Association of elevated cerebrospinal fluid levels of the longevity protein α-Klotho with a delayed onset of cognitive impairment in Parkinson's disease patients.

BACKGROUND AND PURPOSE: Parkinson's disease (PD) is an age-related condition characterized by substantial phenotypic variability. Consequently, pathways and proteins involved in biological aging, such as the central aging pathway comprising insulin-like growth factor 1-α-Klotho-sirtuin 1-forkhead box O3-peroxisome proliferator-activated receptor γ, may potentially influence disease progression. METHODS: Cerebrospinal fluid (CSF) levels of α-Klotho in 471 PD patients were examined. Of the 471 patients, 96 carried a GBA1 variant (PD GBA1), whilst the 375 non-carriers were classified as PD wild-type (PD WT). Each patient was stratified into a CSF α-Klotho tertile group based on the individual level. Kaplan-Meier survival curves and Cox regression analysis stratified by tertile groups were conducted. These longitudinal data were available for 255 patients. Follow-up times reached from 8.4 to 12.4 years. The stratification into PD WT and PD GBA1 was undertaken to evaluate potential continuum patterns, particularly in relation to CSF levels. RESULTS: Higher CSF levels of α-Klotho were associated with a significant later onset of cognitive impairment. Elevated levels of α-Klotho in CSF were linked to higher Montreal Cognitive Assessment scores in male PD patients with GBA1 mutations. CONCLUSIONS: Our results indicate that higher CSF levels of α-Klotho are associated with a delayed cognitive decline in PD. Notably, this correlation is more prominently observed in PD patients with GBA1 mutations, potentially reflecting the accelerated biological aging profile characteristic of individuals harboring GBA1 variants.

Dementia in-patient units in psychiatric hospitals: research priority setting.

AIMS AND METHOD: Dementia in-patient units (DIU) are mental health wards that care for people living with dementia (PLWD) whose symptoms are causing severe distress or potential risk. DIUs look after some of the most vulnerable and unwell people in society, yet they are environments that are underresearched: a recent systematic review revealed only 36 articles worldwide relating to DIUs. To better understand research priorities in DIUs, we undertook a two-round online Delphi survey of PLWD with experience of DIUs, their carers and professionals who work in DIUs. RESULTS: Ten research priorities were described and ranked. The top three were how to use non-pharmacological techniques to manage non-cognitive symptoms of dementia, supporting families and better understanding of how to discharge PLWD safely and healthily. CLINICAL IMPLICATIONS: This is the first Delphi consensus to describe DIU research priorities. This paper will help researchers focus on the areas that matter most to people who use DIUs.

Advancing the Frontier: Neuroimaging Techniques in the Early Detection and Management of Neurodegenerative Diseases.

Alzheimer's and Parkinson's diseases are among the most prevalent neurodegenerative conditions affecting aging populations globally, presenting significant challenges in early diagnosis and management. This narrative review explores the pivotal role of advanced neuroimaging techniques in detecting and managing these diseases at early stages, potentially slowing their progression through timely interventions. Recent advancements in MRI, such as ultra-high-field systems and functional MRI, have enhanced the sensitivity for detecting subtle structural and functional changes. Additionally, the development of novel amyloid-beta tracers and other emerging modalities like optical imaging and transcranial ultrasonography have improved the diagnostic accuracy and capability of existing methods. This review highlights the clinical applications of these technologies in Alzheimer's and Parkinson's diseases, where they have shown improved diagnostic performance, enabling earlier intervention and better prognostic outcomes. Moreover, the integration of artificial intelligence (AI) and longitudinal research is emerging as a promising enhancement to refine early detection strategies further. However, this review also addresses the technical, ethical, and accessibility challenges in the field, advocating for the more extensive use of advanced imaging technologies to overcome these barriers. Finally, we emphasize the need for a holistic approach that incorporates both neurological and psychiatric perspectives, which is crucial for optimizing patient care and outcomes in the management of neurodegenerative diseases.

Perivascular spaces, plasma GFAP, and speeded executive function in neurodegenerative diseases.

INTRODUCTION: We investigated the effect of perivascular spaces (PVS) volume on speeded executive function (sEF), as mediated by white matter hyperintensities (WMH) volume and plasma glial fibrillary acidic protein (GFAP) in neurodegenerative diseases. METHODS: A mediation analysis was performed to assess the relationship between neuroimaging markers and plasma biomarkers on sEF in 333 participants clinically diagnosed with Alzheimer's disease/mild cognitive impairment, frontotemporal dementia, or cerebrovascular disease from the Ontario Neurodegenerative Disease Research Initiative. RESULTS: PVS was significantly associated with sEF (c = -0.125 ± 0.054, 95% bootstrap confidence interval [CI] [-0.2309, -0.0189], p = 0.021). This effect was mediated by both GFAP and WMH. DISCUSSION: In this unique clinical cohort of neurodegenerative diseases, we demonstrated that the effect of PVS on sEF was mediated by the presence of elevated plasma GFAP and white matter disease. These findings highlight the potential utility of imaging and plasma biomarkers in the current landscape of therapeutics targeting dementia. HIGHLIGHTS: Perivascular spaces (PVS) and white matter hyperintensities (WMH) are imaging markers of small vessel disease. Plasma glial fibrillary protein acidic protein (GFAP) is a biomarker of astroglial injury. PVS, WMH, and GFAP are relevant in executive dysfunction from neurodegeneration. PVS's effect on executive function was mediated by GFAP and white matter disease.

Harnessing myelin water fraction as an imaging biomarker of human cerebral aging, neurodegenerative diseases, and risk factors influencing myelination: A review.

Myelin water fraction (MWF) imaging has emerged as a promising magnetic resonance imaging (MRI) biomarker for investigating brain function and composition. This comprehensive review synthesizes the current state of knowledge on MWF as a biomarker of human cerebral aging, neurodegenerative diseases, and risk factors influencing myelination. The databases used include Web of Science, Scopus, Science Direct, and PubMed. We begin with a brief discussion of the theoretical foundations of MWF imaging, including its basis in MR physics and the mathematical modeling underlying its calculation, with an overview of the most adopted MRI methods of MWF imaging. Next, we delve into the clinical and research applications that have been explored to date, highlighting its advantages and limitations. Finally, we explore the potential of MWF to serve as a predictive biomarker for neurological disorders and identify future research directions for optimizing MWF imaging protocols and interpreting MWF in various contexts. By harnessing the power of MWF imaging, we may gain new insights into brain health and disease across the human lifespan, ultimately informing novel diagnostic and therapeutic strategies.

Intestinal microbiota imbalance resulted by anti-Toxoplasma gondii immune responses aggravate gut and brain injury.

BACKGROUND: Toxoplasma gondii infection affects a significant portion of the global population, leading to severe toxoplasmosis and, in immunocompromised patients, even death. During T. gondii infection, disruption of gut microbiota further exacerbates the damage to intestinal and brain barriers. Therefore, identifying imbalanced probiotics during infection and restoring their equilibrium can regulate the balance of gut microbiota metabolites, thereby alleviating tissue damage. METHODS: Vimentin gene knockout (vim-/-) mice were employed as an immunocompromised model to evaluate the influence of host immune responses on gut microbiota balance during T. gondii infection. Behavioral experiments were performed to assess changes in cognitive levels and depressive tendencies between chronically infected vim-/- and wild-type (WT) mice. Fecal samples were subjected to 16S ribosomal RNA (rRNA) sequencing, and serum metabolites were analyzed to identify potential gut probiotics and their metabolites for the treatment of T. gondii infection. RESULTS: Compared to the immunocompetent WT sv129 mice, the immunocompromised mice exhibited lower levels of neuronal apoptosis and fewer neurobehavioral abnormalities during chronic infection. 16S rRNA sequencing revealed a significant decrease in the abundance of probiotics, including several species of Lactobacillus, in WT mice. Restoring this balance through the administration of Lactobacillus murinus and Lactobacillus gasseri significantly suppressed the T. gondii burden in the intestine, liver, and brain. Moreover, transplantation of these two Lactobacillus spp. significantly improved intestinal barrier damage and alleviated inflammation and neuronal apoptosis in the central nervous system. Metabolite detection studies revealed that the levels of various Lactobacillus-related metabolites, including indole-3-lactic acid (ILA) in serum, decreased significantly after T. gondii infection. We confirmed that L. gasseri secreted much more ILA than L. murinus. Notably, ILA can activate the aromatic hydrocarbon receptor signaling pathway in intestinal epithelial cells, promoting the activation of CD8+ T cells and the secretion of interferon-gamma. CONCLUSION: Our study revealed that host immune responses against T. gondii infection severely disrupted the balance of gut microbiota, resulting in intestinal and brain damage. Lactobacillus spp. play a crucial role in immune regulation, and the metabolite ILA is a promising therapeutic compound for efficient and safe treatment of T. gondii infection.

The Effects of Fisetin and Curcumin on Oxidative Damage Caused by Transition Metals in Neurodegenerative Diseases.

Neurodegenerative diseases pose a significant health challenge for the elderly. The escalating presence of toxic metals and chemicals in the environment is a potential contributor to central nervous system dysfunction and the onset of neurodegenerative conditions. Transition metals play a crucial role in various pathophysiological mechanisms associated with prevalent neurodegenerative diseases such as Alzheimer's and Parkinson's. Given the ubiquitous exposure to metals from diverse sources in everyday life, the workplace, and the environment, most of the population faces regular contact with different forms of these metals. Disturbances in the levels and homeostasis of certain transition metals are closely linked to the manifestation of neurodegenerative disorders. Oxidative damage further exacerbates the progression of neurological consequences. Presently, there exists no curative therapy for individuals afflicted by neurodegenerative diseases, with treatment approaches primarily focusing on alleviating pathological symptoms. Within the realm of biologically active compounds derived from plants, flavonoids and curcuminoids stand out for their extensively documented antioxidant, antiplatelet, and neuroprotective properties. The utilization of these compounds holds the potential to formulate highly effective therapeutic strategies for managing neurodegenerative diseases. This review provides a comprehensive overview of the impact of abnormal metal levels, particularly copper, iron, and zinc, on the initiation and progression of neurodegenerative diseases. Additionally, it aims to elucidate the potential of fisetin and curcumin to inhibit or decelerate the neurodegenerative process.

Evaluation of Quality of Life After Use the Virtual Reality in Patients with Neurodegenerative Disease.

Introduction Spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative diseases. Objective To evaluate the living standard of patients with SCA, by applying the Vestibular Disorders Activities of Daily Living Scale (VADL) and Activitiesspecific Balance Confidence Scale (ABC) questionnaires. Methods An uncontrolled clinical trial study was conducted with 28 patients who underwent anamnesis, ENT evaluation, and vestibular assessment and the application of questionnaires VADL and ABC before and after rehabilitation with virtual reality. Results The vestibular exam was altered in 64.3% of the cases. The result between the correlation of the VADL and ABC questionnaires showed significant results in all cases (p < 0.005). The correlation between the ages and disease length with the VADL and ABC questionnaires was significant in the T3 assessment (p = 0.015). The correlation between the disease length and the VADL questionnaire was significant in all cases (p < 0.005). The comparison of the vestibular rehabilitation result (T1 to T2) showed a significant difference for all the applied games, except for the ski slalom. The comparison of the vestibular rehabilitation result (T1 to T3) showed significant difference for all the applied games (p < 0.005) (1st assessment before the start of rehabilitation designated T1, after 10 rehabilitation sessions, considered T2 and, at the end of 20 rehabilitation sessions, called T3). Conclusion We can point out a direct improvement in the living standard, reflected by the reduction of falls, better balance, and march, contributing to a higher self-confidence in patients in daily activities.

Protective Effect of Arzanol against H2O2-Induced Oxidative Stress Damage in Differentiated and Undifferentiated SH-SY5Y Cells.

Oxidative stress can damage neuronal cells, greatly contributing to neurodegenerative diseases (NDs). In this study, the protective activity of arzanol, a natural prenylated α-pyrone-phloroglucinol heterodimer, was evaluated against the H2O2-induced oxidative damage in trans-retinoic acid-differentiated (neuron-like) human SH-SY5Y cells, widely used as a neuronal cell model of neurological disorders. The pre-incubation (for 2 and 24 h) with arzanol (5, 10, and 25 µM) significantly preserved differentiated SH-SY5Y cells from cytotoxicity (MTT assay) and morphological changes induced by 0.25 and 0.5 mM H2O2. Arzanol reduced the generation of reactive oxygen species (ROS) induced by 2 h oxidation with H2O2 0.5 mM, established by 2',7'-dichlorodihydrofluorescein diacetate assay. The 2 h incubation of differentiated SH-SY5Y cells with H2O2 determined a significant increase in the number of apoptotic cells versus control cells, evaluated by propidium iodide fluorescence assay (red fluorescence) and NucView® 488 assay (green fluorescence). Arzanol pre-treatment (2 h) exerted a noteworthy significant protective effect against apoptosis. In addition, arzanol was tested, for comparison, in undifferentiated SH-SY5Y cells for cytotoxicity and its ability to protect against H2O2-induced oxidative stress. Furthermore, the PubChem database and freely accessible web tools SwissADME and pkCSM-pharmacokinetics were used to assess the physicochemical and pharmacokinetic properties of arzanol. Our results qualify arzanol as an antioxidant agent with potential neuroprotective effects against neuronal oxidative stress implicated in NDs.

Study of tree shrew biology and models: A booming and prosperous field for biomedical research.

The tree shrew ( Tupaia belangeri) has long been proposed as a suitable alternative to non-human primates (NHPs) in biomedical and laboratory research due to its close evolutionary relationship with primates. In recent years, significant advances have facilitated tree shrew studies, including the determination of the tree shrew genome, genetic manipulation using spermatogonial stem cells, viral vector-mediated gene delivery, and mapping of the tree shrew brain atlas. However, the limited availability of tree shrews globally remains a substantial challenge in the field. Additionally, determining the key questions best answered using tree shrews constitutes another difficulty. Tree shrew models have historically been used to study hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, myopia, and psychosocial stress-induced depression, with more recent studies focusing on developing animal models for infectious and neurodegenerative diseases. Despite these efforts, the impact of tree shrew models has not yet matched that of rodent or NHP models in biomedical research. This review summarizes the prominent advancements in tree shrew research and reflects on the key biological questions addressed using this model. We emphasize that intensive dedication and robust international collaboration are essential for achieving breakthroughs in tree shrew studies. The use of tree shrews as a unique resource is expected to gain considerable attention with the application of advanced techniques and the development of viable animal models, meeting the increasing demands of life science and biomedical research.

Resistance Exercise Training as a New Trend in Alzheimer's Disease Research: From Molecular Mechanisms to Prevention.

Alzheimer's disease is a pathology characterized by the progressive loss of neuronal connections, which leads to gray matter atrophy in the brain. Alzheimer's disease is the most prevalent type of dementia and has been classified into two types, early onset, which has been associated with genetic factors, and late onset, which has been associated with environmental factors. One of the greatest challenges regarding Alzheimer's disease is the high economic cost involved, which is why the number of studies aimed at prevention and treatment have increased. One possible approach is the use of resistance exercise training, given that it has been shown to have neuroprotective effects associated with Alzheimer's disease, such as increasing cortical and hippocampal volume, improving neuroplasticity, and promoting cognitive function throughout the life cycle. However, how resistance exercise training specifically prevents or ameliorates Alzheimer's disease has not been fully characterized. Therefore, the aim of this review was to identify the molecular basis by which resistance exercise training could prevent or treat Alzheimer's disease.

Cerebellum in Alzheimer's disease and other neurodegenerative diseases: an emerging research frontier.

The cerebellum is crucial for both motor and nonmotor functions. Alzheimer's disease (AD), alongside other dementias such as vascular dementia (VaD), Lewy body dementia (DLB), and frontotemporal dementia (FTD), as well as other neurodegenerative diseases (NDs) like Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and spinocerebellar ataxias (SCA), are characterized by specific and non-specific neurodegenerations in central nervous system. Previously, the cerebellum's significance in these conditions was underestimated. However, advancing research has elevated its profile as a critical node in disease pathology. We comprehensively review the existing evidence to elucidate the relationship between cerebellum and the aforementioned diseases. Our findings reveal a growing body of research unequivocally establishing a link between the cerebellum and AD, other forms of dementia, and other NDs, supported by clinical evidence, pathological and biochemical profiles, structural and functional neuroimaging data, and electrophysiological findings. By contrasting cerebellar observations with those from the cerebral cortex and hippocampus, we highlight the cerebellum's distinct role in the disease processes. Furthermore, we also explore the emerging therapeutic potential of targeting cerebellum for the treatment of these diseases. This review underscores the importance of the cerebellum in these diseases, offering new insights into the disease mechanisms and novel therapeutic strategies.

Superoxide dismutase and neurological disorders.

Superoxide dismutase (SOD) is a common antioxidant enzyme found majorly in living cells. The main physiological role of SOD is detoxification and maintain the redox balance, acts as a first line of defence against Reactive nitrogen species (RNS), Reactive oxygen species (ROS), and other such potentially hazardous molecules. SOD catalyses the conversion of superoxide anion free radicals (O 2 -.) into molecular oxygen (O 2) and hydrogen peroxide (H 2O 2) in the cells. Superoxide dismutases (SODs) are expressed in neurons and glial cells throughout the CNS both intracellularly and extracellularly. Endogenous oxidative stress (OS) linked with enlarged production of reactive oxygen metabolites (ROMs), inflammation, deregulation of redox balance, mitochondrial dysfunction and bioenergetic crisis are found to be prerequisite for neuronal loss in neurological diseases. Clinical and genetic studies indicate a direct correlation between mutations in SOD gene and neurodegenerative diseases, like Amyotrophic Lateral Sclerosis (ALS), Huntington's disease (HD), Parkinson's Disease (PD) and Alzheimer's Disease (AD). Therefore, inhibitors of OS are considered as an optimistic approach to prevent neuronal loss. SOD mimetics like Metalloporphyrin Mn (II)-cyclic polyamines, Nitroxides and Mn (III)- Salen complexes are designed and used as therapeutic extensively in the treatment of neurological disorders. SODs and SOD mimetics are promising future therapeutics in the field of various diseases with OS-mediated pathology.

Unveiling the role of exosomes as cellular messengers in neurodegenerative diseases and their potential therapeutic implications.

Exosomes are a subgroup of extracellular vesicles that function as transmitters, allowing cells to communicate more effectively with each other. However, exosomes may have both beneficial and harmful impacts on central nervous system disorders. Hence, the fundamental molecular mechanisms of the origin of illness and its progression are currently being investigated. The involvement of exosomes in the origin and propagation of neurodegenerative illness has been demonstrated recently. Exosomes provide a representation of the intracellular environment since they include various essential bioactive chemicals. The latest studies have demonstrated that exosomes transport several proteins. Additionally, these physiological vesicles are important in the regeneration of nervous tissue and the healing of neuronal lesions. They also offer a microenvironment to stimulate the conformational variation of concerning proteins for aggregation, resulting in neurodegenerative diseases. The biosynthesis, composition, and significance of exosomes as extracellular biomarkers in neurodegenerative disorders are discussed in this article, with a particular emphasis on their neuroprotective effects.

Exploring the neural and behavioral correlates of cognitive telerehabilitation in mild cognitive impairment with three distinct approaches.

Background: Currently, the impact of drug therapies on neurodegenerative conditions is limited. Therefore, there is a strong clinical interest in non-pharmacological interventions aimed at preserving functionality, delaying disease progression, reducing disability, and improving quality of life for both patients and their caregivers. This longitudinal multicenter Randomized Controlled Trial (RCT) applies three innovative cognitive telerehabilitation (TR) methods to evaluate their impact on brain functional connectivity reconfigurations and on the overall level of cognitive and everyday functions. Methods: We will include 110 participants with mild cognitive impairment (MCI). Fifty-five participants will be randomly assigned to the intervention group who will receive cognitive TR via three approaches, namely: (a) Network-based Cognitive Training (NBCT), (b) Home-based Cognitive Rehabilitation (HomeCoRe), or (c) Semantic Memory Rehabilitation Training (SMRT). The control group (n = 55) will receive an unstructured home-based cognitive stimulation. The rehabilitative program will last either 4 (NBTC) or 6 weeks (HomeCoRe and SMRT), and the control condition will be adapted to each TR intervention. The effects of TR will be tested in terms of Δ connectivity change, obtained from high-density electroencephalogram (HD-EEG) or functional magnetic resonance imaging at rest (rs-fMRI), acquired before (T0) and after (T1) the intervention. All participants will undergo a comprehensive neuropsychological assessment at four time-points: baseline (T0), within 2 weeks (T1), and after 6 (T2) and 12 months (T3) from the end of TR. Discussion: The results of this RCT will identify a potential association between improvement in performance induced by individual cognitive TR approaches and modulation of resting-state brain connectivity. The knowledge gained with this study might foster the development of novel TR approaches underpinned by established neural mechanisms to be validated and implemented in clinical practice.Clinical trial registration: [https://classic.clinicaltrials.gov/ct2/show/NCT06278818], identifier [NCT06278818].

Glutamatergic Neurotransmission in Aging and Neurodegenerative Diseases: A Potential Target to Improve Cognitive Impairment in Aging.

Aging is characterized by the decline in many of the individual's capabilities. It has been recognized that the brain undergoes structural and functional changes during aging that are occasionally associated with the development of neurodegenerative diseases. In this sense, altered glutamatergic neurotransmission, which involves the release, binding, reuptake, and degradation of glutamate (Glu) in the brain, has been widely studied in physiological and pathophysiological aging. In particular, changes in glutamatergic neurotransmission are exacerbated during neurodegenerative diseases and are associated with cognitive impairment, characterized by difficulties in memory, learning, concentration, and decision-making. Thus, in the present manuscript, we aim to highlight the relevance of glutamatergic neurotransmission during cognitive impairment to develop novel strategies to prevent, ameliorate, or delay cognitive decline. To achieve this goal, we provide a comprehensive review of the changes reported in glutamatergic neurotransmission components, such as Glu transporters and receptors during physiological aging and in the most studied neurodegenerative diseases. Finally, we describe the current therapeutic strategies developed to target glutamatergic neurotransmission.

Pore-Forming VDAC Proteins of the Outer Mitochondrial Membrane: Regulation and Pathophysiological Role.

Voltage-dependent anion channels (VDAC1-3) of the outer mitochondrial membrane are a family of pore-forming ß-barrel proteins that carry out controlled "filtration" of small molecules and ions between the cytoplasm and mitochondria. Due to the conformational transitions between the closed and open states and interaction with cytoplasmic and mitochondrial proteins, VDACs not only regulate the mitochondrial membrane permeability for major metabolites and ions, but also participate in the control of essential intracellular processes and pathological conditions. This review discusses novel data on the molecular structure, regulatory mechanisms, and pathophysiological role of VDAC proteins, as well as future directions in this area of research.

Unique Properties of Synaptosomes and Prospects for Their Use for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is a severe neurodegenerative condition affecting millions worldwide. Prevalence of AD correlates with increased life expectancy and aging population in the developed countries. Considering that AD is a multifactorial disease involving various pathological processes such as synaptic dysfunction, neuroinflammation, oxidative stress, and improper protein folding, a comprehensive approach targeting multiple pathways may prove effective in slowing the disease progression. Cellular therapy and its further development in the form of cell vesicle and particularly mitochondrial transplantation represent promising approaches for treating neurodegeneration. The use of synaptosomes, due to uniqueness of their contents, could mark a new stage in the development of comprehensive therapies for neurodegenerative diseases, particularly AD. Synaptosomes contain unique memory mitochondria, which differ not only in size but also in functionality compared to the mitochondria in the neuronal soma. These synaptosomal mitochondria actively participate in cellular communication and signal transmission within synapses. Synaptosomes also contain other elements such as their own protein synthesis machinery, synaptic vesicles with neurotransmitters, synaptic adhesion molecules, and microRNAs - all crucial for synaptic transmission and, consequently, cognitive processes. Complex molecular ensemble ensures maintenance of the synaptic autonomy of mitochondria. Additionally, synaptosomes, with their affinity for neurons, can serve as an optimal platform for targeted drug delivery to nerve cells. This review discusses unique composition of synaptosomes, their capabilities and advantages, as well as limitations of their suggested use as therapeutic agents for treating neurodegenerative pathologies, particularly AD.

The Role of Smad3 in the Realization of the Growth Potential of Different Types of Neural Progenitor Cells and the Secretory Function of Neuroglia.

The features of the participation of Smad3 in the functioning of neural stem cells (NSC), neuronal committed precursors (NCP), and neuroglial elements were studied in vitro. It was found that this intracellular signaling molecule enhances the clonogenic and proliferative activities of NCP and inhibits specialization of neuronal precursors. At the same time, Smad3 does not participate in the realization of the growth potential of NSC. With regard to the secretory function (production of neurotrophic growth factors) of neuroglial cells, the stimulating role of Smad3-mediated signaling was shown. These results indicate the promise of studying the possibility of using Smad3 as a fundamentally new target for neuroregenerative agents.

Post-translational modifications in prion diseases.

More than 650 reversible and irreversible post-translational modifications (PTMs) of proteins have been listed so far. Canonical PTMs of proteins consist of the covalent addition of functional or chemical groups on target backbone amino-acids or the cleavage of the protein itself, giving rise to modified proteins with specific properties in terms of stability, solubility, cell distribution, activity, or interactions with other biomolecules. PTMs of protein contribute to cell homeostatic processes, enabling basal cell functions, allowing the cell to respond and adapt to variations of its environment, and globally maintaining the constancy of the milieu interieur (the body's inner environment) to sustain human health. Abnormal protein PTMs are, however, associated with several disease states, such as cancers, metabolic disorders, or neurodegenerative diseases. Abnormal PTMs alter the functional properties of the protein or even cause a loss of protein function. One example of dramatic PTMs concerns the cellular prion protein (PrPC), a GPI-anchored signaling molecule at the plasma membrane, whose irreversible post-translational conformational conversion (PTCC) into pathogenic prions (PrPSc) provokes neurodegeneration. PrPC PTCC into PrPSc is an additional type of PTM that affects the tridimensional structure and physiological function of PrPC and generates a protein conformer with neurotoxic properties. PrPC PTCC into PrPSc in neurons is the first step of a deleterious sequence of events at the root of a group of neurodegenerative disorders affecting both humans (Creutzfeldt-Jakob diseases for the most representative diseases) and animals (scrapie in sheep, bovine spongiform encephalopathy in cow, and chronic wasting disease in elk and deer). There are currently no therapies to block PrPC PTCC into PrPSc and stop neurodegeneration in prion diseases. Here, we review known PrPC PTMs that influence PrPC conversion into PrPSc. We summarized how PrPC PTCC into PrPSc impacts the PrPC interactome at the plasma membrane and the downstream intracellular controlled protein effectors, whose abnormal activation or trafficking caused by altered PTMs promotes neurodegeneration. We discussed these effectors as candidate drug targets for prion diseases and possibly other neurodegenerative diseases.