TRIM family proteins: roles in proteostasis and neurodegenerative diseases

Neurodegenerative diseases (NDs) are a diverse group of disorders characterized by the progressive degeneration of the structure and function of the central or peripheral nervous systems. One of the major features of NDs, such as Alzheimer''s disease (AD), Parkinson''s disease (PD) and Huntington''s disease (HD), is the aggregation of specific misfolded proteins, which induces cellular dysfunction, neuronal death, loss of synaptic connections and eventually brain damage. By far, a great amount of evidence has suggested that TRIM family proteins play crucial roles in the turnover of normal regulatory and misfolded proteins. To maintain cellular protein quality control, cells rely on two major classes of proteostasis: molecular chaperones and the degradative systems, the latter includes the ubiquitin-proteasome system (UPS) and autophagy; and their dysfunction has been established to result in various physiological disorders including NDs. Emerging evidence has shown that TRIM proteins are key players in facilitating the clearance of misfolded protein aggregates associated with neurodegenerative disorders. Understanding the different pathways these TRIM proteins employ during episodes of neurodegenerative disorder represents a promising therapeutic target. In this review, we elucidated and summarized the diverse roles with underlying mechanisms of members of the TRIM family proteins in NDs.     

The emerging roles of protein homeostasis‐governing pathways in Alzheimer's disease

Pathways governing protein homeostasis are involved in maintaining the structural, quantitative, and functional stability of intracellular proteins and involve the ubiquitin–proteasome system, autophagy, endoplasmic reticulum, and mTOR pathway. Due to the broad physiological implications of protein homeostasis pathways, dysregulation of proteostasis is often involved in the development of multiple pathological conditions, including Alzheimer's disease (AD). Similar to other neurodegenerative diseases that feature pathogenic accumulation of misfolded proteins, Alzheimer's disease is characterized by two pathological hallmarks, amyloid‐β (Aβ) plaques and tau aggregates. Knockout or transgenic overexpression of various proteostatic components in mice results in AD‐like phenotypes. While both Aβ plaques and tau aggregates could in turn enhance the dysfunction of these proteostatic pathways, eventually leading to apoptotic or necrotic neuronal death and pathogenesis of Alzheimer's disease. Therefore, targeting the components of proteostasis pathways may be a promising therapeutic strategy against Alzheimer's disease.     

Harnessing the power of yeast to unravel the molecular basis of neurodegeneration

Several neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), or prion diseases, are known for their intimate association with protein misfolding and aggregation. These disorders are characterized by the loss of specific neuronal populations in the brain and are highly associated with aging, suggesting a decline in proteostasis capacity may contribute to pathogenesis. Nevertheless, the precise molecular mechanisms that lead to the selective demise of neurons remain poorly understood. As a consequence, appropriate therapeutic approaches and effective treatments are largely lacking. The development of cellular and animal models that faithfully reproduce central aspects of neurodegeneration has been crucial for advancing our understanding of these diseases. Approaches involving the sequential use of different model systems, starting with simpler cellular models and ending with validation in more complex animal models, resulted in the discovery of promising therapeutic targets and small molecules with therapeutic potential. Within this framework, the simple and well‐characterized eukaryote Saccharomyces cerevisiae, also known as budding yeast, is being increasingly used to study the molecular basis of several neurodegenerative disorders. Yeast provides an unprecedented toolbox for the dissection of complex biological processes and pathways. Here, we summarize how yeast models are adding to our current understanding of several neurodegenerative disorders.     

The ubiquitin-proteasome system in Alzheimer's disease

Accumulation of proteins is a recurring event in many neurodegenerative diseases, including Alzheimer's disease (AD). Evidence has suggested that protein accumulation may result from a dysfunction in the ubiquitin proteasome system (UPS). Indeed, there is clear genetic and biochemical evidence of an involvement of the ubiquitin proteasome system in AD. This review summarizes the data supporting an involvement of the UPS in the pathogenesis of AD, focusing on the data showing the relationship between Abeta and tau, the two hallmark lesions of AD, and the UPS.     

The Ubiquitin–Proteasome System in Retinal Health and Disease

The ubiquitin–proteasome system (UPS) is the main intracellular pathway for modulated protein turnover, playing an important role in the maintenance of cellular homeostasis. It also exerts a protein quality control through degradation of oxidized, mutant, denatured, or misfolded proteins and is involved in many biological processes where protein level regulation is necessary. This system allows the cell to modulate its protein expression pattern in response to changing physiological conditions and provides a critical protective role in health and disease. Impairments of UPS function in the central nervous system (CNS) underlie an increasing number of genetic and idiopathic diseases, many of which affect the retina. Current knowledge on the UPS composition and function in this tissue, however, is scarce and dispersed. This review focuses on UPS elements reported in the retina, including ubiquitinating and deubiquitinating enzymes (DUBs), and alternative proteasome assemblies. Known and inferred roles of protein ubiquitination, and of the related, SUMO conjugation (SUMOylation) process, in normal retinal development and adult homeostasis are addressed, including modulation of the visual cycle and response to retinal stress and injury. Additionally, the relationship between UPS dysfunction and human neurodegenerative disorders affecting the retina, including Alzheimer's, Parkinson's, and Huntington's diseases, are dealt with, together with numerous instances of retina-specific illnesses with UPS involvement, such as retinitis pigmentosa, macular degenerations, glaucoma, diabetic retinopathy (DR), and aging-related impairments. This information, though still basic and limited, constitutes a suitable framework to be expanded in incoming years and should prove orientative toward future therapy design targeting sight-affecting diseases with a UPS underlying basis.     

感染在神经退行性疾病中的调控机制

神经退行性疾病以突触丢失和神经元死亡为特征,表现为认知功能下降、痴呆和运动功能丧失.流行病学和实验证据提示:慢性细菌、病毒和真菌感染可能是导致神经退行性疾病如阿尔兹海默症(AD)、帕金森病(PD)、肌萎缩性侧索硬化症(ALS)和多发性硬化症(MS)等的危险因素.病原体在中枢神经系统的持续感染可导致一系列细胞生物学功能的...     

Protein Quality Control System in Neurodegeneration: A Healing Company Hard to Beat but Failure is Fatal

A common feature in most neurodegenerative diseases and aging is the progressive accumulation of damaged proteins. Proteins are essential for all crucial biological functions. Under some notorious conditions, proteins loss their three dimensional native conformations and are converted into disordered aggregated structures. Such changes rise into pathological conditions and eventually cause serious protein conformation disorders. Protein aggregation and inclusion bodies formation mediated multifactorial proteotoxic stress has been reported in the progression of Parkinson’s disease (PD), Huntington’s disease (HD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and Prion disease. Ongoing studies have been remarkably informative in providing a systematic outlook for better understanding the concept and fundamentals of protein misfolding and aggregations. However, the precise role of protein quality control system and precursors of this mechanism remains elusive. In this review, we highlight recent insights and discuss emerging cytoprotective strategies of cellular protein quality control system implicated in protein deposition diseases. Our current review provides a clear, understandable framework of protein quality control system that may offer the more suitable therapeutic strategies for protein-associated diseases.     

Emerging role of HDL in brain cholesterol metabolism and neurodegenerative disorders

High-density lipoproteins (HDL) play a key role in cholesterol homeostasis maintenance in the central nervous system (CNS), by carrying newly synthesized cholesterol from astrocytes to neurons, to support their lipid-related physiological functions. As occurs for plasma HDL, brain lipoproteins are assembled through the activity of membrane cholesterol transporters, undergo remodeling mediated by specific enzymes and transport proteins, and finally deliver cholesterol to neurons by a receptor-mediated internalization process. A growing number of evidences indicates a strong association between alterations of CNS cholesterol homeostasis and neurodegenerative disorders, in particular Alzheimer's disease (AD), and a possible role in this relationship may be played by defects in brain HDL metabolism. In the present review, we summarize and critically examine the current state of knowledge on major modifications of HDL and HDL-mediated brain cholesterol transport in AD, by taking into consideration the individual steps of this process. We also describe potential and encouraging HDL-based therapies that could represent new therapeutic strategies for AD treatment. Finally, we revise the main plasma and brain HDL modifications in other neurodegenerative disorders including Parkinson's disease (PD), Huntington's disease (HD), and frontotemporal dementia (FTD).     

Structural basis of bioenergetic protein complexes in Alzheimer's disease pathogenesis

Alzheimer's disease (AD) is a progressive neurodegenerative disease with no cure where the underlying causes remain elusive. Mitochondrial dysfunction has become a prime suspect in AD pathogenesis since bioenergetic deficits precede the pathology. With advancing structural biology techniques at synchrotrons and cryo-electron microscopes, it is becoming possible to determine the structures of key proteins suspected to contribute to the initiation and propagation of AD, and investigate their interactions. In this review, we provide an overview of the recent developments concerning the structural aspects of mitochondrial protein complexes and their assembly factors involved the production of energy, in pursuit of therapies to halt or even reverse this disease in the early stages when mitochondria are most sensitive to amyloid toxicity.     

Dysfunction of the ubiquitin-proteasome system in multiple disease conditions: therapeutic approaches

The ubiquitin-proteasome system (UPS) is the major proteolytic pathway that degrades intracellular proteins in a regulated manner. Deregulation of the UPS has been implicated in the pathogenesis of many neurodegenerative disorders like Alzheimer's disease, Parkinson's diseases, Huntington disease, Prion-like lethal disorders, in the pathogenesis of several genetic diseases including cystic fibrosis, Angelman's syndrome and Liddle syndrome and in many cancers. Multiple lines of evidence have already proved that UPS has the potential to be an exciting novel therapeutic target for the treatment of these diseases. Here I review how aberrant functions of various genes have implicated UPS in many human disorders including neurodegeneration and cancers. I also discuss the finding that some proteasome inhibitors possess a therapeutic potential as drugs against many such diseases.     

Using induced pluripotent stem cell neuronal models to study neurodegenerative diseases

Current application of human induced pluripotent stem cells (hiPSCs) technology in patient-specific models of neurodegenerative disorders recapitulate some of key phenotypes of diseases, representing disease-specific cellular modeling and providing a unique platform for therapeutics development. We review recent efforts toward advancing hiPSCs-derived neuronal cell types and highlight their potential use for the development of more complex in vitro models of neurodegenerative diseases by focusing on Alzheimer's disease, Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. We present evidence from previous works on the important phenotypic changes of various neuronal types in these neurological diseases. We also summarize efforts on conducting low- and high-throughput screening experiments with hiPSCs toward developing potential therapeutics for treatment of neurodegenerative diseases. Lastly, we discuss the limitations of hiPSCs culture system in studying neurodegenerative diseases and alternative strategies to overcome these hurdles.     

Symposium 3: Function and Pathogenesis in Parkinson’s Disease. Synuclein: the third amyloid in Alzheimer's disease

A dramatic paradigm shift in understanding Parkinson's disease (PD) has emerged with implications for Alzheimer's disease (AD) because: (1) Mutations in the alpha‐synuclein (AS) gene cause familial PD, (2) Antibodies to AS detect Lewy bodies (LBs) and dystrophic Lewy neurites in PD, dementia with LBs (DLB), sporadic AD and the LB variant of AD (LBVAD), (3) Insoluble AS filaments are recovered from DLB brains and purified LBs, (4) Recombinant AS assembles into LB‐like filaments and residues 71–82 are essential for filament assembly, (5) AS transgenic mice and flies develop a PD‐like phenotype, (6) Cortical LBs detected with antibodies to AS correlate with dementia in PD, DLB and LBVAD, (7) Antibodies to AS detect LBs in 50% of familial AD, sporadic AD and Down's syndrome brains, (8) AS forms glial cytoplasmic inclusions (GCIs) in multiple system atrophy, (9) Epitopes throughout AS in LBs and GCIs, (10) Filamentous AS aggregates in LBs, GCIs and related lesions contain nitrated tyrosines, (11) Cells transfected with AS and treated with nitric oxide generators develop LB‐like AS inclusions, (12) Bigenic mice overexpressing mutant human APP and AS show an augmentation in AS inclusions. Thus, neurodegenerative diseases characterized by AS pathologies are synucleinopathies, and the filamentous AS lesions in these disorders may result in part from oxidative/nitrative damage to AS. Abnormal interactions of brain proteins may underlie synucleinopathies and other neurodegenerative disorders. Acknowledgements: Supported by NIA/NIH and Alzheimer's Association.     

The role of lysosomal cathepsins in neurodegeneration: Mechanistic insights,diagnostic potential and therapeutic approaches

Lysosomes are ubiquitous organelles with a fundamental role in maintaining cellular homeostasis by mediating degradation and recycling processes. Cathepsins are the most abundant lysosomal hydrolyses and are responsible for the bulk degradation of various substrates. A correct autophagic function is essential for neuronal survival, as most neurons are post-mitotic and thus susceptible to accumulate cellular components. Increasing evidence suggests a crucial role of the lysosome in neurodegeneration as a key regulator of aggregation-prone and disease-associated proteins, such as α-synuclein, β-amyloid and huntingtin. Particularly, alterations in lysosomal cathepsins CTSD, CTSB and CTSL can contribute to the pathogenesis of neurodegenerative diseases as seen for neuronal ceroid lipofuscinosis, synucleinopathies (Parkinson's disease, Dementia with Lewy Body and Multiple System Atrophy) as well as Alzheimer's and Huntington's disease. In this review, we provide an overview of recent evidence implicating CTSD, CTSB and CTSL in neurodegeneration, with a special focus on the role of these enzymes in α-synuclein metabolism. In addition, we summarize the potential role of lysosomal cathepsins as clinical biomarkers in neurodegenerative diseases and discuss potential therapeutic approaches by targeting lysosomal function.     

Involvement and interplay of Parkin, PINK1, and DJ1 in neurodegenerative and neuroinflammatory disorders

The involvement of parkin, PINK1, and DJ1 in mitochondrial dysfunction, oxidative injury, and impaired functioning of the ubiquitin-proteasome system (UPS) has been intensively investigated in light of Parkinson's disease (PD) pathogenesis. However, these pathological mechanisms are not restricted to PD, but are common denominators of various neurodegenerative and neuroinflammatory disorders. It is therefore conceivable that parkin, PINK1, and DJ1 are also linked to the pathogenesis of other neurological diseases, including Alzheimer's disease (AD) and multiple sclerosis (MS). The importance of these proteins in mechanisms underlying neurodegeneration is reflected by the neuroprotective properties of parkin, DJ1, and PINK1 in counteracting oxidative stress and improvement of mitochondrial and UPS functioning. This review provides a concise overview on the cellular functions of the E3 ubiquitin ligase parkin, the mitochondrial kinase PINK1, and the cytoprotective protein DJ1 and their involvement and interplay in processes underlying neurodegeneration in common neurological disorders.     

Dysregulation of Rab5‐mediated endocytic pathways in Alzheimer's disease

Increasing evidence has pointed to that dysregulation of the endo‐lysosomal system is an early cellular phenotype of pathogenesis for Alzheimer's disease (AD). Rab5, a small GTPase, plays a critical role in mediating these processes. Abnormal overactivation of Rab5 has been observed in post‐mortem brain samples of Alzheimer's patients as well as brain samples of mouse models of AD. Recent genome‐wide association studies of AD have identified RIN3 (Ras and Rab interactor 3) as a novel risk factor for the disease. RIN3 that functions as a guanine nucleotide exchange factor for Rab5 may serve as an important activator for Rab5 in AD pathogenesis. In this review, we present recent research highlights on the possible roles of dysregulation of Rab5‐mediated endocytic pathways in contributing to early pathogenesis of AD.      

A novel inhibitor of the insulin/IGF signaling pathway protects from age‐onset,neurodegeneration‐linked proteotoxicity

Aging manipulation is an emerging strategy aimed to postpone the manifestation of late‐onset neurodegenerative disorders such as Alzheimer's (AD) and Huntington's diseases (HD) and to slow their progression once emerged. Reducing the activity of the insulin/IGF signaling cascade (IIS), a prominent aging‐regulating pathway, protects worms from proteotoxicity of various aggregative proteins, including the AD‐associated peptide, Aβ‐ and the HD‐linked peptide, polyQ40. Similarly, IGF1 signaling reduction protects mice from AD‐like disease. These discoveries suggest that IIS inhibitors can serve as new drugs for the treatment of neurodegenerative maladies including AD and HD. Here, we report that NT219, a novel IIS inhibitor, mediates a long‐lasting, highly efficient inhibition of this signaling cascade by a dual mechanism; it reduces the autophosphorylation of the IGF1 receptor and directs the insulin receptor substrates 1 and 2 (IRS 1/2) for degradation. NT219 treatment promotes stress resistance and protects nematodes from AD‐ and HD‐associated proteotoxicity without affecting lifespan. Our discoveries strengthen the theme that IIS inhibition has a therapeutic potential as a cure for neurodegenerative maladies and point at NT219 as a promising compound for the treatment of these disorders through a selective manipulation of aging.     

Aging‐induced Akt activation involves in aging‐related pathologies and Aβ‐induced toxicity

Multicellular signals are altered in the processes of both aging and neurodegenerative diseases, including Alzheimer's disease (AD). Similarities in behavioral and cellular functional changes suggest a common regulator between aging and AD that remains undetermined. Our genetics and behavioral approaches revealed the regulatory role of Akt in both aging and AD pathogenesis. In this study, we found that the activity of Akt is upregulated during aging through epidermal growth factor receptor activation by using the fruit fly as an in vivo model. Downregulation of Akt in neurons improved cell survival, locomotor activity, and starvation challenge in both aged and Aβ42‐expressing flies. Interestingly, increased cAMP levels attenuated both Akt activation‐induced early death and Aβ42‐induced learning deficit in flies. At the molecular level, overexpression of Akt promoted Notch cleavage, suggesting that Akt is an endogenous activity regulator of γ‐secretase. Taken together, this study revealed that Akt is involved in the aging process and Aβ toxicity, and manipulating Akt can restore both neuronal functions and improve behavioral activity during the processes of aging and AD pathogenesis.     

Development of GMP‐1 a molecular chaperone network modulator protecting mitochondrial function and its assessment in fly and mice models of Alzheimer's disease

Mitochondrial dysfunction is an early feature of Alzheimer's disease (AD) and may play an important role in the pathogenesis of disease. It has been shown that amyloid beta peptide (Aβ) and amyloid precursor protein (APP) interact with mitochondria contributing to the mitochondrial dysfunction in AD. Prevention of abnormal protein targeting to mitochondria can protect normal mitochondrial function, increase neuronal survival and at the end, ameliorate symptoms of AD and other neurodegenerative disorders. First steps of mitochondrial protein import are coordinated by molecular chaperones Hsp70 and Hsp90 that bind to the newly synthesized mitochondria‐destined proteins and deliver them to the protein import receptors on the surface of organelle. Here, we have described the development of a novel compound named GMP‐1 that disrupts interactions between Hsp70/Hsp90 molecular chaperones and protein import receptor Tom70. GMP‐1 treatment of SH‐SY5Y cells results in decrease in mitochondria‐associated APP and protects SH‐SY5Y cells from toxic effect of Aβ_1‐42 exposure. Experiments in drosophila and mice models of AD demonstrated neuroprotective effect of GMP‐1 treatment, improvement in memory and behaviour tests as well as restoration of mitochondrial function.     

Alzheimer's disease: Effects of β-amyloid on mitochondria

The impairment of the respiratory chain or defects in the detoxification system can decrease electron transfer efficiency, reduce ATP production, and increase reactive oxygen species (ROS) production by mitochondria. Accumulation of ROS results in oxidative stress, a hallmark of neurodegenerative diseases such as Alzheimer's disease (AD). β-amyloid has been implicated in the pathogenesis of AD, and its accumulation may lead to degeneration of neuronal or non-neuronal cells. There is evidence that β-amyloid interacts with mitochondria but little is known concerning the significance of this interaction in the physiopathology of AD. This review explores possible mechanisms of β-amyloid-induced mitochondrial toxicity.     

Impaired AMPA signaling and cytoskeletal alterations induce early synaptic dysfunction in a mouse model of Alzheimer's disease

Alzheimer's disease (AD) is a devastating neurodegenerative disorder that impairs memory and causes cognitive and psychiatric deficits. New evidences indicate that AD is conceptualized as a disease of synaptic failure, although the molecular and cellular mechanisms underlying these defects remain to be elucidated. Determining the timing and nature of the early synaptic deficits is critical for understanding the progression of the disease and for identifying effective targets for therapeutic intervention. Using single‐synapse functional and morphological analyses, we find that AMPA signaling, which mediates fast glutamatergic synaptic transmission in the central nervous system (CNS), is compromised early in the disease course in an AD mouse model. The decline in AMPA signaling is associated with changes in actin cytoskeleton integrity, which alters the number and the structure of dendritic spines. AMPA dysfunction and spine alteration correlate with the presence of soluble but not insoluble Aβ and tau species. In particular, we demonstrate that these synaptic impairments can be mitigated by Aβ immunotherapy. Together, our data suggest that alterations in AMPA signaling and cytoskeletal processes occur early in AD. Most important, these deficits are prevented by Aβ immunotherapy, suggesting that existing therapies, if administered earlier, could confer functional benefits.