Deposition Of Insoluble Proteins Research Articles

Widespread nuclear lamina injuries defeat proteostatic purposes of α-synuclein amyloid inclusions.

Biogenesis of inclusion bodies (IBs) facilitates protein quality control (PQC). Canonical aggresomes execute degradation of misfolded proteins while non-degradable amyloids sequester into insoluble protein deposits. Lewy bodies (LBs) are filamentous amyloid inclusions of α-synuclein, but PQC benefits and drawbacks associated with LB-like IBs remain underexplored. Here, we report that crosstalk between filamentous LB-like IBs and aggresome-like IBs of α-synuclein (Syn-aggresomes) buffer the load, aggregation state, and turnover of the amyloidogenic protein in mouse primary neurons and HEK293T cells. Filamentous LB-like IBs possess unorthodox PQC capacities of self-quarantining α-synuclein amyloids and being degradable upon receding fresh amyloidogenesis. Syn-aggresomes equilibrate biogenesis of filamentous LB-like IBs by facilitating spontaneous degradation of α-synuclein and conditional turnover of disintegrated α-synuclein amyloids. Thus, both types of IB primarily contribute to PQC. Incidentally, the overgrown perinuclear LB-like IBs become degenerative once these are misidentified by BICD2, a cargo-adapter for the cytosolic motor-protein dynein. Microscopy indicates that microtubules surrounding the perinuclear filamentous inclusions are also distorted, misbalancing the cytoskeleton-nucleoskeleton tension leading to widespread lamina injuries. Together, nucleocytoplasmic mixing, DNA damage, and deregulated transcription of stress chaperones defeat the proteostatic purposes of the filamentous amyloids of α-synuclein.

Sequestrase chaperones protect against oxidative stress-induced protein aggregation and [PSI+] prion formation.

Misfolded proteins are usually refolded to their functional conformations or degraded by quality control mechanisms. When misfolded proteins evade quality control, they can be sequestered to specific sites within cells to prevent the potential dysfunction and toxicity that arises from protein aggregation. Btn2 and Hsp42 are compartment-specific sequestrases that play key roles in the assembly of these deposition sites. Their exact intracellular functions and substrates are not well defined, particularly since heat stress sensitivity is not observed in deletion mutants. We show here that Btn2 and Hsp42 are required for tolerance to oxidative stress conditions induced by exposure to hydrogen peroxide. Btn2 and Hsp42 act to sequester oxidized proteins into defined PQC sites following ROS exposure and their absence leads to an accumulation of protein aggregates. The toxicity of protein aggregate accumulation causes oxidant sensitivity in btn2 hsp42 sequestrase mutants since overexpression of the Hsp104 disaggregase rescues oxidant tolerance. We have identified the Sup35 translation termination factor as an in vivo sequestrase substrate and show that Btn2 and Hsp42 act to suppress oxidant-induced formation of the yeast [PSI+] prion, which is the amyloid form of Sup35. [PSI+] prion formation in sequestrase mutants does not require IPOD (insoluble protein deposit) localization which is the site where amyloids are thought to undergo fragmentation and seeding to propagate their heritable prion form. Instead, both amorphous and amyloid Sup35 aggregates are increased in btn2 hsp42 mutants consistent with the idea that prion formation occurs at multiple intracellular sites during oxidative stress conditions in the absence of sequestrase activity. Taken together, our data identify protein sequestration as a key antioxidant defence mechanism that functions to mitigate the damaging consequences of protein oxidation-induced aggregation.

Tau accumulation in degradative organelles is associated to lysosomal stress

Neurodegenerative disorders are characterized by the brain deposition of insoluble amyloidogenic proteins, such as α-synuclein or Tau, and the concomitant deterioration of cell functions such as the autophagy-lysosomal pathway (ALP). The ALP is involved in the degradation of intracellular macromolecules including protein aggregates. ALP dysfunction due to inherited defects in lysosomal or non-lysosomal proteins causes a group of diseases called lysosomal storage disorders (LSD) because of abnormal accumulation of lysosomal degradation substrates. Supporting the contribution of ALP defects in neurodegenerative diseases, deposition of amyloidogenic proteins occurs in LSD. Moreover, heterozygous mutations of several ALP genes represent risk factors for Parkinson’s disease. The reciprocal contribution of α-synuclein accumulation and lysosomal dysfunction have been extensively studied. However, whether this adverse crosstalk also embraces Tau pathology needs more investigation. Here, we show in human primary fibroblasts that Tau seeds isolated from the brain of Alzheimer’s disease induce Tau accumulation in acidic degradative organelles and lysosomal stress. Furthermore, inhibition of glucocerebrosidase, a lysosomal enzyme mutated in Gaucher’s disease and a main risk for Parkinson’s disease, causes lysosomal dysfunction in primary fibroblasts and contributes to the accumulation of Tau. Considering the presence of Tau lesions in Parkinson’s disease as well as in multiple neurodegenerative disorders including Alzheimer’s disease, our data call for further studies on strategies to alleviate ALP dysfunction as new therapeutic opportunity for neurodegenerative diseases and LSD.

A monocarboxylate transporter rescues frontotemporal dementia and Alzheimer's disease models.

Brains are highly metabolically active organs, consuming 20% of a person's energy at resting state. A decline in glucose metabolism is a common feature across a number of neurodegenerative diseases. Another common feature is the progressive accumulation of insoluble protein deposits, it's unclear if the two are linked. Glucose metabolism in the brain is highly coupled between neurons and glia, with glucose taken up by glia and metabolised to lactate, which is then shuttled via transporters to neurons, where it is converted back to pyruvate and fed into the TCA cycle for ATP production. Monocarboxylates are also involved in signalling, and play broad ranging roles in brain homeostasis and metabolic reprogramming. However, the role of monocarboxylates in dementia has not been tested. Here, we find that increasing pyruvate import in Drosophila neurons by over-expression of the transporter bumpel, leads to a rescue of lifespan and behavioural phenotypes in fly models of both frontotemporal dementia and Alzheimer's disease. The rescue is linked to a clearance of late stage autolysosomes, leading to degradation of toxic peptides associated with disease. We propose upregulation of pyruvate import into neurons as potentially a broad-scope therapeutic approach to increase neuronal autophagy, which could be beneficial for multiple dementias.

The yeast guanine nucleotide exchange factor Sec7 is a bottleneck in spatial protein quality control and detoxifies neurological disease proteins

ER-to-Golgi trafficking partakes in the sorting of misfolded cytoplasmic proteins to reduce their cytological toxicity. We show here that yeast Sec7, a protein involved in proliferation of the Golgi, is part of this pathway and participates in an Hsp70-dependent formation of insoluble protein deposits (IPOD). Sec7 associates with the disaggregase Hsp104 during a mild heat shock and increases the rate of Hsp104 diffusion in an Hsp70-dependent manner when overproduced. Sec7 overproduction increased formation of IPODs from smaller aggregates and mitigated the toxicity of Huntingtin exon-1 upon heat stress while Sec7 depletion increased sensitivity to aẞ42 of the Alzheimer’s disease and α-synuclein of the Parkinson’s disease, suggesting a role of Sec7 in mitigating proteotoxicity.

Syntaxin 5-dependent phosphorylation of the small heat shock protein Hsp42 and its role in protein quality control.

The small heat shock protein Hsp42 and the t-SNARE protein Sed5 have central roles in the sequestration of misfolded proteins into insoluble protein deposits in the yeast Saccharomyces cerevisiae. However, whether these proteins/processes interact in protein quality control (PQC) is not known. Here, we show that Sed5 and anterograde trafficking modulate phosphorylation of Hsp42 partially via the MAPK kinase Hog1. Such phosphorylation, specifically at residue S215, abrogated the co-localization of Hsp42 with the Hsp104 disaggregase, aggregate clearance, chaperone activity, and sequestration of aggregates to IPOD and mitochondria. Furthermore, we found that Hsp42 is hyperphosphorylated in old cells leading to a drastic failure in disaggregation. Old cells also displayed a retarded anterograde trafficking, which, together with slow aggregate clearance and hyperphosphorylation of Hsp42, could be counteracted by Sed5 overproduction. We hypothesize that the breakdown of proper PQC during yeast aging may, in part, be due to a retarded anterograde trafficking leading to hyperphosphorylation of Hsp42.

Clinical Application of 99mTc-Pyrophosphate Scintigraphy for Diagnosis of Cardiac Amyloidosis: A Case Series.

Cardiac amyloidosis (CA) is an infiltrative cardiomyopathy resulting from deposition of insoluble amyloid protein in the myocardial interstitium. The accumulation of amyloid protein causes the myocardium to thicken and stiffen, leading to diastolic dysfunction and, eventually, heart failure. Two primary types of amyloidosis-transthyretin and immunoglobulin light chain-account for nearly 95% of all CA diagnoses. Three case studies are presented. The first demonstrates a patient positive for transthyretin amyloidosis, the second demonstrates a patient positive for light-chain CA, and the third demonstrates a patient showing blood-pool uptake on the [99mTc]Tc-pyrophosphate scan but negative for CA.

Release of frustration drives corneal amyloid disaggregation by brain chaperone

TGFBI-related corneal dystrophy (CD) is characterized by the accumulation of insoluble protein deposits in the corneal tissues, eventually leading to progressive corneal opacity. Here we show that ATP-independent amyloid-β chaperone L-PGDS can effectively disaggregate corneal amyloids in surgically excised human cornea of TGFBI-CD patients and release trapped amyloid hallmark proteins. Since the mechanism of amyloid disassembly by ATP-independent chaperones is unknown, we reconstructed atomic models of the amyloids self-assembled from TGFBIp-derived peptides and their complex with L-PGDS using cryo-EM and NMR. We show that L-PGDS specifically recognizes structurally frustrated regions in the amyloids and releases those frustrations. The released free energy increases the chaperone’s binding affinity to amyloids, resulting in local restructuring and breakage of amyloids to protofibrils. Our mechanistic model provides insights into the alternative source of energy utilized by ATP-independent disaggregases and highlights the possibility of using these chaperones as treatment strategies for different types of amyloid-related diseases.

A Review of Fifteen Years Developing Computational Tools to Study Protein Aggregation

The presence of insoluble protein deposits in tissues and organs is a hallmark of many human pathologies. In addition, the formation of protein aggregates is considered one of the main bottlenecks to producing protein-based therapeutics. Thus, there is a high interest in rationalizing and predicting protein aggregation. For almost two decades, our laboratory has been working to provide solutions for these needs. We have traditionally combined the core tenets of both bioinformatics and wet lab biophysics to develop algorithms and databases to study protein aggregation and its functional implications. Here, we review the computational toolbox developed by our lab, including programs for identifying sequential or structural aggregation-prone regions at the individual protein and proteome levels, engineering protein solubility, finding and evaluating prion-like domains, studying disorder-to-order protein transitions, or categorizing non-conventional amyloid regions of polar nature, among others. In perspective, the succession of the tools we describe illustrates how our understanding of the protein aggregation phenomenon has evolved over the last fifteen years.

Inactive Proteasomes Routed to Autophagic Turnover Are Confined within the Soluble Fraction of the Cell.

Previous studies demonstrated that dysfunctional yeast proteasomes accumulate in the insoluble protein deposit (IPOD), described as the final deposition site for amyloidogenic insoluble proteins and that this compartment also mediates proteasome ubiquitination, a prerequisite for their targeted autophagy (proteaphagy). Here, we examined the solubility state of proteasomes subjected to autophagy as a result of their inactivation, or under nutrient starvation. In both cases, only soluble proteasomes could serve as a substrate to autophagy, suggesting a modified model whereby substrates for proteaphagy are dysfunctional proteasomes in their near-native soluble state, and not as previously believed, those sequestered at the IPOD. Furthermore, the insoluble fraction accumulating in the IPOD represents an alternative pathway, enabling the removal of inactive proteasomes that escaped proteaphagy when the system became saturated. Altogether, we suggest that the relocalization of proteasomes to soluble aggregates represents a general stage of proteasome recycling through autophagy.

A Rare Case of Amyloid Light Chain Amyloidosis with Extensive Hepatic Involvement

Abstract Introduction/Objective Amyloid light chain (AL) amyloidosis is a life-threatening disease entity, with an incidence of 10–15 per million per year in the USA. Amyloidosis is caused by the extracellular deposition of insoluble fibrillary amyloid protein resulting in multiorgan damage. Though amyloidosis is primarily a systemic disease, 10%-20% of cases can be localized. Methods/Case Report We present a case of a 37-year-old male admitted with predominant hepatic manifestations, whose liver biopsy led to the diagnosis of amyloidosis. The patient presented with intermittent abdominal pain, weight loss, persistent hypoglycemia, hepatomegaly, and raised liver enzymes. Imaging studies showed hepatomegaly with a heterogeneous lace like appearance of the liver parenchyma. Liver biopsy revealed an extensive deposition of amyloid protein in peri-sinusoidal spaces. The amyloid protein is highlighted by crystal violet stain and revealed apple- green birefringence on polarized microscopy after Congo red staining. On further evaluation, elevated kappa and lambda free light chains with increased kappa-lambda ratio were identified by serum protein electrophoresis. Subsequent bone marrow aspirate and biopsy identified a monoclonal kappa positive plasma cell neoplasm with an amorphous eosinophilic infiltrate. Liquid chromatography-tandem mass spectrometry on bone marrow biopsy detected a peptide profile consistent with AL (kappa) type amyloid deposition. Results (if a Case Study enter NA) NA. Conclusion AL amyloidosis patients with predominant hepatic involvement have a worse prognosis. Rapid diagnosis and prompt clinical intervention prevents further organ damage. This case study aims to promote awareness of the unusual presentations of amyloidosis.

Updated Outlook of Cerebral Amyloid Angiopathy and Inflammatory Subtypes: Pathophysiology, Clinical Manifestations, Diagnosis and Management.

Cerebral amyloid angiopathy (CAA) is a common untreatable cause of lobar hemorrhages and cognitive decline in the older population. Subset of patients present with its inflammatory subtype with rapid decline in cognitive functions and neurological deficits. Most commonly the underlying pathophysiology of this disease is deposition of insoluble amyloid protein into blood vessel walls which results in vessel fragility leading to local neurotoxicity which may eventually leads to lobar hemorrhages and cognitive decline. The term "Amyloid Spell" encompasses transient focal neurological deficits which is commonly misdiagnosed as seizures or transient ischemic attack in the emergency department. Radiologic findings in these patients may reveal microbleeds, cortical superficial siderosis, white matter hyperintensities, and cerebral edema which support the clinical diagnosis which could be otherwise challenging. CAA diagnostic criteria require CT (Edinburgh Criteria) or MRI imaging, or neuropathology. The diagnosis can be suspected without imaging or neuropathology but cannot be confirmed. This review article provides a critical outlook on different types of presentations, updated diagnostic criteria and management of CAA patients illustrating underlying mechanisms associated with neuronal injury secondary to amyloid deposition.

Diving in the big blue: Atypical Mott cells in rapidly fatal primary amyloidosis.

A 75-year-old man with no previous medical history presented at the emergency unit with asthenia, anorexia, weight loss, and progressively increasing dyspnea revealing acute heart failure (N-terminal pro b-type natriuretic peptide:16 667 ng/L; troponemia: 47 ng/L). Echocardiography showed a granular appearance of the myocardium and interventricular septal hypertrophy, suggestive of amyloidosis. Chemistry disclosed high levels of immunoglobulin kappa light chains at 1240 mg/L (lambda light chains 14 mg/L; κ/λ ratio 86) and a detectable but unquantifiable IgA κ peak. Myocardial biopsies pathology showed an endocardium thickened by fibrosis. Within the myocardium, the presence of interstitial fibrillary deposits stained by Congo red and birefringent in polarized light confirmed the diagnosis of cardiac amyloid light-chain (AL) amyloidosis. The search for other organ damage disclosed vegetative involvement with orthostatic hypotension, icteric cholestasis (bilirubin 51.8 mg/L), undocumented digestive involvement (diarrhea with evocative endoscopic lesions), and glomerulonephritis (urinary proteinuria 4 g/24 h with 3 g/24 h albumin and 1 g/24 h immunoglobulin light chains). A bone marrow aspirate displayed 17% of plasma cells. Interestingly, a particular pattern of huge atypical Mott cells was identified (Figure 1A,B). The latter had so many cytoplasmic inclusions that the cytoplasm, and the nucleus could not be discriminated. These atypical cells are however plasma cells with an endoplasmic reticulum loaded with immunoglobulins and should be integrated as such in cell counts. Classical plasma cells and typical Mott cells with a few Russel bodies were also present (Figure 1C) indicating a continuum in the shape of the diseased plasma cells. Treatment with cyclophosphamide–bortezomib–dexamethasone-daratumumab was initiated in emergency. Unfortunately, the patient died 3 days later, of multiple organ failure. No additional septic or toxic causes could be identified. Mott cells are activated plasma cells containing intracytoplasmic inclusions with a “bunch of grapes” appearance. These inclusions, called Russell bodies, are dilated cisternae of the endoplasmic reticulum containing condensed immunoglobulins. They were identified in 1901 by the surgeon F.W Mott in the brains of monkeys with trypanosomiasis. Mott cells have been described in various pathological conditions: reactive plasmacytosis, monoclonal gammopathies, high grade B-cell lymphomas, Wiskott-Aldrich syndrome, and von Recklinghausen neurofibromatosis. AL amyloidosis is caused by clonal expansion of plasma cells producing misfolded immunoglobulin light chains responsible for the deposition of insoluble fibrillar proteins in many organs. Those most frequently affected are the kidneys, heart, liver, and peripheral nervous system. AL amyloidosis is a rare disease, and its diagnosis is often delayed. Although associated with a poor prognosis, AL amyloidosis presents a heterogeneous clinical expression and evolution. To our knowledge, the presence of Mott cells has rarely been described in this pathology. KR, ME, and BLC wrote the manuscript. KR, ME, and BLC performed biological analyses. CS treated the patient. All authors critically reviewed the manuscript. The authors have no conflict of interest to disclose. The authors received no specific funding for this work. The research was conducted in accordance with the principles embodied in the Declaration of Helsinki and in accordance with local statutory requirements.

THE EXTREME HETEROGENEITY OF AMYLOIDOSIS AT CLINICAL PRESENTATION

Amyloidosis is a rare and complex disease characterized by pathological extracellular tissue deposition of insoluble fibrillar protein in tissues which can cause severe organ dysfunction and result in various clinical manifestations depending on the affected area and the amount of material deposited. The symptoms of the disorder are nonspecific and, therefore, it may be difficult to suspect a diagnosis. To show the diagnostic spectrum in a disease with broad clinical and nonspecific manifestations, such as extreme weight loss, macroglossia and nephrotic syndrome. A 70-year-old man seeked medical attention due to important edema of ankles with Godet Sign 3+. During clinical evaluation, urinalysis exhibited proteinuria of 6000mg/24h, indicating nephrotic proteinuria. The patient reported mild fatigue and dyspnea. An echocardiogram suggested cardiac amyloidosis, which was confirmed after a fat pad biopsy stained with Congo Red under polarized light. The patient performed autologous bone marrow transplantation and is doing well after a two year follow up. An 83-year-old woman presented with macroglossia, leading her to have difficulty in eating. At physical examination, the skin manifestation known as raccoon's eyes due to vascular infiltration of amyloid fibrils in a symmetrical periorbital distribution was present. A fat pad biopsy was performed and revealed amyloid deposits. Furthermore, due to the presence of anemia, a bone marrow smear detected Multiple Myeloma (20% plasmocytes), suggesting secondary amyloidosis. The patient began treatment with daratumumab two months ago. A 62-year-old man seeked medical attention due to intense weight loss of over 39 pounds in a 6-month period. At physical examination, the patient was pale (3+/4), had intense muscle atrophy, depicting a consumptive syndrome. Due to anemia, a bone marrow trephine was performed, surprisingly revealing amyloid deposits. This report shows three very different clinical presentations of amyloidosis, reinforcing the extreme heterogeneity of the disorder. Besides the most common sites for amyloid deposits, it's important to notice the possibility of bone marrow infiltration and extreme weight loss. Therefore, it's crucial to beware of amyloidosis's multiple manifestations for better clinical investigation. In case 1, the patient was diagnosed with nephrotic syndrome, hence the kidneys being one of the most affected organs by amyloid deposits. The patient also showed cardiac involvement, where manifestations may include arrhythmias and heart failure. Those symptoms, when associated with signs of nephrotic syndrome, should raise suspicion for amyloidosis as the underlying cause. In case 2, a woman presenting with macroglossia developed, later on, periorbital purpura from amyloid deposits. The manifestation, known as raccoon's eyes, is characteristic of amyloidosis, but it is rare and only present in less than 10% of cases. In case 3, a 62-year-old patient presented with extreme weight loss and a consumptive syndrome. Due to his state of anemia, a bone marrow biopsy was performed and revealed amyloid deposits. A bone marrow biopsy is highly useful when determining the precursor protein while also screening for possible tissue infiltration and deposition.

Primary Systemic Amyloidosis of Tongue: Pitfall and Challenges in the Diagnosis

Amyloidosis is caused by the deposition of insoluble fibrillary protein in tissues and organs resulting in severe organ dysfunction. The clinical presentation for the diagnosis of amyloidosis is nonspecific, making it one of the most underdiagnosed conditions. Treatment is now available and is effective in improving patients’ survival and quality of life. We present a case of generalized amyloidosis in a 71-year-old patient admitted with a diagnosis of benign neoplasm of the root of the tongue. Subsequently, she underwent surgical treatment followed by purulent-septic complications developed leading to death. Microscopic examination of the biopsy tissue revealed deposits of amyloid and the patient was diagnosed to have primary generalized amyloidosis. These facts confirm the essential need to differentiate tumors from amyloidosis. Hence, this paper aims to provide physicians with knowledge about the clinical presentation that raises the suspicion of amyloidosis, bearing in mind the importance of early diagnosis.

A rare case of Liraglutide-induced iatrogenic amyloidosis

Abstract Iatrogenic amyloidosis has been linked to injectable drugs such as Enfuvirtide and insulin, which can cause cutaneous deposition of insoluble proteins. We present a rare case in which Liraglutide injections resulted in an iatrogenic amyloidosis. Our patient is a 63 year-old female with a 12-year history of type 2 diabetes mellitus complicated by peripheral neuropathy, on Liraglutide for 10 years, who presented with a 4-month history of developing abdominal subcutaneous masses. She underwent abdominal soft tissue mass excision and biopsy, which revealed Congo red stain positive for amyloid and apple green birefringence on polarization. Lab work and skeletal survey showed no abnormalities. Serum protein electrophoresis revealed no monoclonal protein. Mass spectrometry of amyloid tissue at Mayo clinic revealed Liraglutide detection by immunohistochemistry using glucagon antibodies, dense amyloid deposits typical of amyloid caused by injectable drugs, and a peptide profile inconclusive for an amyloid type-all confirming a diagnosis of iatrogenic amyloidosis caused by Liraglutide injection. This case highlights a very rare side effect of Liraglutide injections. If biopsy confirms amyloid deposits, further workup is absolutely necessary to differentiate the forms of amyloidosis, as the treatment varies based on the kind of amyloidosis. Diabetic patients who are on Liraglutide can have other signs and symptoms which overlap with symptoms of AL amyloidosis. Hence further workup including mass spectroscopy to type the amyloid are vital.

A Potential Mechanism for Targeting Aggregates With Proteasomes and Disaggregases in Liquid Droplets.

Insoluble protein deposits are hallmarks of neurodegenerative disorders and common forms of dementia. The aberrant aggregation of misfolded proteins involves a complex cascade of events that occur over time, from the cellular to the clinical phase of neurodegeneration. Declining neuronal health through increased cell stress and loss of protein homeostasis (proteostasis) functions correlate with the accumulation of aggregates. On the cellular level, increasing evidence supports that misfolded proteins may undergo liquid-liquid phase separation (LLPS), which is emerging as an important process to drive protein aggregation. Studying the reverse process of aggregate disassembly and degradation has only recently gained momentum, following reports of enzymes with distinct aggregate-disassembly activities. In this review, we will discuss how the ubiquitin-proteasome system and disaggregation machineries such as VCP/p97 and HSP70 system may disassemble and/or degrade protein aggregates. In addition to their canonically associated functions, these enzymes appear to share a common feature: reversibly assembling into liquid droplets in an LLPS-driven manner. We review the role of LLPS in enhancing the disassembly of aggregates through locally increasing the concentration of these enzymes and their co-proteins together within droplet structures. We propose that such activity may be achieved through the concerted actions of disaggregase machineries, the ubiquitin-proteasome system and their co-proteins, all of which are condensed within transient aggregate-associated droplets (TAADs), ultimately resulting in aggregate clearance. We further speculate that sustained engagement of these enzymatic activities within TAADs will be detrimental to normal cellular functions, where these activities are required. The possibility of facilitating endogenous disaggregation and degradation activities within TAADs potentially represents a novel target for therapeutic intervention to restore protein homeostasis at the early stages of neurodegeneration.

POS-530 SYSTEMIC LUPUS AND RENAL AMYLOIDOSIS: A RARE ASSOCIATION

Systemic lupus erythematosus (SLE) is the most common autoimmune disease responsible for kidney damage. Amyloidosis is a large group of diseases diagnosed histologically by the presence of insoluble protein deposits in tissues. AA Amyloidosis is a well-known complication of chronic inflammatory, rheumatic and malignant diseases. However, the occurrence of renal or multivisceral amyloidosis is considered exceptional during the course of a systemic lupus erythematosus. We report a new observation .

Neuromuscular Complications of Systemic Amyloidosis

Systemic amyloidosis is characterized by extracellular deposition of insoluble fibrillar proteins in multiple tissues, frequently at a distance from the site of synthesis. The 2 most common forms, light chain (AL) and transthyretin (ATTR) amyloidosis can cause peripheral neuropathy and, rarely, myopathy. Diagnosis can be challenging, and abundant suspicion is required to identify patients. As neurological manifestations of amyloidosis may precede involvement of other organs by several years, recognizing amyloid neuropathy and myopathy are crucial, especially in this new and exciting era of effective therapies for AL and ATTR neuropathy. This review will focus on the neuromuscular manifestations of AL and ATTR amyloidosis, diagnostic approaches, and recent advances in the treatment of amyloid neuropathy.

Renal Amyloidosis: A Clinicopathological Study From a Tertiary Care Hospital in Pakistan.

IntroductionSystemic amyloidosis can affect any organ in the body, but the kidney is the most commonly involved site. It is characterized by the extracellular deposition of insoluble fibrillar proteins. Amyloid deposits can be identified histologically by Congo red stain, which gives apple-green birefringence under polarized light. Typing of renal amyloidosis is done by direct immunofluorescence on frozen tissue. The most common types of amyloidosis seen in renal tissue are amyloid light chain (AL) primary amyloidosis and amyloid A (AA) secondary amyloidosis. Although primary amyloidosis is considered the most common type in western countries, however, in the subcontinent region, secondary amyloidosis is more common.The spectrum of signs and symptoms in renal amyloidosis is variable including isolated proteinuria, nephrotic syndrome, hypertension, hypotension, and renal insufficiency. The present study aims to evaluate the incidence and aetiology of various types of renal amyloidosis, determine their distribution within the kidney, and study various clinicopathological features.ObjectiveThe present study aims to evaluate the aetiology and clinicopathological profile of renal amyloidosis, determine its various types, and their distribution within the kidney.Materials and methodsThis retrospective cross-sectional study was conducted from 1st January 2013 to 31st December 2020 at the Department of Histopathology, Shifa International Hospital (SIH), Islamabad. All renal biopsies diagnosed as renal amyloidosis were included in the study. Data were analysed using SPSS version 23 (IBM Corp., Armonk, NY). Frequency and percentages were calculated for qualitative variables, and mean and standard deviation were calculated for quantitative variables.ResultsA total of 131 cases were diagnosed with renal amyloidosis during the study period of eight years (from 1st January 2013 to 31st December 2020) at SIH. The age range varied from 17 to 82 years. The mean age of the patients was 45 ± 16.33 years. Out of 131 patients, 82 (62.6%) were males and 49 (37.4%) were females. Amongst them, 72 (54%) cases were diagnosed with secondary AA amyloidosis and 16 (12%) cases were diagnosed with primary AL amyloidosis. The rest of the cases 43 (34%) were of indeterminate type. The associated conditions in secondary amyloidosis were tuberculosis in 41 (57%), rheumatoid arthritis in 16 (22%), ankylosing spondylitis in five (7%), lymphoma in three (4%), diabetes in two (3%), and chronic osteomyelitis, chronic heart disease, hepatitis, and vasculitis in one case each (1.7%). Out of 16 cases reported with AL amyloidosis, 10 cases (62.5%) had a history of multiple myeloma. The most common clinical presentation was nephrotic syndrome followed by subnephrotic proteinuria, renal failure, and hypertension.ConclusionThe findings of the present study show underlying etiological factors and clinicopathological characteristics of renal amyloidosis. AA amyloidosis is the most common type of renal amyloidosis in our study and tuberculosis is the most common aetiological factor. AL amyloidosis is less frequent in our population.