The Effect of Different System Parameters on the Movement of Microbial Cells Using Light-Induced Dielectrophoresis.

The manipulation of single particles remains a topic of interest with many applications. Here we characterize the impact of selected parameters on the motion of single particles thanks to dielectrophoresis (DEP) induced by visible light, in a technique called Light-induced Dielectrophoresis, or LiDEP, also known as optoelectronic tweezers, optically induced DEP, and image-based DEP. Baker's yeast and Candida cells are exposed to an electric field gradient enabled by shining a photoconductive material with a specific pattern of visible light, and their response is measured in terms of the average cell velocity towards the gradient. The impact on cell velocity when varying the shape and color of the light pattern, as well as the distance from the cell to the pattern, is presented. The experimental setup featured a commercial light projector featuring digital light processing (DLP) technology but mechanically modified to accommodate a 40× microscope objective lens. The minimal resolution achieved on the light pattern was 8 µm. Experimental results show the capability for single cell manipulation and the possibility of using different shapes, colors, and distances to determine the average cell velocity.

Exploring the pathophysiological influence of heme oxygenase-1 on neuroinflammation and depression: A study of phytotherapeutic-based modulation.

BACKGROUND: The heme oxygenase (HO) system plays a significant role in neuroprotection and reduction of neuroinflammation and neurodegeneration. The system, via isoforms HO-1 and HO-2, regulates cellular redox balance. HO-1, an antioxidant defense enzyme, is highlighted due to its association with depression, characterized by heightened neuroinflammation and impaired oxidative stress responses. METHODOLOGY: We observed the pathophysiology of HO-1 and phytochemicals as its modulator. We explored Science Direct, Scopus, and PubMed for a comprehensive literature review. Bibliometric and temporal trend analysis were done using VOSviewer. RESULTS: Several phytochemicals can potentially alleviate neuroinflammation and oxidative stress-induced depressive symptoms. These effects result from inhibiting the MAPK and NK-κB pathways - both implicated in the overproduction of pro-inflammatory factors - and from the upregulation of HO-1 expression mediated by Nrf2. Bibliometric and temporal trend analysis further validates these associations. CONCLUSION: In summary, our findings suggest that antidepressant agents can mitigate neuroinflammation and depressive disorder pathogenesis via the upregulation of HO-1 expression. These agents suppress pro-inflammatory mediators and depressive-like symptoms, demonstrating that HO-1 plays a significant role in the neuroinflammatory process and the development of depression.

Cyanobacterial Proteomics: Diversity and Dynamics.

Cyanobacteria (oxygenic photoautrophs) comprise a diverse group holding significance both environmentally and for biotechnological applications. The utilization of proteomic techniques has significantly influenced investigations concerning cyanobacteria. Application of proteomics allows for large-scale analysis of protein expression and function within cyanobacterial systems. The cyanobacterial proteome exhibits tremendous functional, spatial, and temporal diversity regulated by multiple factors that continuously modify protein abundance, post-translational modifications, interactions, localization, and activity to meet the dynamic needs of these tiny blue greens. Modern mass spectrometry-based proteomics techniques enable system-wide examination of proteome complexity through global identification and high-throughput quantification of proteins. These powerful approaches have revolutionized our understanding of proteome dynamics and promise to provide novel insights into integrated cellular behavior at an unprecedented scale. In this Review, we present modern methods and cutting-edge technologies employed for unraveling the spatiotemporal diversity and dynamics of cyanobacterial proteomics with a specific focus on the methods used to analyze post-translational modifications (PTMs) and examples of dynamic changes in the cyanobacterial proteome investigated by proteomic approaches.

Targeting the vivid facets of apolipoproteins as a cardiovascular risk factor in rheumatoid arthritis.

Mostly, cardiovascular diseases are blamed for casualties in rheumatoid arthritis (RA) patients. Customarily, dyslipidemia is probably the most prevalent underlying cause of untimely demise in people suffering from RA as it hastens the expansion of atherosclerosis. The engagement of inflammatory cytokines like tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6), etc., is crucial in the progression and proliferation of both RA and abnormal lipid parameters. Thus, lipid abnormalities should be monitored frequently in patients with both primary and advanced RA stages. An advanced lipid profile examination, i.e., direct role of apolipoproteins associated with various lipid molecules is a more dependable approach for better understanding of the disease and selecting suitable therapeutic targets. Therefore, studying their apolipoproteins is more relevant than assessing RA patients' altered lipid profile levels. Among the various apolipoprotein classes, Apo A1 and Apo B are primarily being focused. In addition, it also addresses how calculating Apo B:Apo A1 ratio can aid in analyzing the disease's risk. The marketed therapies available to control lipid abnormalities are associated with many other risk factors. Hence, directly targeting Apo A1 and Apo B would provide a better and safer option.

Reactive oxygen species (ROS)-mediated oxidative stress in chronic liver diseases and its mitigation by medicinal plants.

Reactive oxygen species (ROS) play a crucial role in cell survival regulation, and its low levels may act as indicators to encourage cellular proliferation. In contrast, elevated levels of ROS may lead to apoptosis. Stability between generating and eliminating ROS allows the retention of effective functioning of redox-sensitive signaling proteins under physiologic conditions. Cells typically maintain redox homeostasis to guarantee appropriate responses to internal and external stimuli. However, oxidative stress occurs when the oxidation product level exceeds the number of standard antioxidant systems. ROS can cause harm to all types of hepatic cells, including endothelial cells, hepatocytes, Kupffer cells, and stellate cells. High levels of ROS may lead to tissue edema, ischemia, fibrosis, cell death, or malignant transformation and may eventually lead to complete tissue damage. Antioxidants in our body exist in a homeostatic balance with other enzymes involved in the repair of cellular functions in addition to the non-enzymatic molecules such as urate, bilirubin, several vitamins, and reduced glutathione to maintain the levels of ROS in the interest of cellular homeostasis. This balance may, however, get disturbed in case of acute or chronic liver injury due to the accumulation of ROS. In the current manuscript, we aim to review the relevance of oxidative stress and its indicator of liver injury in chronic liver diseases such as alcoholic and non-alcoholic fatty liver diseases and hepatitis. Since reactive oxidation species may also lead to lipid peroxidation and promote ferroptosis, we have also evaluated their impact on epigenetic modifications, such as oxidative damage to histone proteins and DNA methylation, and the differential expression of genes related to cellular injury. We also want to highlight the potential of traditional herbal medicines as redox regulators for managing chronic liver diseases.

Understanding the Therapeutic Approaches for Neuroprotection.

The term "neurodegenerative disorders" refers to a group of illnesses in which deterioration of nerve structure and function is a prominent feature. Cognitive capacities such as memory and decision-making deteriorate as a result of neuronal damage. The primary difficulty that remains is safeguarding neurons since they do not proliferate or regenerate spontaneously and are therefore not substituted by the body after they have been damaged. Millions of individuals throughout the world suffer from neurodegenerative diseases. Various pathways lead to neurodegeneration, including endoplasmic reticulum stress, calcium ion overload, mitochondrial dysfunction, reactive oxygen species generation, and apoptosis. Although different treatments and therapies are available for neuroprotection after a brain injury or damage, the obstacles are inextricably connected. Several studies have revealed the pathogenic effects of hypothermia, different breathed gases, stem cell treatments, mitochondrial transplantation, multi-pharmacological therapy, and other therapies that have improved neurological recovery and survival outcomes after brain damage. The present review highlights the use of therapeutic approaches that can be targeted to develop and understand significant therapies for treating neurodegenerative diseases.

Promising role of Vitamin D and plant metabolites against COVID-19: Clinical trials review.

Vitamin D possesses immunomodulatory qualities and is protective against respiratory infections. Additionally, it strengthens adaptive and cellular immunity and boosts the expression of genes involved in oxidation. Experts suggested taking vitamin D supplements to avoid and treat viral infection and also COVID-19, on the other hand, since the beginning of time, the use of plants as medicines have been vital to human wellbeing. The WHO estimates that 80 % of people worldwide use plants or herbs for therapeutic purposes. Secondary metabolites from medicinal plants are thought to be useful in lowering infections from pathogenic microorganisms due to their ability to inhibit viral protein and enzyme activity by binding with them. As a result, this manuscript seeks to describe the role of vitamin D and probable plant metabolites that have antiviral activities and may be complementary to the alternative strategy against COVID-19 in a single manuscript through reviewing various case studies.

BIN1 in the Pursuit of Ousting the Alzheimer's Reign: Impact on Amyloid and Tau Neuropathology.

Alzheimer's disease contributes to 60-70% of all dementia cases in the general population. Belonging to the BIN1/amphiphysin/RVS167 (BAR) superfamily, the bridging integrator (BIN1) has been identified to impact two major pathological hallmarks in Alzheimer's disease (AD), i.e., amyloid beta (Aß) and tau accumulation. Aß accumulation is found to increase by BIN1 knockdown in cortical neurons in late-onset AD, due to BACE1 accumulation at enlarged early endosomes. Two BIN1 mutants, KR and PL, were identified to exhibit Aß accumulation. Furthermore, BIN1 deficiency by BIN1-related polymorphisms impairs the interaction with tau, thus elevating tau phosphorylation, altering synapse structure and tau function. Even though the precise role of BIN1 in the neuronal tissue needs further investigation, the authors aim to throw light on the potential of BIN1 and unfold its implications on tau and Aß pathology, to aid AD researchers across the globe to examine BIN1, as an appropriate target gene for disease management.

Pretilachlor-induced physiological, biochemical and morphological changes in Indian paddy field agroecosystem inhabited Anabaena doliolum.

Pretilachlor is a systemic, pre-emergence herbicide applied in the paddy fields to kill narrow and broadleaf weeds. The present study evaluates the toxicity of pretilachlor on the non-target diazotrophic free-living cyanobacterium Anabaena doliolum, commonly found in the paddy fields of eastern Uttar Pradesh (India) and used as a biofertilizer. A.doliolum was subjected to several doses (0, 2, 5, 7, 10, 20 and 40 µg/ml) of pretilachlor and its effects were examined in terms of alterations in cellular morphology, ultrastructure, physiology, and biochemical attributes. The treatment of pretilachlor decreased the growth, total pigment content and photosynthetic efficiency of the test organism in a dose-dependent manner. The decline in growth was observed on 20th day at 2, 5, 7, 10, 20 and 40 µg/ml of pretilachlor concentration by 4, 9, 26, 47, 71 and 92%, respectively. Furthermore, Chlorophyll a and phycocyanin levels were noticeably declined. As a result, the photosynthetic performance also registered a similar decline as measured by chlorophyll fluorescence. However, carotenoid content increased by 13%, 41% and 53% at 5, 10 and 20 µg/ml on 5th day reflecting its protective property. A marked increase in fluorescence intensity and malondialdehyde content by 2.65 and 2.45 folds at 10 and 20 µg/ml on 7th day was registered. The enzymatic antioxidants (SOD and CAT) and a concurrent increase in glutathione reductase activity were registered (1.75 and 2.11-fold at 20 and 40 µg/ml on 5th day), indicating pretilachlor mediated ROS generation. Moreover, ultrastructural studies done by SEM and TEM revealed plasma membrane and thylakoid membrane damage and fragmentation. These findings have contributed to the broader comprehension of the stress responses triggered by pretilachlor in cyanobacteria. Moreover, they can aid in the evaluation of the detrimental impact of pretilachlor on A. doliolum, given their crucial function as a nitrogen contributor in paddy fields.

Understanding the mechanistic pathways and clinical aspects associated with protein and gene based biomarkers in breast cancer.

Cancer is one of the most widespread and severe diseases with a huge mortality rate. In recent years, the second-leading mortality rate of any cancer globally has been breast cancer, which is one of the most common and deadly cancers found in women. Detecting breast cancer in its initial stages simplifies treatment, decreases death risk, and recovers survival rates for patients. The death rate for breast cancer has risen to 0.024 % in some regions. Sensitive and accurate technologies are required for the preclinical detection of BC at an initial stage. Biomarkers play a very crucial role in the early identification as well as diagnosis of women with breast cancer. Currently, a wide variety of cancer biomarkers have been discovered for the diagnosis of cancer. For the identification of these biomarkers from serum or other body fluids at physiological amounts, many detection methods have been developed. In the case of breast cancer, biomarkers are especially helpful in discovering those who are more likely to develop the disease, determining prognosis at the time of initial diagnosis and choosing the best systemic therapy. In this study we have compiled various clinical aspects and signaling pathways associated with protein-based biomarkers and gene-based biomarkers.

Current trends in epigenetic, cellular and molecular pathways in management of rheumatoid arthritis.

Rheumatoid arthritis is a systemic chronic polyarticular autoimmune disorder of joints and joint membrane mainly affecting feet and hands. The pathological manifestation of the disease includes infiltration of immune cells, hyperplasia of the lining of synovium, formation of pannus and bone and cartilage destruction. If left untreated, the appearance of small focal necrosis, adhesion of granulation, and formation of fibrous tissue on the surface of articular cartilage is noted. The disease primarily affects nearly 1% of the population globally, women being more affected than men with a ratio 2:1 and can initiate regardless of any age. The synovial fibroblast in rheumatoid arthritis individuals exhibits an aggressive phenotype which upregulates the manifestation of protooncogenes, adhesive compounds, inflammatory cytokines and matrix-deteriorating enzymes. Apart from the inflammatory effects of cytokines, chemokines are also noted to induce swelling and pain in arthritic individuals by residing in synovial membrane and forming pannus. The current treatment of rheumatoid arthritis includes treatment with non-steroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, treatment with biologics such as inhibitors of TNF-α, interleukins, platelet activating factor, etc. which provides significant relief from symptoms and aids in management of the disease. The current review highlights the pathogenesis involved in the onset of rheumatoid arthritis and also covers epigenetic, cellular and molecular parameters associated with it to aid better and advanced therapeutic approaches for management of the debilitating disease.

Exploring the molecular pathways and therapeutic implications of angiogenesis in neuropathic pain.

Recently, much attention has been paid to chronic neuro-inflammatory condition underlying neuropathic pain. It is generally linked with thermal hyperalgesia and tactile allodynia. It results due to injury or infection in the nervous system. The neuropathic pain spectrum covers a variety of pathophysiological states, mostly involved are ischemic injury viral infections associated neuropathies, chemotherapy-induced peripheral neuropathies, autoimmune disorders, traumatic origin, hereditary neuropathies, inflammatory disorders, and channelopathies. In CNS, angiogenesis is evident in inflammation of neurons and pain in bone cancer. The role of chemokines and cytokines is dualistic; their aggressive secretion produces detrimental effects, leading to neuropathic pain. However, whether the angiogenesis contributes and exists in neuropathic pain remains doubtful. In the present review, we elucidated summary of diverse mechanisms of neuropathic pain associated with angiogenesis. Moreover, an overview of multiple targets that have provided insights on the VEGF signaling, signaling through Tie-1 and Tie-2 receptor, erythropoietin pathway promoting axonal growth are also discussed. Because angiogenesis as a result of these signaling, results in inflammation, we focused on the mechanisms of neuropathic pain. These factors are mainly responsible for the activation of post-traumatic regeneration of the PNS and CNS. Furthermore, we also reviewed synthetic and herbal treatments targeting angiogenesis in neuropathic pain.

Salinity pretreatment synergies heat shock toxicity in cyanobacterium Anabaena PCC7120.

This study was undertaken to bridge the knowledge gap pertaining to cyanobacteria's response to pretreatment. The result elucidates the synergistic effect of pretreatment toxicity in cyanobacterium Anabaena PCC7120 on morphological and biochemical attributes. Chemical (salt) and physical (heat) stress-pretreated cells exhibited significant and reproducible changes in terms of growth pattern, morphology, pigments, lipid peroxidation, and antioxidant activity. Salinity pretreatment showed more than a five-fold decrease in the phycocyanin content but a six-fold and five-fold increase in carotenoid, lipid peroxidation (MDA content), and antioxidant activity (SOD and CAT) at 1 h and on 3rd day of treatment, respectively, giving the impression of stress-induced free radicals that are scavenged by antioxidants when compared to heat shock pretreatment. Furthermore, quantitative analysis of transcript (qRT-PCR) for FeSOD and MnSOD displayed a 3.6- and 1.8-fold increase in salt-pretreated (S-H) samples. The upregulation of transcript corresponding to salt pretreatment suggests a toxic role of salinity in synergizing heat shock. However, heat pretreatment suggests a protective role in mitigating salt toxicity. It could be inferred that pretreatment enhances the deleterious effect. However, it further showed that salinity (chemical stress) augments the damaging effect of heat shock (physical stress) more profoundly than physical stress on chemical stress possibly by modulating redox balance via activation of antioxidant responses. Our study reveals that upon pretreatment of heat, the negative effect of salt can be mitigated in filamentous cyanobacteria, thus providing a foundation for improved cyanobacterial tolerance to salt stress.

Molecular Aspects and Therapeutic Implications of Herbal Compounds Targeting Different Types of Cancer.

Due to genetic changes in DNA (deoxyribonucleic acid) sequences, cancer continues to be the second most prevalent cause of death. The traditional target-directed approach, which is confronted with the importance of target function in healthy cells, is one of the most significant challenges in anticancer research. Another problem with cancer cells is that they experience various mutations, changes in gene duplication, and chromosomal abnormalities, all of which have a direct influence on the potency of anticancer drugs at different developmental stages. All of these factors combine to make cancer medication development difficult, with low clinical licensure success rates when compared to other therapy categories. The current review focuses on the pathophysiology and molecular aspects of common cancer types. Currently, the available chemotherapeutic drugs, also known as combination chemotherapy, are associated with numerous adverse effects, resulting in the search for herbal-based alternatives that attenuate resistance due to cancer therapy and exert chemo-protective actions. To provide new insights, this review updated the list of key compounds that may enhance the efficacy of cancer treatment.

Postulating the possible cellular signalling mechanisms of antibody drug conjugates in Alzheimer's disease.

Alzheimer's disease (AD) is one of the most common neurodegenerative disorders in the world. Although the basic pathology of the disease is elucidated, it is difficult to restore or prevent the worsening of neurodegeneration and its symptoms. Antibody and small molecule-based approaches have been studied and are in study individually, but a combined approach like conjugation has not been performed to date. The conjugation between antibodies and drugs which are already used for Alzheimer's treatment or developed specifically for this purpose may have better efficacy and dual action in mitigating Alzheimer's disease. A probable mechanism for antibody-drug conjugates in Alzheimer's disease is discussed in the present review.

Evaluation of different surface treated implants after provisionalization: A 6-month prospective study.

Background: Replacing missing teeth with dental implants has become the best treatment option; therefore, clinicians need to understand the predictability of the treatment. Surface treatment of implants is one of the methods to improve osseointegration, thus improving the quality of treatment. Increasing esthetic awareness among patients has led to the popularity of immediate provisionalization of dental implants. This study investigated the effect of surface treatment on implant stability when loaded with immediate non-functional temporary prostheses and compared the superiority of one surface treatment over the other in terms of osseointegration by evaluating implant stability quotient (ISQ). Methods: Twenty implants with different surface treatments were placed, i.e., resorbable blast media (RBM) surface and alumina blasted/acid-etched (AB/AE) surfaces. All the implants were non-functionally loaded, and ISQ was measured immediately after implant placement and 6 and 12 weeks after non-functional loading. Crestal bone levels, mPI, mSBI, and peri-implant probing depths were compared for both groups at 1, 3, and 6 months. Results: At 12 weeks, all the implants showed desirable ISQ, indicating successful osseointegration. The increase in ISQ at 12 weeks was significantly higher for RBM implants compared to baseline, indicating a more predictable course of osseointegration. Crestal bone levels recorded at 1, 3, and 6 months did not significantly differ between the groups. All other parameters showed comparable values for both groups at all intervals. Conclusion: Replacing missing teeth with dental implants with immediate non-functional restorations is a predictable treatment option.

Evaluation of Electrosurgery and Diode Laser in Gingival Depigmentation.

Introduction: Gingival depigmentation is a surgical procedure done to eliminate or reduce gingival hyperpigmentation. Various techniques are employed such as scalpel de-epithelization, gingivectomy, electrosurgery, use of chemical agents, cryosurgery, and lasers. The present study was conducted to assess the efficacy of laser and electrosurgical procedure in reducing gingival pigmentation in terms of pain, wound healing, and recurrence of melanin pigmentation. Methodology: A prospective study was conducted on 40 subjects affected by melanin pigmentation. Group I patients were treated with electrosurgery and Group II patients with diode laser procedure. Evaluation for pain was done intraoperatively, 24 hours and 7 days using VAS. Wound healing and recurrence of pigmentation was assessed at one month and three months. Results: No significant difference was noted between the two groups for pain assessment at 7 days with P > 0.001. Both electrosurgery and laser group showed significant differences between intraoperative time period to 24 hours and 24 hours to 7 days at P < 0.001 for pain. Conclusion: Esthetic demands necessitate cosmetic gingival depigmentation procedure. Laser diode photoablation proves to be an effective and reliable technique in achieving the same.

Phycochemistry and bioactivity of cyanobacterial secondary metabolites.

Microbes are a huge contributor to people's health around the world since they produce a lot of beneficial secondary metabolites. Cyanobacteria are photosynthetic prokaryotic bacteria cosmopolitan in nature. Adaptability of cyanobacteria to wide spectrum of environment can be contributed to the production of various secondary metabolites which are also therapeutic in nature. As a result, they are a good option for the development of medicinal molecules. These metabolites could be interesting COVID-19 therapeutic options because the majority of these compounds have demonstrated substantial pharmacological actions, such as neurotoxicity, cytotoxicity, and antiviral activity against HCMV, HSV-1, HHV-6, and HIV-1. They have been reported to produce a single metabolite active against wide spectrum of microbes like Fischerella ambigua produces ambigols active against bacteria, fungi and protozoa. Similarly, Moorea producens produces malygomides O and P, majusculamide C and somocystinamide which are active against bacteria, fungi and tumour cells, respectively. In addition to the above, Moorea sp. produce apratoxin A and dolastatin 15 possessing anti cancerous activity but unfortunately till date only brentuximab vedotin (trade name Adcetris), a medication derived from marine peptides, for the treatment of Hodgkin lymphoma and anaplastic large cell lymphoma has been approved by FDA. However, several publications have effectively described and categorised cyanobacterial medicines based on their biological action. In present review, an effort is made to categorize cyanobacterial metabolites on the basis of their phycochemistry. The goal of this review is to categorise cyanobacterial metabolites based on their chemical functional group, which has yet to be described.

Elucidating the Neuroprotective Effect of Tecoma stans Leaf Extract in STZ-Induced Diabetic Neuropathy.

Background: Diabetes is considered one of the most encyclopedic metabolic disorders owing to an alarming rise in the number of patients, which is increasing at an exponential rate. With the current therapeutics, which only aims to provide symptomatic and momentary relief, the scientists are shifting gears to explore alternative therapies which not only can target diabetes but can also help in limiting the progression of diabetic complications including diabetic neuropathy (DN). Methods: Tecoma stans leaf methanolic extract was prepared using the Soxhlet method. A streptozotocin (STZ; 45 mg/kg)-induced diabetic animal model was used and treatment with oral dosing of T. stans leaf extract at the different doses of 200 mg/kg, 300 mg/kg, and highest dose, i.e., 400 mg/kg, was initiated on day 3 after STZ administration. The pharmacological response for general and biochemical (angiogenic, inflammatory, and oxidative) parameters and behavioral parameters were compared using Gabapentin as a standard drug with the results from the test drug. Results: Parameters associated with the pathogenesis of diabetic neuropathy were evaluated. For general parameters, different doses of T. stans extract (TSE) on blood sugar showed significant effects as compared to the diabetic group. Also, the results from biochemical analysis and behavioral parameters showed significant positive effects in line with general parameters. The combination therapy of TSE at 400 mg/kg with a standard drug produced nonsignificant effects in comparison with the normal group. Conclusion: The leaves of T. stans possess antidiabetic effects along with promising effects in the management of DN by producing significant effects by exhibiting antioxidative, antiangiogenic, and anti-inflammatory properties, which are prognostic markers for DN, and thus, T. stans can be considered as an emerging therapeutic option for DN.

Exploring the Role of Ubiquitin-Proteasome System in Parkinson's Disease.

Over the last decade, researchers have discovered that a group of apparently unrelated neurodegenerative disorders, such as Parkinson's disease, have remarkable cellular and molecular biology similarities. Protein misfolding and aggregation are involved in all of the neurodegenerative conditions; as a result, inclusion bodies aggregation starts in the cells. Chaperone proteins and ubiquitin (26S proteasome's proteolysis signal), which aid in refolding misfolded proteins, are frequently found in these aggregates. The discovery of disease-causing gene alterations that code for multiple ubiquitin-proteasome pathway proteins in Parkinson's disease has strengthened the relationship between the ubiquitin-proteasome system and neurodegeneration. The specific molecular linkages between these systems and pathogenesis, on the other hand, are unknown and controversial. We outline the current level of knowledge in this article, focusing on important unanswered problems.