Rakesh Kumar

Karolinska Institutet | KI · Department of Biosciences and Nutrition

Dementia with Lewy Bodies (DLB) is the second most common cause of neurodegenerative dementia but the field is still lacking a specific biomarker for its core pathology: alpha-synuclein. Real-time quaking induced conversion (RT-QuIC) has recently emerged as a strong candidate of alpha-synuclein biomarker. However, the variability in the technique p...

Metal ions, such as copper and zinc ions, have been shown to strongly modulate the self-assembly of the amyloid-β (Aβ) peptide into insoluble fibrils, and elevated concentrations of metal ions have been found in amyloid plaques of Alzheimer's patients. Among the physiological transition metal ions, Cu(II) ions play an outstanding role since they ca...

Biomolecules are known to interact with metals and produce nanostructured hybrid materials with diverse morphologies and functions. In spite of the great advancement in the principles of biomimetics for designing complex nano-bio structures, the interplay between the physical properties of biomolecules such as sequence, charge, and hydrophobicity w...

Recombinant spider silk proteins (spidroins) have multiple potential applications in development of novel biomaterials, but their multimodal and aggregation-prone nature have complicated production and straightforward applications. Here, we report that recombinant miniature spidroins, and importantly also the N-terminal domain (NT) on its own, rapi...

Amyloid-β peptide (Aβ) aggregation is one of the hallmarks of Alzheimer's disease (AD). Mutations in Aβ are associated with early onset familial AD, and the Arctic mutant E22G (Aβarc) is an extremely aggregation-prone variant. Here, we show that BRICHOS, a natural anti-amyloid chaperone domain, from Bri2 efficiently inhibits aggregation of Aβarc by...

The size of amyloid seeds is known to modulate their autocatalytic amplification and cellular toxicity. However, the seed size-dependent secondary nucleation mechanism, toxicity, and disease-associated biological processes mediated by α-synuclein (α-Syn) fibrils are largely unknown. Using the cellular model and in vitro reconstitution, we showed th...

α-Synuclein (α-Syn) amyloids in synucleinopathies are suggested to be structurally and functionally diverse, reminiscent of prion-like strains. But how the aggregation of the same precursor protein results in the formation of fibril polymorphs remains elusive. Here, we demonstrate the structure-function relationship of two polymorphs, pre-matured f...

Findings of early cerebral amyloid-β deposition in mice after peripheral injection of amyloid-β-containing brain extracts, and in humans following cadaveric human growth hormone treatment raised concerns that amyloid-β aggregates and possibly Alzheimer's disease may be transmissible between individuals. Yet, proof that Aβ actually reaches the brain...

Alzheimer’s disease (AD) is characterized by impaired protein homeostasis leading to amyloid-β peptide (Aβ) amyloidosis. Amyloid precursor protein (APP) knock-in mice exhibit robust Aβ pathology, providing possibilities to determine its effect on protein homeostasis including autophagy. Here we compared human AD postmortem brain tissue with brains...

The size of the amyloid seeds is known to modulate their autocatalytic amplification and cellular toxicity. However, the seed size-dependent secondary nucleation mechanism, toxicity, and disease-associated biological processes mediated by α-synuclein (α-Syn) fibrils are largely unknown. Using the cellular model and in vitro reconstitution, we showe...

Amyloid fibrils are mechanically robust and partly resistant to proteolytic degradation, making them potential candidates for scaffold materials in cell culture, tissue engineering, drug delivery and other applications. Such applications of amyloids would benefit from the possibility to functionalize the fibrils, for example by adding growth factor...

Photothermal effects of metal nanoparticles (NPs) are used for various biotechnological applications. Although NPs have been used in a polymerase chain reaction (PCR), the effects of shape on the photothermal properties and its efficiency on PCR are less explored. The present study reports the synthesis of triangular gold and silver NPs, which can...

α-Synuclein (α-Syn) aggregation and amyloid formation is directly linked with Parkinson's disease pathogenesis. However, the early events involved in this process remain unclear. Here, using the in vitro reconstitution and cellular model, we show that liquid-liquid phase separation of α-Syn precedes its aggregation. In particular, in vitro generate...

Synucleinopathies are a class of neurodegenerative diseases, including Parkinson’s disease (PD), Dementia with Lewy bodies (DLB) and Multiple System Atrophy (MSA). The common pathological hallmark of synucleinopathies is the filamentous α-synuclein (α-Syn) aggregates along with membrane components in cytoplasmic inclusions in the brain. β-Synuclein...

α-Synuclein (α-Syn) amyloid fibrils in synucleinopathies (such as Parkinson's disease (PD), multiple system atrophy (MSA)) are structurally and functionally different, reminiscent of prion-like strains. However, how a single protein can form different fibril polymorphs in various synucleinopathies is not known. Here, we demonstrate the structure-fu...

α-Synuclein (α-Syn) aggregation and amyloid formation is directly linked with Parkinsons disease (PD) pathogenesis. However, the early events involved in this process remain unclear. Here, using in vitro reconstitution and cellular model, we show that liquid-liquid phase separation (LLPS) of α-Syn precedes its aggregation. In particular, in vitro g...

Altered intestinal permeability has been correlated with Parkinson’s pathophysiology in the enteric nervous system, before manifestations in the central nervous system (CNS). The inflammatory endotoxin or lipopolysaccharide (LPS) released by gut bacteria is known to modulate α-synuclein amyloidogenesis through the formation of intermediate nucleati...

Amyloids are highly ordered nanofibril and its tensile strength is similar to that of steel, which makes them resistant to extreme pH and temperature. Based on this rationale, we demonstrate a facile synthesis of palladium (Pd), copper (Cu), platinum (Pt), gold (Au) and silver (Ag) nanocomposites using α-Synuclein (α-Syn) fibrils as a template. We...

Amyloid formation of α-synuclein (α-Syn) and its familial mutations are directly linked with Parkinson’s disease (PD) pathogenesis. Recently, a new familial α-Syn mutation (A53E) was discovered, associated with an early-onset aggressive form of PD, which delays the α-Syn aggregation. When we overexpressed WT and A53E proteins in cells, neither of t...

Amyloid fibrils are cross-β-sheet rich protein/peptide fibrils that are typically associated with neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease. Recently, functional amyloids have been discovered where amyloids are implicated in performing normal physiological functions of the host organism rather than creating diseases. Th...

Parkinson's disease is a sporadic disorder in which both environmental and cellular factors play a major role in the initiation of this disease. Glycosaminoglycans (GAGs) are integral components of the extracellular matrix and are known to influence amyloid aggregation of several proteins, including α-synuclein (α-Syn). However, the mechanism by wh...

Graphene‐based hybrid nanomaterials have been shown to have great potential in various biotechnology applications including enzyme sensing and bone tissue engineering. Harnessing the unique properties of graphene and material strength of amyloids, a graphene–amyloid composite film is developed that can self‐organize into periodic troughs and crests...

α-Synuclein (α-Syn) aggregation and amyloid formation are associated with loss of dopaminergic neurons in Parkinson’s disease (PD). In addition, familial mutations in α-Syn are shown to be one of the definite causes of PD. Here we have extensively studied familial PD associated α-Syn G51D, H50Q and E46K mutations using Drosophila model system. Our...

The involvement of α-synuclein (α-Syn) amyloid formation in Parkinson’s disease (PD) pathogenesis is supported by the discovery of α-Syn gene (SNCA) mutations linked with familial PD, which are known to modulate the oligomerization and aggregation of α-Syn. Recently, the A53V mutation has been discovered, which leads to the late-onset PD. In the pr...

Syn) aggregation is associated with Parkinson's disease (PD) pathogenesis. In PD, the role of oligomer versus fibrils in neuronal cell death is debatable but recent studies suggest oligomers are a proximate neurotoxin. Here, we show that soluble α-Syn monomers convert from solution to gel state on incubation at high concentration that might be rele...

Familial mutations in α-synuclein affect the immediate chemical environment of the protein’s backbone, changing its aggregation kinetics, forming diverse structural and functional intermediates. This study, concerning two oppositely aggregating mutants...

Aggregation of α-synuclein (α-Syn) into toxic oligomers and fibrils leads to Parkinson’s disease (PD) pathogenesis. Molecules that can inhibit the fibrillization and oligomerization of α-Syn have potential therapeutic value. Here, we studied four selective amyloid inhibitors: Dopamine (Dopa), Amphotericin-B (Amph), Epigallocatechingallate (EGCG) an...

Amyloid based hydrogels can mimic the extracellular matrix and serve as matrices for tissue engineering both in vitro and in vivo. A pH responsive self-assembled amyloid hydrogel system is used to encapsulate various growth factors for driving stem cell differentiation toward neuronal lineage. Diffusion studies with fluorescence recovery after phot...