18) or miR-96-5p in neurons. The regulatory mechanism of neuronal GSH production mediated by EAAC1 may be a new target in therapeutic strategies for these neurodegenerative diseases. This review describes the regulatory mechanism of neuronal GSH production and its potential therapeutic application in the treatment of neurodegenerative diseases.

CD4 T cells mediate brain inflammation and neurodegeneration in a mouse model of Parkinson's disease.

Abstract: α-Synuclein, a key pathological component of Parkinson's disease, has been implicated in the activation of the innate and adaptive immune system. This immune activation includes microgliosis, increased inflammatory cytokines, and the infiltration of T cells into the CNS. More recently, peripherally circulating CD4 and CD8 T cells derived from individuals with Parkinson's disease have been shown to produce Th1/Th2 cytokines in response to α-synuclein, suggesting there may be a chronic memory T cell response present in Parkinson's disease. To understand the potential effects of these α-syn associated T cell responses we used an α-synuclein overexpression mouse model, T cell-deficient mice, and a combination of immunohistochemistry and flow cytometry. In this study, we found that α-synuclein overexpression in the midbrain of mice leads to the upregulation of the major histocompatibility complex II (MHCII) protein on CNS myeloid cells as well as the infiltration of IFNγ producing CD4 and CD8 T cells into the CNS. Interestingly, genetic deletion of TCRβ or CD4, as well as the use of the immunosuppressive drug fingolimod, were able to reduce the CNS myeloid MHCII response to α-synuclein. Furthermore, we observed that CD4-deficient mice were protected from the dopaminergic cell loss observed due to α-syn overexpression. These results suggest that T cell responses associated with α-synuclein pathology may be damaging to key areas of the CNS in Parkinson's disease and that targeting these T cell responses could be an avenue for disease modifying treatments.

Neuroprotective effects of flavone luteolin in neuroinflammation and neurotrauma.

Abstract: Neuroinflammation leads to neurodegeneration, cognitive defects, and neurodegenerative disorders. Neurotrauma/traumatic brain injury (TBI) can cause activation of glial cells, neurons, and neuroimmune cells in the brain to release neuroinflammatory mediators. Neurotrauma leads to immediate primary brain damage (direct damage), neuroinflammatory responses, neuroinflammation, and late secondary brain damage (indirect) through neuroinflammatory mechanism. Secondary brain damage leads to chronic inflammation and the onset and progression of neurodegenerative diseases. Currently, there are no effective and specific therapeutic options to treat these brain damages or neurodegenerative diseases. Flavone luteolin is an important natural polyphenol present in several plants that show anti-inflammatory, antioxidant, anticancer, cytoprotective, and macrophage polarization effects. In this short review article, we have reviewed the neuroprotective effects of luteolin in neurotrauma and neurodegenerative disorders and pathways involved in this mechanism. We have collected data for this study from publications in the PubMed using the keywords luteolin and mast cells, neuroinflammation, neurodegenerative diseases, and TBI. Recent reports suggest that luteolin suppresses systemic and neuroinflammatory responses in Coronavirus disease 2019 (COVID-19). Studies have shown that luteolin exhibits neuroprotective effects through various mechanisms, including suppressing immune cell activation, such as mast cells, and inflammatory mediators released from these cells. In addition, luteolin can suppress neuroinflammatory response, activation of microglia and astrocytes, oxidative stress, neuroinflammation, and the severity of neuroinflammatory diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and TBI pathogenesis. In conclusion, luteolin can improve cognitive decline and enhance neuroprotection in neurodegenerative diseases, TBI, and stroke.

Andrographolide suppresses NLRP3 inflammasome activation in microglia through induction of Parkin-mediated Mitophagy in in-vitro and in-vivo models of Parkinson disease

Abstract: Cellular communication linking microglia activation and dopaminergic neuronal loss play an imperative role in the progression of Parkinson’s disease (PD); however, underlying molecular mechanisms are not precise and require further elucidation. NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome activation is extensively studied in context to microglial activation and progressive dopaminergic neuronal loss in PD. Several pathophysiological factors such as oxidative stress, mitochondrial dysfunction impaired mitophagy plays a crucial role in activating NLRP3 inflammasome complex. Hence, regulation of microglial activation through mitophagy could be a valuable strategy in controlling microglia mediated neurodegeneration. In this study we have developed a model of inflammasome activation by combining LPS with a mitochondrial complex-I inhibitor MPP+. The idea of using MPP+ after priming mouse microglia with LPS was to disrupt mitochondria and release reactive oxygen species, which act as Signal 2 in augmenting NLRP3 assembly, thereby releasing potent inflammatory mediators such as active interleukin-1 beta (IL-1β) and IL-18. LPS-MPP+ combination was seen to impaired the mitophagy by inhibiting the initial step of autophagosome formation as evidenced by protein expression and confocal imaging data. Treatment with Andrographolide promoted the parkin-dependent autophagic flux formation in microglia; resulting in the removal of defective mitochondria which in turn inhibit NLRP3 inflammasome activation. Additionally, the neuroprotective role of Andrographolide in inhibiting NLRP3 activation together with salvage ATP level via promoting parkin-dependent mitophagy was seen in the substantial nigra par compacta (SNpc) region of mice brain. Furthermore, Andrographolide rescued the dopaminergic neuron loss and improved the behavioural parameters in animal model. Collectively, our results reveal the role of mitophagy in the regulation of NLRP3 inflammasome by removing defective mitochondria. In addition, andrographolide was seen to abate NLRP3 inflammasome activation in microglia and rescue dopaminergic neuron loss.

Mitochondria and Parkinson's Disease: Clinical, Molecular, and Translational Aspects.

Abstract: Mitochondrial dysfunction represents a well-established player in the pathogenesis of both monogenic and idiopathic Parkinson's disease (PD). Initially originating from the observation that mitochondrial toxins cause PD, findings from genetic PD supported a contribution of mitochondrial dysfunction to the disease. Here, proteins encoded by the autosomal recessively inherited PD genes Parkin, PTEN-induced kinase 1 (PINK1), and DJ-1 are involved in mitochondrial pathways. Additional evidence for mitochondrial dysfunction stems from models of autosomal-dominant PD due to mutations in alpha-synuclein (SNCA) and leucine-rich repeat kinase 2 (LRRK2). Moreover, patients harboring alterations in mitochondrial polymerase gamma (POLG) often exhibit signs of parkinsonism. While some molecular studies suggest that mitochondrial dysfunction is a primary event in PD, others speculate that it is the result of impaired mitochondrial clearance. Most recent research even implicated damage-associated molecular patterns released from non-degraded mitochondria in neuroinflammatory processes in PD. Here, we summarize the manifold literature dealing with mitochondria in the context of PD. Moreover, in light of recent advances in the field of personalized medicine, patient stratification according to the degree of mitochondrial impairment followed by mitochondrial enhancement therapy may hold potential for at least a subset of genetic and idiopathic PD cases. Thus, in the second part of this review, we discuss therapeutic approaches targeting mitochondrial dysfunction with the aim to prevent or delay neurodegeneration in PD.

Triad of TDP43 control in neurodegeneration: autoregulation, localization and aggregation.

Abstract: Cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP43; also known as TARDBP or TDP-43) is a key pathological feature of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP43 typically resides in the nucleus but can shuttle between the nucleus and the cytoplasm to exert its multiple functions, which include regulation of the splicing, trafficking and stabilization of RNA. Cytoplasmic mislocalization and nuclear loss of TDP43 have both been associated with ALS and FTD, suggesting that calibrated levels and correct localization of TDP43 — achieved through an autoregulatory loop and tightly controlled nucleocytoplasmic transport — safeguard its normal function. Furthermore, TDP43 can undergo phase transitions, including its dispersion into liquid droplets and its accumulation into irreversible cytoplasmic aggregates. Thus, autoregulation, nucleocytoplasmic transport and phase transition are all part of an intrinsic control system regulating the physiological levels and localization of TDP43, and together are essential for the cellular homeostasis that is affected in neurodegenerative disease. Accumulation of TAR DNA-binding protein 43 (TDP43) in the neuronal cytoplasm and its loss from the nucleus are characteristic features of several neurodegenerative diseases. Tziortzouda, Van Den Bosch and Hirth describe three intrinsic mechanisms that control TDP43 levels and localization and are altered to drive pathology.

Cardiolipin, Mitochondria, and Neurological Disease

Abstract: Over the past decade, it has become clear that lipid homeostasis is central to cellular metabolism. Lipids are particularly abundant in the central nervous system (CNS) where they modulate membrane fluidity, electric signal transduction, and synaptic stabilization. Abnormal lipid profiles reported in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and traumatic brain injury (TBI), are further support for the importance of lipid metablism in the nervous system. Cardiolipin (CL), a mitochondria-exclusive phospholipid, has recently emerged as a focus of neurodegenerative disease research. Aberrant CL content, structure, and localization are linked to impaired neurogenesis and neuronal dysfunction, contributing to aging and the pathogenesis of several neurodegenerative diseases, such as AD and PD. Furthermore, the highly tissue-specific acyl chain composition of CL confers it significant potential as a biomarker to diagnose and monitor the progression in several neurological diseases. CL also represents a potential target for pharmacological strategies aimed at treating neurodegeneration. Given the equipoise that currently exists between CL metabolism, mitochondrial function, and neurological disease, we review the role of CL in nervous system physiology and monogenic and neurodegenerative disease pathophysiology, in addition to its potential application as a biomarker and pharmacological target.