4.4 Protein misfolding and associated diseases
5 min read•august 1, 2024
Protein misfolding is a crucial issue in cellular biology, causing proteins to lose their function and form harmful aggregates. This process can lead to severe consequences, including neurodegenerative diseases like Alzheimer's and Parkinson's, highlighting the importance of proper protein folding.
Understanding protein misfolding is essential for grasping the broader concepts of protein structure and function. By exploring the causes, consequences, and potential treatments for misfolding, we gain insights into the delicate balance required for proteins to maintain their proper shape and carry out their vital roles in the body.
Protein misfolding: Causes and consequences
Protein misfolding and its effects on protein structure and function
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Top images from around the web for Protein misfolding and its effects on protein structure and function
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- Protein misfolding occurs when a protein fails to adopt or maintain its native, functional three-dimensional structure
- Caused by mutations in the protein's amino acid sequence, errors in protein synthesis, or exposure to environmental stressors (heat, oxidative stress, changes in pH)
- Misfolded proteins often expose hydrophobic regions normally buried within the protein's interior
- Exposed regions can interact with other proteins, leading to protein and the formation of insoluble protein deposits
- Misfolded proteins can lose their biological function, leading to a loss of cellular function and potential cell death
- Particularly problematic for proteins that play critical roles in cellular processes (enzymes, signaling molecules, structural proteins)
Cellular responses to protein misfolding and their consequences
- The accumulation of misfolded proteins can trigger cellular stress responses
- Unfolded protein response (UPR) in the endoplasmic reticulum
- Heat shock response in the cytosol
- These responses aim to restore protein homeostasis
- Increasing the production of molecular
- Promoting the degradation of misfolded proteins
- Chronic protein misfolding can overwhelm the cell's quality control mechanisms
- Leads to the formation of protein aggregates
- Development of protein misfolding diseases (, , )
Molecular mechanisms of protein aggregation
Intermolecular interactions driving protein aggregation
- Protein aggregation occurs when misfolded proteins interact through exposed hydrophobic regions, forming oligomers and larger aggregates
- Driven by intermolecular interactions (hydrogen bonding, van der Waals forces, hydrophobic interactions)
- Amyloid fibrils are a specific type of protein aggregate characterized by a cross-β structure
- β-strands from multiple protein molecules align perpendicular to the fibril axis, forming a highly stable, insoluble structure
- The formation of amyloid fibrils typically involves a nucleation-dependent polymerization process
- Consists of a lag phase (oligomers and nuclei form) followed by a rapid growth phase (fibrils elongate by the addition of monomers or oligomers)
Factors influencing protein aggregation and amyloid formation
- Amyloid formation is influenced by various factors
- Protein concentration, temperature, pH
- Presence of co-factors (metal ions, glycosaminoglycans)
- These factors can modulate the kinetics and thermodynamics of the aggregation process
- Certain amino acid sequences, known as aggregation-prone regions (APRs), are more likely to promote amyloid formation
- Often enriched in hydrophobic and β-sheet-promoting amino acids (valine, isoleucine, phenylalanine)
- Molecular chaperones, such as heat shock proteins (HSPs), can help prevent protein aggregation
- Bind to misfolded proteins and promote their refolding or degradation
- When the capacity of chaperones is exceeded, protein aggregation can occur
Protein misfolding in neurodegenerative diseases
Neurodegenerative diseases and their link to protein misfolding
- Neurodegenerative diseases (Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), (ALS)) are characterized by the progressive loss of neurons in specific regions of the brain or spinal cord
- Protein misfolding and aggregation are common features of many neurodegenerative diseases
- Each disease is associated with the misfolding and aggregation of specific proteins (amyloid-β (Aβ) and tau in AD, α-synuclein in PD, huntingtin in HD, TDP-43 or SOD1 in ALS)
Pathological effects of misfolded and aggregated proteins in neurons
- The accumulation of misfolded and aggregated proteins in neurons can lead to various pathological effects
- Synaptic dysfunction, impaired axonal transport, mitochondrial dysfunction, oxidative stress, neuroinflammation
- These processes collectively contribute to neuronal dysfunction and cell death
- The spread of misfolded proteins from one neuron to another, known as prion-like propagation, has been proposed as a mechanism for the progressive nature of neurodegenerative diseases
- Involves the release of misfolded proteins from affected cells and their uptake by neighboring cells, leading to the seeding of new aggregates
Genetic factors contributing to protein misfolding in neurodegenerative diseases
- Genetic mutations in the genes encoding disease-associated proteins can increase the propensity for misfolding and aggregation
- Mutations in the APP, PSEN1, or PSEN2 genes can lead to familial forms of AD
- Mutations in the SNCA gene can cause familial PD
- The exact mechanisms linking protein misfolding and aggregation to are not fully understood and may vary between diseases
- Targeting protein misfolding and aggregation is a promising therapeutic strategy for neurodegenerative disorders
Strategies for protein misfolding diseases
Enhancing cellular protein quality control mechanisms
- Enhancing the cellular protein quality control machinery is one approach to prevent and treat protein misfolding diseases
- Upregulating the expression of molecular chaperones (HSPs)
- Boosting the activity of protein degradation pathways (ubiquitin-proteasome system (UPS), autophagy)
- Small molecules that activate the heat shock response have shown promise in animal models of neurodegenerative diseases
- HSP90 inhibitors or compounds that activate heat shock factor 1 (HSF1)
- Compounds that enhance the activity of the UPS or autophagy have also demonstrated potential in preclinical studies
- Proteasome activators or mTOR inhibitors
Targeting misfolded proteins and aggregates
- Directly targeting misfolded proteins or aggregates is another strategy for treating protein misfolding diseases
- Using small molecules, antibodies, or peptides that bind to specific conformations of misfolded proteins
- Prevent their aggregation or promote their clearance
- Antibodies targeting Aβ or tau have been extensively studied for the treatment of AD, with several candidates currently in clinical trials
- Small molecules that inhibit the aggregation of α-synuclein or promote its clearance are being developed for the treatment of PD
Reducing the production of disease-associated proteins
- Reducing the production of disease-associated proteins is another approach, particularly for diseases caused by genetic mutations that lead to the overproduction of misfolding-prone proteins
- Using antisense oligonucleotides (ASOs) or RNA interference (RNAi) to selectively reduce the expression of the mutant protein
- ASOs targeting huntingtin have shown promise in preclinical models of HD and are currently being tested in clinical trials
- RNAi-based therapies targeting α-synuclein are being developed for the treatment of PD
Modulating cellular pathways disrupted by protein misfolding
- Modulating cellular pathways that are disrupted by protein misfolding and aggregation is another therapeutic strategy
- Targeting neuroinflammation, oxidative stress, mitochondrial dysfunction, or synaptic dysfunction
- Compounds that reduce neuroinflammation have shown potential in animal models of neurodegenerative diseases
- Microglial inhibitors or anti-inflammatory drugs
- Antioxidants and mitochondrial-targeted therapies are being explored to mitigate oxidative stress and mitochondrial dysfunction in protein misfolding diseases
Combination therapies for effective treatment
- Combination therapies that target multiple aspects of protein misfolding and its consequences may be necessary for the effective treatment of neurodegenerative diseases
- Given the complex nature of these disorders, a multi-pronged approach that addresses the various pathological processes involved in neurodegeneration is likely to be most successful
Key Terms to Review (19)
Aggregation: Aggregation is the process by which proteins clump together, often resulting from misfolding, which can lead to the formation of insoluble fibrils or aggregates. This phenomenon is particularly significant in understanding how misfolded proteins can accumulate and disrupt normal cellular functions, leading to various diseases.
Alzheimer's Disease: Alzheimer's disease is a progressive neurodegenerative disorder characterized by the gradual decline in cognitive function, including memory, reasoning, and communication abilities. It is the most common cause of dementia, and it is strongly linked to the misfolding of proteins in the brain, leading to the formation of amyloid plaques and tau tangles that disrupt neural communication and ultimately result in cell death.
Amyloidosis: Amyloidosis is a group of diseases characterized by the abnormal accumulation of amyloid proteins in various tissues and organs, leading to disruption of normal function. This protein misfolding occurs when proteins aggregate into fibrils that deposit in organs such as the heart, kidneys, liver, and nervous system, ultimately affecting their ability to operate properly.
Amyotrophic lateral sclerosis: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons in the brain and spinal cord, leading to muscle weakness and atrophy. This condition is characterized by the misfolding of proteins, particularly superoxide dismutase 1 (SOD1), which can aggregate and disrupt cellular functions, contributing to the death of motor neurons.
Beta-amyloid: Beta-amyloid is a peptide that forms sticky plaques in the brain, primarily associated with Alzheimer's disease and other neurodegenerative disorders. These plaques are formed from the improper cleavage of amyloid precursor protein (APP) and are a hallmark of Alzheimer's pathology, leading to synaptic dysfunction and neuronal loss.
Chaperones: Chaperones are specialized proteins that assist in the proper folding and assembly of other proteins within the cell. They play a critical role in ensuring proteins reach their functional forms by preventing misfolding and aggregation, which is essential for maintaining cellular health and function. Chaperones are involved in various levels of protein structure, helping nascent polypeptide chains fold into their secondary, tertiary, and quaternary structures, and are also pivotal in mitigating the consequences of protein misfolding associated with various diseases.
Denaturation: Denaturation refers to the process in which a protein loses its native three-dimensional structure due to the disruption of non-covalent interactions, often caused by external factors such as heat, pH changes, or chemical agents. This structural change can lead to the loss of biological function and is critical in understanding how proteins fold and how misfolded proteins can lead to diseases.
Gene therapy: Gene therapy is a medical technique that involves the modification or manipulation of genes to treat or prevent disease. It aims to correct defective genes responsible for disease development, potentially offering a permanent solution rather than just alleviating symptoms. By introducing, removing, or altering genetic material within a person's cells, gene therapy can address issues related to protein misfolding and associated diseases, which often stem from genetic mutations.
Huntington's Disease: Huntington's Disease is a genetic neurodegenerative disorder caused by a mutation in the HTT gene, leading to the progressive breakdown of nerve cells in the brain. This disease is characterized by motor dysfunction, cognitive decline, and psychiatric symptoms, with its pathology closely related to protein misfolding and aggregation that disrupt normal cellular functions.
Neurodegeneration: Neurodegeneration is the progressive loss of structure or function of neurons, leading to their death. This process is often associated with various neurological diseases, where the accumulation of misfolded proteins can disrupt cellular functions and contribute to the degeneration of neuronal cells. As neurons deteriorate, it can lead to cognitive decline, movement disorders, and a range of debilitating symptoms that significantly impact quality of life.
NMR Spectroscopy: Nuclear Magnetic Resonance (NMR) spectroscopy is a powerful analytical technique used to determine the structure, dynamics, and interactions of molecules by observing the magnetic properties of atomic nuclei. It connects the physical properties of molecular systems to biological functions and is integral in studying biomolecular interactions, protein structures, and dynamics.
Parkinson's Disease: Parkinson's disease is a progressive neurological disorder characterized by the degeneration of dopamine-producing neurons in the brain, particularly in an area called the substantia nigra. This loss of dopamine leads to movement-related symptoms such as tremors, rigidity, and bradykinesia. The disease is often associated with protein misfolding, specifically the accumulation of alpha-synuclein protein into aggregates known as Lewy bodies, highlighting its connection to protein misfolding and related diseases.
Primary Structure: Primary structure refers to the linear sequence of amino acids in a protein, which is determined by the genetic code within nucleic acids. This unique sequence dictates how the protein will fold and ultimately function in biological processes. The primary structure is crucial because even a single change in this sequence can affect the protein's shape and function, leading to various cellular outcomes.
Small molecule inhibitors: Small molecule inhibitors are low molecular weight compounds that can selectively bind to specific proteins or enzymes, inhibiting their function. These inhibitors play a crucial role in drug discovery and development, particularly in targeting dysfunctional proteins involved in diseases such as cancer and neurodegenerative disorders. They are valuable tools in understanding protein interactions and pathways, making them essential in tackling current challenges in the field and addressing issues related to protein misfolding.
Tau protein: Tau protein is a microtubule-associated protein primarily found in neurons, where it stabilizes microtubules and supports their structural integrity. Abnormalities in tau protein, such as hyperphosphorylation, can lead to its aggregation into neurofibrillary tangles, a hallmark of several neurodegenerative diseases, connecting tau to critical processes involved in protein misfolding and associated diseases.
Tauopathy: Tauopathy refers to a group of neurodegenerative diseases characterized by the abnormal accumulation of tau protein in the brain, leading to neuronal dysfunction and cell death. These diseases are linked to protein misfolding, where tau proteins undergo structural changes that cause them to form tangles and aggregates, disrupting normal cellular function and contributing to cognitive decline.
Tertiary structure: Tertiary structure refers to the overall three-dimensional shape of a protein that results from the folding and interactions of its secondary structures, such as alpha helices and beta sheets. This unique conformation is crucial for the protein's function, influencing how it interacts with other molecules and performs its biological roles.
Ubiquitination: Ubiquitination is a cellular process that involves the attachment of ubiquitin, a small protein, to a target protein, marking it for degradation or altering its function. This process plays a critical role in regulating protein turnover, maintaining cellular homeostasis, and controlling various cellular processes, including the response to stress and protein misfolding.
X-ray crystallography: X-ray crystallography is a powerful technique used to determine the atomic structure of crystalline materials by analyzing the diffraction patterns produced when X-rays are scattered by the crystal lattice. This method is essential in revealing detailed information about biomolecular structures, which is crucial for understanding their function and interactions.