Autophagy in the central nervous system: implications for neurodegenerative disorders

The autophagy-lysosomal pathway is a major proteolytic pathway that in mammalian systems mainly comprises of macroautophagy and chaperone-mediated autophagy. The former is relatively non-selective and involves bulk degradation of proteins and organelles, whereas the latter is selective for certain cytosolic proteins. These autophagy pathways are important in development, differentiation, cellular remodeling and survival during nutrient starvation. Autophagy is crucial for neuronal homeostasis and acts as a local housekeeping process, since neurons are post-mitotic cells and require effective protein degradation to prevent accumulation of toxic aggregates. A growing body of evidence now suggests that dysfunction of autophagy causes accumulation of abnormal proteins and/or damaged organelles. Such accumulation has been linked to synaptic dysfunction, cellular stress and neuronal death. Abnormal autophagy may be involved in the pathology of both chronic nervous system disorders, such as proteinopathies (Alzheimer's, Parkinson's, Huntington's disease) and acute brain injuries. Although autophagy is generally beneficial, its aberrant activation may also exert a detrimental role in neurological diseases depending on the environment and the insult, leading to autophagic neuronal death. In this review we summarize the current knowledge regarding the role of autophagy-lysosomal pathway in the central nervous system and discuss the implication of autophagy dysregulation in human neurological diseases and animal models.     

Autophagy and neurodegenerative disorders

Accumulation of aberrant proteins and inclusion bodies are hallmarks in most neurodegenerative diseases. Consequently, these aggregates within neurons lead to toxic effects, overproduction of reactive oxygen species and oxidative stress. Autophagy is a significant intracellular mechanism that removes damaged organelles and misfolded proteins in order to maintain cell homeostasis. Excessive or insufficient autophagic activity in neurons leads to altered homeostasis and influences their survival rate, causing neurodegeneration. The review article provides an update of the role of autophagic process in representative chronic and acute neurodegenerative disorders.     

Metals in our minds: therapeutic implications for neurodegenerative disorders

BACKGROUND: Abnormal interactions of copper or iron in the brain with metal-binding proteins (such as amyloid-beta peptide [Abeta] or neuromelanin) that lead to oxidative stress have emerged as important potential mechanisms in brain ageing and neurodegenerative disorders. Although a controlled study of desferrioxamine in Alzheimer's disease(AD) had some promising results, concerns about toxicity and brain delivery have limited trials of traditional chelators. The therapeutic significance of metal dysregulation in neurodegenerative disorders has remained difficult to test. RECENT DEVELOPMENTS: Clioquinol was identified as a prototype metal-protein-attenuating compound (MPAC). In a blinded and controlled 9 week study of a mouse model of AD, oral clioquinol decreased brain Abeta by 49% without systemic toxicity. The concentrations of copper and zinc in the brain rose by about 15% in mice treated with clioquinol. Two other studies in mice showed that the raising of brain copper concentrations through diet or genetics could lower amyloid load and increase survival. A recent placebo-controlled trial in 36 patients with AD showed that clioquinol (250-750 mg daily) reduced plasma concentrations of Abeta(1-42), raised plasma concentrations of zinc, and-in a subset with moderate dementia-slowed cognitive decline over 24 weeks. Two recent experiments also showed the neuroprotective effects of iron chelation in a mouse model of Parkinson's disease. WHERE NEXT?: The experimental and transgenic-animal studies of metal-protein interactions are convincing but do not provide conclusive answers either about causality or whether this strategy will protect against neurodegeneration in human beings. The finding that clioquinol could modulate plasma concentrations of amyloid and cognition in patients with AD needs to be interpreted cautiously, but is an important first step. Clioquinol was withdrawn because of concerns of its association with subacute myelo-optic neuropathy in Japan; therefore, any additional studies with this drug will likely be small and closely monitored proof-of-concept studies. The development of optimal second-generation MPACs is a desirable goal and may permit greater insights into the significance of metal-protein interactions across several neurodegenerative disorders.     

Dysfunctional autophagy in Alzheimer’s disease: pathogenic roles and therapeutic implications

Neuronal autophagy is essential for neuronal survival and the maintenance of neuronal homeostasis. Increasing evidence has implicated autophagic dysfunction in the pathogenesis of Alzheimer’s disease (AD). The mechanisms underlying autophagic failure in AD involve several steps, from autophagosome formation to degradation. The effect of modulating autophagy is context-dependent. Stimulation of autophagy is not always beneficial. During the implementation of therapies that modulate autophagy, the nature of the autophagic defect, the timing of intervention, and the optimal level and duration of modulation should be fully considered.     

Neuroprotective and metabolic effects of resveratrol: therapeutic implications for Huntington's disease and other neurodegenerative disorders

Resveratrol is a naturally occurring polyphenolic compound associated with beneficial effects on aging, metabolic disorders, inflammation and cancer in animal models and resveratrol is currently being tested in numerous clinical trials. Resveratrol may exert these effects by targeting several key metabolic sensor/effector proteins, such as AMPK, SIRT1, and PGC-1α. Resveratrol has also received considerable attention recently for its potential neuroprotective effects in neurodegenerative disorders where AMPK, SIRT1 or PGC-1α may represent promising therapeutic targets. A recent study published in Experimental Neurology (Ho et al., 2010) examined the therapeutic potential of a micronised proprietary resveratrol formulation, SRT501 in the N171-82Q transgenic mouse model of Huntington's disease (HD). HD is a progressive and devastating genetic neurodegenerative disorder that is associated with downregulation of PGC-1α activity. The Ho et al. study found that SRT501 treatment did not lead to significant improvement in weight loss, motor performance, survival and striatal atrophy. However, other studies have reported neuroprotective effects of resveratrol and a distantly related polyphenol, fisetin, in HD models. HD has been associated with diabetes mellitus. Interestingly, evidence from the Ho et al. study suggests a resveratrol formulation induced beneficial anti-diabetic effect in N171-82Q mice. This commentary summarizes the pertinent outcomes from the Ho et al. study and discusses the further prospects of resveratrol and other polyphenols, including novel grape-derived polyphenols, in the treatment of HD and other neurodegenerative disorders.     

Kynurenines in chronic neurodegenerative disorders: future therapeutic strategies

Parkinson’s, Alzheimer’s and Huntington’s diseases are chronic neurodegenerative disorders of a progressive nature which lead to a considerable deterioration of the quality of life. Their pathomechanisms display some common features, including an imbalance of the tryptophan metabolism. Alterations in the concentrations of neuroactive kynurenines can be accompanied by devastating excitotoxic injuries and metabolic disturbances. From therapeutic considerations, possibilities that come into account include increasing the neuroprotective effect of kynurenic acid, or decreasing the levels of neurotoxic 3-hydroxy-l-kynurenine and quinolinic acid. The experimental data indicate that neuroprotection can be achieved by both alternatives, suggesting opportunities for further drug development in this field.     

Emerging roles of J proteins in neurodegenerative disorders

Several families of proteins called molecular chaperones comprise the cellular machinery that has evolved to maintain protein structure and eliminate misfolded proteins in the cell. In experimental animal models, chaperones have been shown to be powerful inhibitors of neurodegeneration. As such, molecular chaperones represent exciting pharmaceutical targets that potentially eliminate aberrant cellular proteins and slow disease progression. Current evidence indicates that the J protein family is the basis of selective chaperone action in the cell. Hence, J proteins are currently attracting attention as novel therapeutic targets for a number of neurodegenerative disorders.     

Impulse control disorders in eating disorders: clinical and therapeutic implications

OBJECTIVE: Few studies have explored impulse control disorders (ICDs) in women with bulimia nervosa (BN). We explored the prevalence of lifetime ICDs in women with BN, compared the severity of eating disorder symptoms in women with BN with and without ICD, and compared their personality profiles to females with one form of ICD, namely, pathologic gambling. METHOD: A total sample of 269 female patients consecutively admitted to our unit participated in the current study (173 BN without comorbid ICD [BN - ICD]; 54 BN with comorbid ICD [BN + ICD]; and 42 pathologic gamblers [PG]). All participants were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria. EVALUATION: Assessment measures included the Symptom Checklist-90 revised and the Temperament and Character Inventory-revised, as well as a number of other clinical and psychopathologic indices. RESULTS: In BN, the observed lifetime prevalence of ICD was 23.8%. Lifetime compulsive buying (17.6%) and intermittent explosive disorder (13.2%) were the most frequently reported ICD. Bulimia nervosa subtype was not significantly associated with lifetime ICD (P = .051) or with ICD subtype (P = .253). After using multinomial regression models, we observed that BN + ICD and PG showed the highest scores on novelty seeking (P < .0001). But BN + ICD women had the lowest scores on self-directedness (P < .03) and higher scores on general psychopathology (P < .01) and drug abuse (P < .01). CONCLUSIONS: Individuals with BN + lifetime ICD presented more extreme personality profiles, especially on novelty seeking and impulsivity, and general psychopathology than individuals with BN without ICD. On some personality traits, those BN + ICD more closely resembled individuals with PG than those with BN without ICD.     

Latrepirdine: molecular mechanisms underlying potential therapeutic roles in Alzheimer's and other neurodegenerative diseases

Latrepirdine (Dimebon^TM) was originally marketed as a non-selective antihistamine in Russia. It was repurposed as an effective treatment for patients suffering from Alzheimer''s disease (AD) and Huntington''s disease (HD) following preliminary reports showing its neuroprotective functions and ability to enhance cognition in AD and HD models. However, latrepirdine failed to show efficacy in phase III trials in AD and HD patients following encouraging phase II trials. The failure of latrepirdine in the clinical trials has highlighted the importance of understanding the precise mechanism underlying its cognitive benefits in neurodegenerative diseases before clinical evaluation. Latrepirdine has shown to affect a number of cellular functions including multireceptor activity, mitochondrial function, calcium influx and intracellular catabolic pathways; however, it is unclear how these properties contribute to its clinical benefits. Here, we review the studies investigating latrepirdine in cellular and animal models to provide a complete evaluation of its mechanisms of action in the central nervous system. In addition, we review recent studies that demonstrate neuroprotective functions for latrepirdine-related class of molecules including the β-carbolines and aminopropyl carbazoles in AD, Parkinson''s disease and amyotrophic lateral sclerosis models. Assessment of their neuroprotective effects and underlying biological functions presents obvious value for developing structural analogues of latrepirdine for dementia treatment.     

Autophagy and its neuroprotection in neurodegenerative diseases

It has been suggested that protein misfolding and aggregation contribute significantly to the development of neurodegenerative diseases.Misfolded and aggregated proteins are cleared by ubiquitin proteasomal system (UPS) and by both Micro and Macro autophagy lysosomal pathway (ALP).Autophagosomal dysfunction has been implicated in an increasing number of diseases including neurodegenerative diseases.Autophagy is a cellular self-eating process that plays an important role in neuroprotection as well as neuronal injury and death.While a decrease in autophagic activity interferes with protein degradation and possibly organelle turnover,increased autophagy has been shown to facilitate the clearance of aggregation-prone proteins and promote neuronal survival in a number of disease models.On the other hand,too much autophagic activity can be detrimental,suggesting the regulation of autophagy is critical in dictating cell fate.In this review paper,we will discuss various aspects of ALP biology and its dual functions in neuronal cell death and survival.We will also evaluate the role of autophagy in neurodegenerative diseases including Alzheimer’s disease,Parkinson’s disease,Huntington’s disease,amyotrophic lateral sclerosis.Finally,we will explore the therapeutic potential of autophagy modifiers in several neurodegenerative diseases.     

Autophagy, inflammation and neurodegenerative disease

Autophagy is emerging as a central regulator of cellular health and disease and, in the central nervous system (CNS), this homeostatic process appears to influence synaptic growth and plasticity. Herein, we review the evidence that dysregulation of autophagy may contribute to several neurodegenerative diseases of the CNS. Up-regulation of autophagy may prevent, delay or ameliorate at least some of these disorders, and - based on recent findings from our laboratory - we speculate that this goal may be achieved using a safe, simple and inexpensive approach.     

Role of the NLRP3 inflammasome in neurodegenerative diseases and therapeutic implications

Neurodegenerative diseases are a group of neuronal disorders caused by progressive neuronal cell death in different regions of the human brain.Alzheimer's disease(AD)and Parkinson's disease(PD)are the most common types of neurodegenerative diseases that affect millions of people worldwide.There is no cure available for either disease.One of the pathological hallmarks of neurodegenerative diseases is the abnormal protein aggregation in the central nervous system.     

The therapeutic potential of siRNA in gene therapy of neurodegenerative disorders

RNA interference using small inhibitory RNA (siRNA) has become a powerful tool to downregulate mRNA levels by cellular nucleases that become activated when a sequence homology between the siRNA and a respective mRNA molecule is detected. Therefore siRNA can be used to silence genes involved in the pathogenesis of various diseases associated with a known genetic background. As for many neurodegenerative disorders a causative therapy is unavailable, siRNA holds a promising option for the development of novel therapeutic strategies. Here we discuss different siRNA target strategies aiming for an allele-specific degradation of disease-inducing mRNA and we review the literature in the field of siRNA and its application in animal models of neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) and spinocerebellar ataxia (SCA1).     

Macrophage attenuation of neuronal excitability: implications for pathogenesis of neurodegenerative disorders

Brain macrophages (and microglia) play a crucial role in central nervous system immune and inflammatory responses. They are also critical cells in the pathogenesis of neurodegenerative disorders. To understand how macrophages cause neural cell dysfunction, we investigated the effects of mouse bone marrow-derived macrophages (BMDMs) on rat cortical neuronal physiology in a BMDM-neuronal co-culture system using whole-cell patch clamp techniques. When co-cultured with neuronal cells, BMDMs hyperpolarized the neuronal membrane and attenuated both spontaneous and electrically evoked firings through a decrease in membrane input resistance. The average duration of evoked action potentials (APs) and the latency to fire the APs, in response to a constant depolarizing current injection, were significantly increased by BMDMs. These results indicate that BMDMs attenuate neuronal excitability. Further investigation revealed that BMDMs hyperpolarize neuronal membranes by enhancing neuronal delayed rectifier potassium current (IK), which was blocked by tetraethylammonium. This BMDM-induced attenuation on neuronal excitability may contribute to the pathogenesis of neuronal dysfunction and damage as seen in neurodegenerative disorders.     

"Apoptotic" biochemical cascades in synaptic compartments: roles in adaptive plasticity and neurodegenerative disorders.

Apoptosis is a form of cell death historically defined by morphological and biochemical changes that occur in the cell body and nucleus. However, in contrast to nonneuronal cells in which apoptosis has been most intensively studied, neurons exhibit elaborate morphologies with synaptic connections often located at sites a great distance from the cell body. Signaling events occurring in synaptic terminals are believed to play important roles in either promoting (e.g., activation of glutamate receptors in postsynaptic spines) or preventing (e.g., activation of neurotrophic factors in presynaptic terminals) neuronal cell death in various physiological and pathological settings. We have found that apoptotic biochemical cascades can be activated locally in synaptic terminals and neurites and have shown that such cascades can result in local functional and morphological alterations and can also propagate to the cell body resulting in neuronal death. Prostate apoptosis response-4 production, caspase activation, loss of plasma membrane phospholipid asymmetry, mitochondrial dysfunction, and production of factors capable of inducing nuclear chromatin condensation and fragmentation can all occur locally in synaptic terminals in response to various stimuli. Activation of receptors for neurotrophic factors (e.g., basic fibroblast growth factor, secreted form of amyloid precursor protein alpha, and activity-dependent neurotrophic factor) and cytokines (e.g., tumor necrosis factor-alpha) in synaptic terminals can exert synaptoprotective actions that either can be transduced locally or may require signals to the nucleus and back. In addition to their roles in synaptic degeneration and neuron death, apoptotic cascades may play roles in synaptic plasticity. For example, we found that caspase activation can lead to proteolysis of certain glutamate receptor subunits and that this action of capases is correlated with reduced calcium responses to glutamate. We propose that apoptotic cascades function in a continuum in which low levels of activation play roles in adaptive responses to "stressors," whereas higher levels of activation mediate synaptic degeneration and cell death.