Dysfunction of constitutive and inducible ubiquitin-proteasome system in amyotrophic lateral sclerosis: implication for protein aggregation and immune response

The ubiquitin-proteasome system (UPS) is the major intracellular proteolytic mechanism controlling the degradation of misfolded/abnormal proteins. A common hallmark in amyotrophic lateral sclerosis (ALS) and in other neurodegenerative disorders is the accumulation of misfolded/abnormal proteins into the damaged neurons, leading to the formation of cellular inclusions that are mostly ubiquitin-positive. Although proteolysis is a complex mechanism requiring the participation of different pathways, the abundant accumulation of ubiquitinated proteins strongly suggests an important contribution of UPS to these neuropathological features. The use of cellular and animal models of ALS, particularly those expressing mutant SOD1, the gene mutation most represented in familiar ALS, has provided significant evidence for a role of UPS in protein inclusions formation and motor neuron death. This review will specifically discuss this piece of evidence and provide suggestions of potential strategies for therapeutic intervention. We will also discuss the finding that, unlike the constitutive proteasome subunits, the inducible subunits are overexpressed early during disease progression in SOD1 mice models of ALS. These subunits form the immunoproteasome and generate peptides for the major histocompatibility complex class I molecules, suggesting a role of this system in the immune responses associated with the pathological features of ALS. Since recent discoveries indicate that innate and adaptive immunity may influence the disease process, in this review we will also provide evidence of a possible connection between immune-inflammatory reactions and UPS function, in the attempt to better understand the etiopathology of ALS and to identify appropriate targets for novel treatment strategies of this devastating disease.     

The recycling endosome and its role in neurological disorders

The recycling endosome (RE) is an organelle in the endocytic pathway where plasma membranes (proteins and lipids) internalized by endocytosis are processed back to the cell surface for reuse. Endocytic recycling is the primary way for the cell to maintain constituents of the plasma membrane (Griffiths et al., 1989), i.e., to maintain the abundance of receptors and transporters on cell surfaces. Membrane traffic through the RE is crucial for several key cellular processes including cytokinesis and cell migration. In polarized cells, including neurons, the RE is vital for the generation and maintenance of the polarity of the plasma membrane. Many RE dependent cargo molecules are known to be important for neuronal function and there is evidence that improper function of key proteins in RE-associated pathways may contribute to the pathogenesis of neurological disorders, including Huntington's disease. The function of the RE in neurons is poorly understood. Therefore, there is need to understand how membrane dynamics in RE-associated pathways are affected or participate in the development or progression of neurological diseases. This review summarizes advances in understanding endocytic recycling associated with the RE, challenges in elucidating molecular mechanisms underlying RE function, and evidence for RE dysfunction in neurological disorders.     

Heat shock proteins: Cellular and molecular mechanisms in the central nervous system

Emerging evidence indicates that heat shock proteins (HSPs) are critical regulators in normal neural physiological function as well as in cell stress responses. The functions of HSPs represent an enormous and diverse range of cellular activities, far beyond the originally identified roles in protein folding and chaperoning. HSPs are now understood to be involved in processes such as synaptic transmission, autophagy, ER stress response, protein kinase and cell death signaling. In addition, manipulation of HSPs has robust effects on the fate of cells in neurological injury and disease states. The ongoing exploration of multiple HSP superfamilies has underscored the pluripotent nature of HSPs in the cellular context, and has demanded the recent revamping of the nomenclature referring to these families to reflect a re-organization based on structure and function. In keeping with this re-organization, we first discuss the HSP superfamilies in terms of protein structure, regulation, expression and distribution in the brain. We then explore major cellular functions of HSPs that are relevant to neural physiological states, and from there we discuss known and proposed HSP impacts on major neurological disease states. This review article presents a three-part discussion on the array of HSP families relevant to neuronal tissue, their cellular functions, and the exploration of therapeutic targets of these proteins in the context of neurological diseases.     

Semaphorins in development and adult brain: Implication for neurological diseases

As a group, Semaphorins are expressed in most tissues and this distribution varies considerably with age. Semaphorins are dynamically expressed during embryonic development and their expression is often associated with growing axons. This expression decreases with maturity and several observations support the idea that in adult brain the expression of secreted Semaphorins is sensitive to electrical activity and experience. The functional role of Semaphorins in guiding axonal projections is well established and more recent evidence points to additional roles in the development, function and reorganization of synaptic complexes. Semaphorins exert the majority of their effects by binding to cognate receptor proteins through their extracellular domains. A common theme is that Semaphorin-triggered signalling induces the rearrangement of the actin and microtubule cytoskeleton. Mutations in Semaphorin genes are linked to several human diseases associated with neurological changes, but their actual influence in the pathogenesis of these diseases remains to be demonstrated. In addition, Semaphorins and their receptors are likely to mediate cross-talk between neurons and other cell types, including in pathological situations where their influence can be damaging or favourable depending on the context. We discuss how the manipulation of Semaphorin function might be crucial for future clinical studies.     

Brain excitability and connectivity of neuronal assemblies in Alzheimer's disease: From animal models to human findings

The human brain contains about 100 billion neurons forming an intricate network of innumerable connections, which continuously adapt and rewire themselves following inputs from external and internal environments as well as the physiological synaptic, dendritic and axonal sculpture during brain maturation and throughout the life span.     

Presenilin mouse and zebrafish models for dementia: focus on neurogenesis

Autosomal dominant mutations in the presenilin gene PSEN cause familial Alzheimer's disease (AD), a neurological disorder pathologically characterized by intraneuronal accumulation and extracellular deposition of amyloid-β in plaques and intraneuronal, hyperphosphorylated tau aggregation in neurofibrillary tangles. Presenilins (PS/PSENs) are part of the proteolytic γ-secretase complex, which cleaves substrate proteins within the membrane. Cleavage of the amyloid precursor protein (APP) by γ-secretase releases amyloid-β peptides. Besides its role in the processing of APP and other transmembrane proteins, presenilin plays an important role in neural progenitor cell maintenance and neurogenesis. In this review, we discuss the role of presenilin in relation to neurogenesis and neurodegeneration and review the currently available presenilin animal models. In addition to established mouse models, zebrafish are emerging as an attractive vertebrate model organism to study the role of presenilin during the development of the nervous system and in neurodegenerative disorders involving presenilin. Zebrafish is a suitable model organism for large-scale drug screening, making this a valuable model to identify novel therapeutic targets for AD.     

Hsp90 regulates tau pathology through co-chaperone complexes in Alzheimer's disease

Alzheimer's disease is a tauopathy which involves the deposition of microtubule-associated tau proteins into neurofibrillary tangles. Post-translational modifications, in particular site-specific phosphorylations, affect the conformation of tau protein which is an intrinsically disordered protein. These structural changes significantly increase the affinity of tau protein for certain molecular chaperones. Hsp90 is a major cellular chaperone which assembles large complexes with a variety of co-chaperones. The main function of Hsp90 complexes is to maintain protein quality control and assist in protein degradation via proteasomal and autophagic-lysosomal pathways. Tau protein is a client protein for these Hsp90 complexes. If the tau protein is in an abnormal or modified form, then it can trigger the recruitment of CHIP protein, a co-chaperone with E3 activity, to the complex which induces the ubiquitination of tau protein and activates its downstream degradation processes. Large immunophilins, FKBP51 and FKBP52 are also co-chaperones of Hsp90-tau complexes. These proteins contain peptidylprolyl cis/trans isomerase activity which catalyzes phosphorylation-dependent rotation in pSer/Thr-Pro peptide bond. The proline switch in the tau conformation triggers dephosphorylation of Ser/Thr residues phosphorylated, e.g. by two well-known tau kinases Cdk5 and GSK-3β. Binding of PP5 protein phosphatase to Hsp90 complex, can also dephosphorylate tau protein. Subsequently, dephosphorylated tau protein can be shuttled back to the microtubules. It seems that high-affinity binding of abnormal tau to Hsp90 complexes may have some counteracting effects on the aggregation process, since Hsp90 inhibitors can ameliorate the aggregation process in several neurodegenerative diseases. We will review the role of Hsp90 chaperone network in the regulation of tau biology and pathology in Alzheimer's disease.     

The serotonergic system in ageing and Alzheimer's disease

Alzheimer's disease (AD) is one of the major neurodegenerative diseases that deteriorates cognitive functions and primarily affects associated brain regions involved in learning and memory, such as the neocortex and the hippocampus. Following the discovery and establishment of its role as a neurotransmitter, serotonin (5-HT), was found to be involved in a multitude of neurophysiological processes including mnesic function, through its dedicated pathways and interaction with cholinergic, glutamatergic, GABAergic and dopaminergic transmission systems. Abnormal 5-HT neurotransmission contributes to the deterioration of cognitive processes in ageing, AD and other neuropathologies, including schizophrenia, stress, mood disorders and depression. Numerous studies have confirmed the pathophysiological role of the 5-HT system in AD and that several drugs enhancing 5-HT neurotransmission are effective in treating the AD-related cognitive and behavioural deficits. Here we present a comprehensive overview of the role of serotonergic neurotransmission in brain development, maturation and ageing, discuss its role in higher brain function and provide an in depth account of pathological modifications of serotonergic transmission in neurological diseases and AD.     

Toward understanding Machado-Joseph disease

Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is the most common inherited spinocerebellar ataxia and one of many polyglutamine neurodegenerative diseases. In MJD, a CAG repeat expansion encodes an abnormally long polyglutamine (polyQ) tract in the disease protein, ATXN3. Here we review MJD, focusing primarily on the function and dysfunction of ATXN3 and on advances toward potential therapies. ATXN3 is a deubiquitinating enzyme (DUB) whose highly specialized properties suggest that it participates in ubiquitin-dependent proteostasis. By virtue of its interactions with VCP, various ubiquitin ligases and other ubiquitin-linked proteins, ATXN3 may help regulate the stability or activity of many proteins in diverse cellular pathways implicated in proteotoxic stress response, aging, and cell differentiation. Expansion of the polyQ tract in ATXN3 is thought to promote an altered conformation in the protein, leading to changes in interactions with native partners and to the formation of insoluble aggregates. The development of a wide range of cellular and animal models of MJD has been crucial to the emerging understanding of ATXN3 dysfunction upon polyQ expansion. Despite many advances, however, the principal molecular mechanisms by which mutant ATXN3 elicits neurotoxicity remain elusive. In a chronic degenerative disease like MJD, it is conceivable that mutant ATXN3 triggers multiple, interconnected pathogenic cascades that precipitate cellular dysfunction and eventual cell death. A better understanding of these complex molecular mechanisms will be important as scientists and clinicians begin to focus on developing effective therapies for this incurable, fatal disorder.     

Biological metals and Alzheimer's disease: Implications for therapeutics and diagnostics

The equilibrium of metal ions is critical for many physiological functions, particularly in the central nervous system, where metals are essential for development and maintenance of enzymatic activities, mitochondrial function, myelination, neurotransmission as well as learning and memory. Due to their importance, cells have evolved complex machinery for controlling metal-ion homeostasis. However, disruption of these mechanisms, or absorption of detrimental metals with no known biological function, alter the ionic balance and can result in a disease state, including several neurodegenerative disorders such as Alzheimer's disease. Understanding the complex structural and functional interactions of metal ions with the various intracellular and extracellular components of the central nervous system, under normal conditions and during neurodegeneration, is essential for the development of effective therapies. Accordingly, assisting the balance of metal ions back to homeostatic levels has been proposed as a disease-modifying therapeutic strategy for Alzheimer's disease as well as other neurodegenerative diseases.     

Driving GDNF expression: the green and the red traffic lights

Glial cell line-derived neurotrophic factor (GDNF) is widely recognized as a potent survival factor for dopaminergic neurons of the nigrostriatal pathway that degenerate in Parkinson's disease (PD). In animal models of PD, GDNF delivery to the striatum or the substantia nigra protects dopaminergic neurons against subsequent toxin-induced injury and rescues previously damaged neurons, promoting recovery of the motor function. Thus, GDNF was proposed as a potential therapy to PD aimed at slowing down, halting or reversing neurodegeneration, an issue addressed in previous reviews. However, the use of GDNF as a therapeutic agent for PD is hampered by the difficulty in delivering it to the brain. Another potential strategy is to stimulate the endogenous expression of GDNF, but in order to do that we need to understand how GDNF expression is regulated. The aim of this review is to do a comprehensive analysis of the state of the art on the control of endogenous GDNF expression in the nervous system, focusing mainly on the nigrostriatal pathway. We address the control of GDNF expression during development, in the adult brain and after injury, and how damaged neurons signal glial cells to up-regulate GDNF. Pharmacological agents or natural molecules that increase GDNF expression and show neuroprotective activity in animal models of PD are reviewed. We also provide an integrated overview of the signalling pathways linking receptors for these molecules to the induction of GDNF gene, which might also become targets for neuroprotective therapies in PD.     

Alteration of protein folding and degradation in motor neuron diseases: Implications and protective functions of small heat shock proteins

Motor neuron diseases (MNDs) are neurodegenerative disorders that specifically affect the survival and function of upper and/or lower motor neurons. Since motor neurons are responsible for the control of voluntary muscular movement, MNDs are characterized by muscle spasticity, weakness and atrophy. Different susceptibility genes associated with an increased risk to develop MNDs have been reported and several mutated genes have been linked to hereditary forms of MNDs. However, most cases of MNDs occur in sporadic forms and very little is known on their causes. Interestingly, several molecular mechanisms seem to participate in the progression of both the inherited and sporadic forms of MNDs. These include cytoskeleton organization, mitochondrial functions, DNA repair and RNA synthesis/processing, vesicle trafficking, endolysosomal trafficking and fusion, as well as protein folding and protein degradation. In particular, accumulation of aggregate-prone proteins is a hallmark of MNDs, suggesting that the protein quality control system (molecular chaperones and the degradative systems: ubiquitin-proteasome-system and autophagy) are saturated or not sufficient to allow the clearance of these altered proteins. In this review we mainly focus on the MNDs associated with disturbances in protein folding and protein degradation and on the potential implication of a specific class of molecular chaperones, the small heat shock proteins (sHSPs/HSPBs), in motor neuron function and survival. How boosting of specific HSPBs may be a potential useful therapeutic approach in MNDs and how mutations in specific HSPBs can directly cause motor neuron degeneration is discussed.     

Apoptosis-inducing factor: a matter of neuron life and death

The mitochondrial flavoprotein apoptosis-inducing factor (AIF) is the main mediator of caspase-independent apoptosis-like programmed cell death. Upon pathological permeabilization of the outer mitochondrial membrane, AIF is translocated to the nucleus, where it participates in chromatin condensation and is associated to large-scale DNA fragmentation. Heavy down-regulation of AIF expression in mutant mice or reduced AIF expression achieved with small interfering RNA (siRNA) provides neuroprotection against acute neurodegenerative insults. Paradoxically, in addition to its pro-apoptotic function, AIF likely plays an anti-apoptotic role by regulating the production of reactive oxygen species (ROS) via its putative oxidoreductase and peroxide scavenging activities. In this review, we discuss accumulating evidence linking AIF to both acute and chronic neurodegenerative processes by emphasising mechanisms underlying the dual roles apparently played by AIF in these processes.     

Eating ourselves to death (and despair): The contribution of adiposity and inflammation to depression

Obesity and related metabolic conditions are of epidemic proportions in most of the world, affecting both adults and children. The accumulation of lipids in the body in the form of white adipose tissue in the abdomen is now known to activate innate immune mechanisms. Lipid accumulation causes adipocytes to directly secrete the cytokines interleukin (IL) 6 and tumor necrosis factor α (TNFα), but also monocyte chemoattractant protein 1 (MCP-1), which results in the accumulation of leukocytes in fat tissue. This sets up a chronic inflammatory state which is known to mediate the association between obesity and conditions such as cardiovascular disease, type 2 diabetes, and cancer. There is also a substantial literature linking inflammation with risk for depression. This includes the observations that: (1) people with inflammatory diseases such as multiple sclerosis, cardiovascular disease, and psoriasis have elevated rates of depression; (2) many people administered inflammatory cytokines such as interferon α develop depression that is indistinguishable from depression in non-medically ill populations; (3) a significant proportion of depressed persons show upregulation of inflammatory factors such as IL-6, C-reactive protein, and TNFα; (4) inflammatory cytokines can interact with virtually every pathophysiologic domain relevant to depression, including neurotransmitter metabolism, neuroendocrine function, and synaptic plasticity. While many factors may contribute to the association between inflammatory mediators and depression, we hypothesize that increased adiposity may be one causal pathway. Mediational analysis suggests a bi-directional association between adiposity and depression, with inflammation possibly playing an intermediary role.     

The ubiquitin proteasome system in neurodegenerative diseases: Culprit,accomplice or victim?

A shared hallmark for many neurodegenerative disorders is the accumulation of toxic protein species which is assumed to be the cause for these diseases. Since the ubiquitin proteasome system (UPS) is the most important pathway for selective protein degradation it is likely that it is involved in the aetiology neurodegenerative disorders. Indeed, impairment of the UPS has been reported to occur during neurodegeneration. Although accumulation of toxic protein species (amyloid β) are in turn known to impair the UPS the relationship is not necessarily causal. We provide an overview of the most recent insights in the roles the UPS plays in protein degradation and other processes. Additionally, we discuss the role of the UPS in clearance of the toxic proteins known to accumulate in the hallmarks of neurodegenerative diseases. The present paper will focus on critically reviewing the involvement of the UPS in specific neurodegenerative diseases and will discuss if UPS impairment is a cause, a consequence or both of the disease.     

Neurochemical pathways involved in the protective effects of nicotine and ethanol in preventing the development of Parkinson's disease: potential targets for the development of new therapeutic agents

In this short review, neurochemical targets are identified where nicotine, and possibly ethanol, may interact to prevent the occurrence of Parkinson's disease. These are (a) the nicotinic acetycholine receptors present in the nigrostriatal area or on the surface of microglia, (b) monoamine oxidases and (c) inducible nitric oxide synthase. If such induced changes can be verified in clinical studies, this may help in the design of new therapeutic drugs which may be of relevance to diminish the incidence and perhaps the progression of the debilitating condition of Parkinson's disease.