The 70 kilodalton heat shock proteins are a family of conserved ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms. Intracellularly localized Hsp70s are an important part of the cell's machinery for protein folding, performing chaperoning functions, and helping to protect cells from the adverse effects of physiological stresses. Additionally, membrane-bound Hsp70s have been identified as a potential target for cancer therapies and their extracellularly localized counterparts have been identified as having both membrane-bound and membrane-free structures.
The tau proteins are a group of six highly soluble protein isoforms produced by alternative splicing from the gene MAPT. They have roles primarily in maintaining the stability of microtubules in axons and are abundant in the neurons of the central nervous system (CNS), where the cerebral cortex has the highest abundance. They are less common elsewhere but are also expressed at very low levels in CNS astrocytes and oligodendrocytes.
Inclusion bodies are aggregates of specific types of protein found in neurons, a number of tissue cells including red blood cells, bacteria, viruses, and plants. Inclusion bodies of aggregations of multiple proteins are also found in muscle cells affected by inclusion body myositis and hereditary inclusion body myopathy.
Neuroprotection refers to the relative preservation of neuronal structure and/or function. In the case of an ongoing insult the relative preservation of neuronal integrity implies a reduction in the rate of neuronal loss over time, which can be expressed as a differential equation. It is a widely explored treatment option for many central nervous system (CNS) disorders including neurodegenerative diseases, stroke, traumatic brain injury, spinal cord injury, and acute management of neurotoxin consumption. Neuroprotection aims to prevent or slow disease progression and secondary injuries by halting or at least slowing the loss of neurons. Despite differences in symptoms or injuries associated with CNS disorders, many of the mechanisms behind neurodegeneration are the same. Common mechanisms of neuronal injury include decreased delivery of oxygen and glucose to the brain, energy failure, increased levels in oxidative stress, mitochondrial dysfunction, excitotoxicity, inflammatory changes, iron accumulation, and protein aggregation. Of these mechanisms, neuroprotective treatments often target oxidative stress and excitotoxicity—both of which are highly associated with CNS disorders. Not only can oxidative stress and excitotoxicity trigger neuron cell death but when combined they have synergistic effects that cause even more degradation than on their own. Thus limiting excitotoxicity and oxidative stress is a very important aspect of neuroprotection. Common neuroprotective treatments are glutamate antagonists and antioxidants, which aim to limit excitotoxicity and oxidative stress respectively.
A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy, tauopathies, and prion diseases. Neurodegeneration can be found in the brain at many different levels of neuronal circuitry, ranging from molecular to systemic. Because there is no known way to reverse the progressive degeneration of neurons, these diseases are considered to be incurable; however research has shown that the two major contributing factors to neurodegeneration are oxidative stress and inflammation. Biomedical research has revealed many similarities between these diseases at the subcellular level, including atypical protein assemblies and induced cell death. These similarities suggest that therapeutic advances against one neurodegenerative disease might ameliorate other diseases as well.
In cellular biology, stress granules are biomolecular condensates in the cytosol composed of proteins and RNAs that assemble into 0.1–2 μm membraneless organelles when the cell is under stress. The mRNA molecules found in stress granules are stalled translation pre-initiation complexes associated with 40S ribosomal subunits, translation initiation factors, poly(A)+ mRNAs and RNA-binding proteins (RBPs). While they are membraneless organelles, stress granules have been proposed to be associated with the endoplasmatic reticulum. There are also nuclear stress granules. This article is about the cytosolic variety.
Protein kinase RNA-activated also known as protein kinase R (PKR), interferon-induced, double-stranded RNA-activated protein kinase, or eukaryotic translation initiation factor 2-alpha kinase 2 (EIF2AK2) is an enzyme that in humans is encoded by the EIF2AK2 gene on chromosome 2. PKR is a serine/tyrosine kinase that is 551 amino acids long.
In medicine, proteinopathy, or proteopathy, protein conformational disorder, or protein misfolding disease, is a class of diseases in which certain proteins become structurally abnormal, and thereby disrupt the function of cells, tissues and organs of the body. Often the proteins fail to fold into their normal configuration; in this misfolded state, the proteins can become toxic in some way or they can lose their normal function. The proteinopathies include such diseases as Creutzfeldt–Jakob disease and other prion diseases, Alzheimer's disease, Parkinson's disease, amyloidosis, multiple system atrophy, and a wide range of other disorders. The term proteopathy was first proposed in 2000 by Lary Walker and Harry LeVine.
TIA1 or Tia1 cytotoxic granule-associated rna binding protein is a 3'UTR mRNA binding protein that can bind the 5'TOP sequence of 5'TOP mRNAs. It is associated with programmed cell death (apoptosis) and regulates alternative splicing of the gene encoding the Fas receptor, an apoptosis-promoting protein. Under stress conditions, TIA1 localizes to cellular RNA-protein conglomerations called stress granules. It is encoded by the TIA1 gene.
TAR DNA-binding protein 43 is a protein that in humans is encoded by the TARDBP gene.
Vacuolar protein sorting ortholog 35 (VPS35) is a protein involved in autophagy and is implicated in neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease (AD). VPS35 is part of a complex called the retromer, which is responsible for transporting select cargo proteins between vesicular structures and the Golgi apparatus. Mutations in the VPS35 gene (VPS35) cause aberrant autophagy, where cargo proteins fail to be transported and dysfunctional or unnecessary proteins fail to be degraded. There are numerous pathways affected by altered VPS35 levels and activity, which have clinical significance in neurodegeneration. There is therapeutic relevance for VPS35, as interventions aimed at correcting VPS35 function are in speculation.
Triggering receptor expressed on myeloid cells 2(TREM2) is a protein that in humans is encoded by the TREM2 gene. TREM2 is expressed on macrophages, immature monocyte-derived dendritic cells, osteoclasts, and microglia, which are immune cells in the central nervous system. In the liver, TREM2 is expressed by several cell types, including macrophages, that respond to injury. In the intestine, TREM2 is expressed by myeloid-derived dendritic cells and macrophage. TREM2 is overexpressed in many tumor types and has anti-inflammatory activities. It might therefore be a good therapeutic target.
Fox-1 homolog A, also known as ataxin 2-binding protein 1 (A2BP1) or hexaribonucleotide-binding protein 1 (HRNBP1) or RNA binding protein, fox-1 homolog (Rbfox1), is a protein that in humans is encoded by the RBFOX1 gene.
In molecular biology, protein aggregation is a phenomenon in which intrinsically-disordered or mis-folded proteins aggregate either intra- or extracellularly. Protein aggregates have been implicated in a wide variety of diseases known as amyloidoses, including ALS, Alzheimer's, Parkinson's and prion disease.
Fasudil (INN) is a potent Rho-kinase inhibitor and vasodilator. Since it was discovered, it has been used for the treatment of cerebral vasospasm, which is often due to subarachnoid hemorrhage, as well as to improve the cognitive decline seen in stroke patients. It has been found to be effective for the treatment of pulmonary hypertension. It has been demonstrated that fasudil could improve memory in normal mice, identifying the drug as a possible treatment for age-related or neurodegenerative memory loss.
Richard I. Morimoto is a Japanese American molecular biologist. He is the Bill and Gayle Cook Professor of Biology and Director of the Rice Institute for Biomedical Research at Northwestern University.
Primary age-related tauopathy (PART) is a neuropathological designation introduced in 2014 to describe the neurofibrillary tangles (NFT) that are commonly observed in the brains of normally aged and cognitively impaired individuals that can occur independently of the amyloid plaques of Alzheimer's disease (AD). The term and diagnostic criteria for PART were developed by a large group of neuropathologists, spearheaded by Drs. John F. Crary and Peter T. Nelson. Despite some controversy, the term PART has been widely adopted, with the consensus criteria cited over 1130 times as of April 2023 according to Google Scholar.
FAST kinase domain-containing protein 5 (FASTKD5) is a protein that in humans is encoded by the FASTKD5 gene on chromosome 20. This protein is part of the FASTKD family, which is known for regulating the energy balance of mitochondria under stress. FASTKD5 is also required for RNA granules to process precursor mRNAs not flanked by tRNAs.
Tara Spires-Jones is professor of neurodegeneration and deputy director of the Centre for Discovery Brain Sciences at the University of Edinburgh. She is also a group leader in the UK Dementia Research Institute.
Chaperome refers to the ensemble of all cellular molecular chaperone and co-chaperone proteins that assist protein folding of misfolded proteins or folding intermediates in order to ensure native protein folding and function, to antagonize aggregation-related proteotoxicity and ensuing protein loss-of-function or protein misfolding-diseases such as the neurodegenerative diseases Alzheimer's, Huntington's or Parkinson's disease, as well as to safeguard cellular proteostasis and proteome balance.
