The generation and cell death of newly generated cells have critical roles in brain development and maintenance in the embryonic and adult brain. Alterations in these processes are also seen in ...neurodegenerative diseases. Genes that are key players in neurodegenerative diseases (α‐synuclein, presenilin‐1, tau, huntingtin) are also physiologically involved in modulating brain plasticity. Interestingly, in some neurodegenerative diseases, the specific alterations in neurogenic areas such as the dentate gyrus and subventricular zone/olfactory bulb system parallel the early or premotor symptoms that are seen in the early stages of these diseases, such as depression, anxiety or olfactory dysfunction. We will review the modulation of neurogenesis in animal models and human brains of Parkinson’s disease, Huntington’s disease and Alzheimer’s disease.
Neuronal degeneration is a common mechanism of many neurological diseases including Parkinson's disease (PD), Alzheimer's disease (AD), and Multiple Sclerosis (MS). While AD and PD are classical ...neurodegenerative diseases, the primary pathology in MS is driven by autoimmune inflammation, attacking oligodendrocytes and thereby inducing neurodegeneration. In AD and PD, immune cells are also considered to play an important role in the disease progression. While the role of local central nervous system (CNS) innate immune cells is well described, a potential influence of adaptive immune cells in PD and AD is not yet fully understood.Here, we aim to summarize findings concerning adaptive immune cells in PD pathogenesis and compare them to AD and MS. In the first part, we focus on disease-specific alterations of lymphocytes in the circulating blood. Subsequently, we describe what is known about CNS-infiltrated lymphocytes and mechanisms of their infiltration. Finally, we summarize published data and try to understand the mechanisms of how lymphocytes contribute to neurodegeneration in PD, AD, and MS.Lymphocytes are critically involved in the pathogenesis of MS, and clarifying the role of lymphocytes in PD and AD pathogenesis might lead to an identification of a common signature of lymphocytes in neurodegeneration and thus pave the road towards novel treatment options.
The gut–brain axis is a bidirectional communication system driven by neural, hormonal, metabolic, immunological, and microbial signals. Signaling events from the gut can modulate brain function and ...recent evidence suggests that the gut–brain axis may play a pivotal role in linking gastrointestinal and neurological diseases. Accordingly, accumulating evidence has suggested a link between inflammatory bowel diseases (IBDs) and neurodegenerative, as well as neuroinflammatory diseases. In this context, clinical, epidemiological and experimental data have demonstrated that IBD predisposes a person to pathologies of the central nervous system (CNS). Likewise, a number of neurological disorders are associated with changes in the intestinal environment, which are indicative for disease-mediated gut–brain inter-organ communication. Although this axis was identified more than 20 years ago, the sequence of events and underlying molecular mechanisms are poorly defined. The emergence of precision medicine has uncovered the need to take into account non-intestinal symptoms in the context of IBD that could offer the opportunity to tailor therapies to individual patients. The aim of this review is to highlight recent findings supporting the clinical and biological link between the gut and brain, as well as its clinical significance for IBD as well as neurodegeneration and neuroinflammation. Finally, we focus on novel human-specific preclinical models that will help uncover disease mechanisms to better understand and modulate the function of this complex system.
Sporadic amyotrophic lateral sclerosis (sALS) is the most common form of ALS, however, the molecular mechanisms underlying cellular damage and motor neuron degeneration remain elusive. To identify ...molecular signatures of sALS we performed genome-wide expression profiling in laser capture microdissection-enriched surviving motor neurons (MNs) from lumbar spinal cords of sALS patients with rostral onset and caudal progression. After correcting for immunological background, we discover a highly specific gene expression signature for sALS that is associated with phosphorylated TDP-43 (pTDP-43) pathology. Transcriptome–pathology correlation identified casein kinase 1ε (
CSNK1E
) mRNA as tightly correlated to levels of pTDP-43 in sALS patients. Enhanced crosslinking and immunoprecipitation in human sALS patient- and healthy control-derived frontal cortex, revealed that TDP-43 binds directly to and regulates the expression of CSNK1E mRNA. Additionally, we were able to show that pTDP-43 itself binds RNA. CK1E, the protein product of
CSNK1E,
in turn interacts with TDP-43 and promotes cytoplasmic accumulation of pTDP-43 in human stem-cell-derived MNs. Pathological TDP-43 phosphorylation is therefore, reciprocally regulated by CK1E activity and TDP-43 RNA binding. Our framework of transcriptome–pathology correlations identifies candidate genes with relevance to novel mechanisms of neurodegeneration.
The aggregation of proteins into oligomers and amyloid fibrils is characteristic of several neurodegenerative diseases, including Parkinson disease (PD). In PD, the process of aggregation of ...α-synuclein (α-syn) from monomers, via oligomeric intermediates, into amyloid fibrils is considered the disease-causative toxic mechanism. We developed α-syn mutants that promote oligomer or fibril formation and tested the toxicity of these mutants by using a rat lentivirus system to investigate loss of dopaminergic neurons in the substantia nigra. The most severe dopaminergic loss in the substantia nigra is observed in animals with the α-syn variants that form oligomers (i.e., E57K and E35K), whereas the α-syn variants that form fibrils very quickly are less toxic. We show that α-syn oligomers are toxic in vivo and that α-syn oligomers might interact with and potentially disrupt membranes.
Hereditary spastic paraplegia (HSP) is a heterogeneous group of rare motor neuron disorders characterized by progressive weakness and spasticity of the lower limbs. HSP type 11 (SPG11-HSP) is linked ...to pathogenic variants in the SPG11 gene and it represents the most frequent form of complex autosomal recessive HSP. The majority of SPG11-HSP patients exhibit additional neurological symptoms such as cognitive decline, thin corpus callosum, and peripheral neuropathy. Yet, the mechanisms of SPG11-linked spectrum diseases are largely unknown. Recent findings indicate that spatacsin, the 280 kDa protein encoded by SPG11, may impact the autophagy-lysosomal machinery. In this update, we summarize the current knowledge of SPG11-HSP. In addition to clinical symptoms and differential diagnosis, our work aims to link the different clinical manifestations with the respective structural abnormalities and cellular in vitro phenotypes. Moreover, we describe the impact of localization and function of spatacsin in different neuronal systems. Ultimately, we propose a model in which spatacsin bridges between neurodevelopmental and neurodegenerative phenotypes of SPG11-linked disorders.
Inflammatory bowel disease (IBD) comprises Crohn’s disease (CD) and ulcerative colitis (UC) and is associated with neuropsychiatric symptoms like anxiety and depression. Both conditions strongly ...worsen IBD disease burden. In the present review, we summarize the current understanding of the pathogenesis of depression and anxiety in IBD. We present a stepwise cascade along a gut–immune–brain axis initiated by evasion of chronic intestinal inflammation to pass the epithelial and vascular barrier in the gut and cause systemic inflammation. We then summarize different anatomical transmission routes of gut-derived peripheral inflammation into the central nervous system (CNS) and highlight the current knowledge on neuroinflammatory changes in the CNS of preclinical IBD mouse models with a focus on microglia, the brain-resident macrophages. Subsequently, we discuss how neuroinflammation in IBD can alter neuronal circuitry to trigger symptoms like depression and anxiety. Finally, the role of intestinal microbiota in the gut–immune–brain axis in IBD will be reviewed. A more comprehensive understanding of the interaction between the gastrointestinal tract, the immune system and the CNS accounting for the similarities and differences between UC and CD will pave the path for improved prediction and treatment of neuropsychiatric comorbidities in IBD and other inflammatory diseases.
Contacts between endosomes and the endoplasmic reticulum (ER) promote endosomal tubule fission, but the mechanisms involved and consequences of tubule fission failure are incompletely understood. We ...found that interaction between the microtubule-severing enzyme spastin and the ESCRT protein IST1 at ER-endosome contacts drives endosomal tubule fission. Failure of fission caused defective sorting of mannose 6-phosphate receptor, with consequently disrupted lysosomal enzyme trafficking and abnormal lysosomal morphology, including in mouse primary neurons and human stem cell-derived neurons. Consistent with a role for ER-mediated endosomal tubule fission in lysosome function, similar lysosomal abnormalities were seen in cellular models lacking the WASH complex component strumpellin or the ER morphogen REEP1. Mutations in
,
, or
cause hereditary spastic paraplegia (HSP), a disease characterized by axonal degeneration. Our results implicate failure of the ER-endosome contact process in axonopathy and suggest that coupling of ER-mediated endosomal tubule fission to lysosome function links different classes of HSP proteins, previously considered functionally distinct, into a unifying pathway for axonal degeneration.
Nurr1, an orphan nuclear receptor, plays an essential role in the generation and maintenance of dopaminergic neurons in the brain. Rare mutations in
Nurr1 are associated with familial Parkinson's ...disease, but the underlying basis for this relationship has not been established. Here, we demonstrate that Nurr1 unexpectedly functions to inhibit expression of pro-inflammatory neurotoxic mediators in both microglia and astrocytes. Reduced Nurr1 expression results in exaggerated inflammatory responses in microglia that are further amplified by astrocytes, leading to the production of factors that cause death of tyrosine hydroxylase-expressing neurons. Nurr1 exerts anti-inflammatory effects by docking to NF-κB-p65 on target inflammatory gene promoters in a signal-dependent manner. Subsequently, Nurr1 recruits the CoREST corepressor complex, resulting in clearance of NF-κB-p65 and transcriptional repression. These studies suggest that Nurr1 protects against loss of dopaminergic neurons in Parkinson's disease in part by limiting the production of neurotoxic mediators by microglia and astrocytes.
Autophagy is a conserved catabolic pathway with emerging functions in mammalian neurodevelopment and human neurodevelopmental diseases. The mechanisms controlling autophagy in neuronal development ...are not fully understood. Here, we found that conditional deletion of the Forkhead Box O transcription factors FoxO1, FoxO3, and FoxO4 strongly impaired autophagic flux in developing neurons of the adult mouse hippocampus. Moreover, FoxO deficiency led to altered dendritic morphology, increased spine density, and aberrant spine positioning in adult-generated neurons. Strikingly, pharmacological induction of autophagy was sufficient to correct abnormal dendrite and spine development of FoxO-deficient neurons. Collectively, these findings reveal a novel link between FoxO transcription factors, autophagic flux, and maturation of developing neurons.
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•FoxOs control morphology and spine density of adult-born hippocampal neurons•Autophagic flux is severely impaired in FoxO-deficient, adult-born neurons•Induction of autophagy rescues dendrite and spine deficits of FoxO-ablated neurons
Schäffner et al. identify FoxO transcription factors as critical regulators of autophagic flux in adult hippocampal neurogenesis and show that FoxO-dependent autophagic flux is necessary for morphological maturation and synaptic integration of adult-born hippocampal neurons.
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