Traumatic Brain Injury & Mechanisms of Neurodegeneration 4-5

What is Traumatic Brain Injury (TBI)?

What is Traumatic Brain Injury (TBI)?

It is a head injury that disrupts normal brain function, involving physical damage to brain tissue.

What are some common causes of TBI?

Falls, motor vehicle accidents, struck by/against events, assault, and intentional self-harm.

How are TBI rates collected, and what methods impact the variation in rates?

Rates are collected through ED visits, hospitalizations, and deaths, with variations based on data collection methods.

How has trauma care advancement impacted TBI mortality rates?

Advances in trauma care and ICU have reduced TBI mortality rates from ~50% in the 1970s to ~17% in 2003.

How is clinical severity of TBI assessed?

Glasgow Coma Scale.

What distinguishes penetrating TBI from nonpenetrating (blunt) TBI?

Penetrating TBI breaks the dura, exposing the brain, while nonpenetrating (blunt) TBI keeps the dura intact with potential severe internal damage.

What are examples of focal injuries in TBI?

Examples of focal injuries in TBI include cerebral contusion, extradural hemorrhage, subarachnoid hemorrhage, subdural hemorrhage, scalp lacerations, and skull fractures

What is a cerebral contusion?

A bruise on the brain, which can be on the surface or intracerebral.

What are the common locations for cerebral contusions?

Frontal and temporal lobes due to sharp bony surfaces.

How does laceration of the brain tissue occur?

It results from tearing of brain tissue leading to ruptured blood vessels, bleeding, hematomas, edema, and increased intracranial pressure.

What are the types of skull fractures?

Depressed, linear, radiating, bursting, and meridional fractures.

What are the common consequences of laceration injuries in traumatic brain injuries?

Laceration injuries can result in bleeding, haematomas, oedema, and increased intracranial pressure (ICP).

Describe the causes and types of skull fractures seen in traumatic brain injuries.

Skull fractures can be depressed (from impact with objects), linear (from impact of solid objects), radiating, bursting, or meridional.

How do gunshot injuries affect the brain in traumatic brain injuries?

Gunshot injuries create a path of disrupted brain tissue, pressure waves causing herniation, and potential ricochet off the skull causing additional damage.

What are the primary blast effects in traumatic brain injuries?

Primary blast effects are caused by the blast wave itself, leading to injuries from the pressure wave of the explosion.

Explain the role of inertia in traumatic brain injuries and its effects on the brain.

Inertia in TBIs leads to linear acceleration causing superficial lesions and rotational head movement causing deep cerebral lesions, potentially resulting in concussions and axonal injuries.

How does the brain's minimal internal structural support contribute to its vulnerability in traumatic brain injury?

The lack of internal structural support makes the brain less tolerant to inertial forces, increasing vulnerability.

What type of lesions does linear acceleration typically cause in traumatic brain injury?

Linear acceleration causes superficial lesions, with the gray matter closest to the surface being most susceptible.

How does rotational head movement impact traumatic brain injuries?

Rotational head movement leads to deeper cerebral lesions, potential concussions, and injuries to deep cerebral white matter and axons.

What is diffuse axonal injury (DAI) and how is it caused?

DAI is caused by shearing forces that tear or stretch axons due to differential movements of brain layers during acceleration and rotational forces.

Describe the mechanism of axonal stretch injury in traumatic brain injuries.

Axonal stretch injury results in intracellular changes, altered neurofilaments, increased calcium influx, depolarization, and possible axotomy.

How does acute axonal stretch and strain lead to axonal depolarization?

It causes intracellular calcium increase, axon permeability changes, and Na+ channel activation resulting in depolarization.

What are the key mechanisms of secondary brain injury post-TBI?

Include depolarization, excitotoxicity, disruption of Ca2+ homeostasis, free-radical generation, BBB disruption, ischemic injury, and edema formation.

Describe the general pathophysiology of TBI during the second stages.

Involves sustained membrane depolarization, excessive glutamate release, Ca2+ influx, lipid peroxidation, free radical generation, and activation of caspases.

What is the impact of Ca2+-induced axonal injury?

Results in protease activation, microtubule destruction, cytoskeleton breakdown, axonal disconnection, ROS generation, phospholipase activation, and BBB damage.

How does Diffuse Axonal Injury (DAI) occur in relation to Ca homeostatic mechanisms?

Failure of Ca homeostasis results in the excessive accumulation and release of Ca, leading to irreversible and catastrophic accumulation in axons.

What are the consequences of failure of calcium homeostasis in pathological states?

Excessive axonal Ca accumulation leading to structural and functional demise of axons.

Why is diffuse axonal injury (DAI) considered a powerful predictor of mortality and morbidity?

It is a strong predictor because it leads to persistent coma and functional decline, with low chances of regaining consciousness.

How does the blood-brain barrier (BBB) function in restricting access to the brain?

It restricts bloodborne factors and immune cells due to tight junctions in brain endothelium, aided by astrocytes.

What changes occur in the BBB during traumatic brain injury (TBI) that lead to dysfunction?

TBI disrupts tight junctions, induces oxidative stress, inflammation, alters transporter activity, and causes vascular changes.

What causes vasogenic edema in traumatic brain injury?

Increased BBB permeability allows the accumulation of plasma-derived osmotically active molecules and water, leading to vasogenic edema.

What are the key mechanisms involved in causing Vasogenic Edema?

Endothelial tight junction disruption, glial cell activation, BBB hyperpermeability, and fluid extravasation.

What are the main consequences of Cell Swelling in brain injuries?

Altered metabolite levels, increased ICP, compressed blood vessels, reduced tissue blood flow, and potential herniation.

What are some microcirculatory derangements seen in TBI?

Stenosis and loss of microvasculature, breakdown of the blood-brain barrier due to astrocyte foot processes swelling.

How does astrogliosis contribute to secondary injury?

Astrogliosis leads to dysfunction in glutamate uptake and neuronal depolarization through excitotoxic mechanisms.

What role does calcium influx play in white and gray matter after TBI?

Calcium influx is a key initiating event in a molecular cascade causing delayed cell death or dysfunction and axonal disconnection.

escribe the impact of excitotoxicity in neurons after TBI.

Excitotoxicity, from calcium and zinc influx, leads to free radicals generation, mitochondrial dysfunction, and receptor modifications.

How do inflammatory cells contribute to secondary injury in TBI?

Inflammatory cells release proinflammatory cytokines, contributing to cell death cascades or receptor modifications.

What are neurodegenerative diseases characterized by?

They are characterized by heterogeneous clinical and pathological expressions, affecting specific subsets of neurons with unknown causes.

What is the primary risk factor for neurodegenerative diseases?

Increasing age, particularly 65 years and older.

Describe the typical symptoms of Huntington's Disease (HD).

Changes in cognition and physical ability, random uncontrolled movement (chorea), rigidity, and psychomotor decline.

What are some typical symptoms of Alzheimer's Disease (AD)?

Memory loss (especially short term), difficulty concentrating, confusion.

List some common symptoms of Parkinson's Disease (PD).

Tremors, slowed motion, muscle stiffness, loss of automatic movement, speech changes.

What are the primary symptoms associated with Huntington's Disease (HD)?

Changes in cognition and physical ability, random uncontrolled movement (chorea), rigidity, psychomotor decline.

What symptoms are observed in Motor Neuron Disease (MND/ALS)?

Muscle weakness, muscle twitching, progressive paralysis.

Describe the symptoms of Prion Disease.

Rapidly developing dementia, confusion, fatigue, personality changes, difficulty walking, difficulty speaking, muscle spasms.

How do nascent polypeptides achieve proper folding in cotranslational folding?

Nascent polypeptides are assisted by specialized chaperones like the nascent polypeptide-associated complex (NAC).

What mechanism aids in the refolding of misfolded proteins to attain correct spatial structures?

Misfolded proteins can be refolded by specialized chaperones to achieve proper folding

Misfolded proteins can be refolded by specialized chaperones to achieve proper folding.

What is the system responsible for degrading misfolded proteins that fail to refold properly?

The 26S proteasome degrades molecules that fail to fold properly in the cell.

How are damaged or misfolded proteins removed from cells to maintain proteostasis?

Protein degradation processes like autophagy and ubiquitin/proteasome system remove damaged or misfolded proteins.

Which motor protein is responsible for transporting cargoes from the cell body to the axon tip in neurons?

Kinesin is the motor protein that moves cargoes from the cell body to the axon tip in neurons (anterograde transport).

What role do molecular chaperones play in proteostasis mechanisms?

Molecular chaperones aid in the assembly and disassembly of proteins to maintain proper folding and prevent aggregation.

Describe the Unfolded Protein Response (UPR) and its role in proteostasis.

The UPR is triggered by misfolded proteins in the endoplasmic reticulum, aiming to relieve ER stress by regulating protein folding and degradation.

How do motor proteins contribute to axonal transport in neurons?

Motor proteins like Kinesin and Dynein transport cargoes along microtubules, facilitating movement from the cell body to the axon tip and vice versa.

What is the significance of the balance between anterograde and retrograde transport in axonal transport?

Maintaining balance ensures proper distribution of cellular components, preventing distal accumulation or depletion within the neuron.

How does ER stress relate to neurodegenerative diseases?

ER stress, caused by misfolded proteins, triggers stress-response mechanisms that modulate gene expression to restore proteostasis, crucial in neurodegenerative diseases.

How does heat exposure lead to protein aggregation in the cytosol according to the Heat-Shock Response (HSR)?

Heat exposure causes protein aggregation in the cytosol.

Which chaperone family is involved in recognizing protein aggregates in the cytosol during the Heat-Shock Response (HSR)?

The HSP70 family chaperone identifies protein aggregates.

What is the role of HSF-1 in the Heat-Shock Response (HSR)?

HSF-1 translocates to the nucleus, trimerizes, and regulates target gene expression.

What triggers the Endoplasmic Reticulum Unfolded Protein Response (UPRER)?

ER stress caused by protein aggregation in the ER lumen.

How does the Mitochondrial Unfolded Protein Response (UPRmt) detect increased protein aggregates?

HSP70 chaperone HSP-6 detects increased protein aggregates.

What is the role of BiP in the context of ER stress and the UPR?

BiP identifies misfolded proteins, activates IRE-1, and promotes the splicing and translation of XBP-1.

How does PERK respond to protein aggregation-mediated ER stress?

PERK activates ATF-4 migration to the nucleus, phosphorylates eIF2a to prevent ribosome assembly, and regulates target gene networks.

What is the main goal of the Unfolded Protein Response (UPR) in the ER?

The UPR aims to restore cell function by halting protein translation, degrading misfolded proteins, and increasing molecular chaperone production.

How does BiP function under normal cell homeostasis?

BiP binds to PERK, IRE1, and ATF6 under basal conditions, activating stress-relieving pathways during ER stress by binding misfolded proteins.

What role does IRE1a play in degrading misfolded proteins during ER stress?

IRE1a becomes activated when BiP is recruited away, and it removes a small intron in XBP1 to activate the transcription factor under stress.

What is the consequence of chronic ER stress in relation to ATF4?

Chronic ER stress can lead to targeted translation of ATF4, a transcription factor that can initiate cell death.

How is the degradation of misfolded proteins controlled during ER stress?

IRE1α is responsible for the controlled degradation of misfolded proteins in response to ER stress.

What is the role of ATF6 in UPR signaling pathways?

ATF6, when activated, translocates to the Golgi where it is cleaved into an active transcription factor that increases chaperone expression.

Describe the activation process of PERK in the UPR signaling pathways.

PERK undergoes dimerization, autophosphorylation, and then phosphorylates eIF2 to block new protein production in the cytoplasm.

How does the separation of BiP from ATF6 affect UPR signaling?

When BiP is sequestered from ATF6, ATF6 moves to the Golgi for cleavage into an active transcription factor.

How does the PERK pathway function in the Unfolded Protein Response (UPR) in the ER?

PERK phosphorylates eIF2, leading to ATF4 activation, transcription of genes for ER homeostasis, and reduced workload by inhibiting specific protein translation.

What is the role and process of ATF6 pathway activation in the UPR in the ER?

BiP dissociation from ATF6 triggers its movement to the Golgi, where cleavage by S1P and S2P generates an active bZip transcription factor for gene induction.

xplain the activation and function of the IRE1 pathway in the ER's Unfolded Protein Response.

IRE1 endoribonuclease dimerizes, splices XBP1 to induce UPR-responsive genes, and activates ER chaperones and ERAD pathway components.

What triggers the general UPRER mechanisms, and what is the role of XBP-1 in this process?

Accumulation of aggregated proteins triggers UPRER. XBP-1, after splicing, migrates to the nucleus to activate expression of ER chaperones and ERAD components.

How does the ER stress response lead to the activation of the PERK pathway and its subsequent functions?

Protein aggregation triggers PERK activation, leading to ATF-4 nuclear migration, regulation of gene networks, and eIF2 phosphorylation to ease ER workload.

How does PERK influence protein translation during ER stress?

PERK phosphorylates eIF2, inhibiting translation of proteins needing chaperones, reducing ER workload

Describe the role of ATF-6 in response to ER stress.

ATF-6 is transported to Golgi, cleaved, moves to nucleus, enhancing expression of xbp-1 and ERAD component genes.

What is the purpose of XBP-1, ATF-4, and ATF-6(N) transcripts during ER stress?

Transcripts export to cytosol, translated to form ER-resident chaperones and ERAD components for proteostasis maintenance.

How does the Ubiquitin Proteasome System (UPS) contribute to protein degradation in cells?

UPS adds Ub chains to defective proteins, targets them to proteasome for breakdown, recycling amino acids for cell homeostasis.

Explain the process and significance of autophagy in cellular protein degradation.

Autophagy degrades dysfunctional proteins and cellular components via the lysosome, preventing cellular damage and maintaining homeostasis.

How are defective mitochondria removed in the process of autophagy?

Defective mitochondria are removed by isolating them in an autophagosome, which then fuses with a lysosome to form an autolysosome for degradation.

Explain the process of macroautophagy and what it engulfs within a cell.

Macroautophagy involves a phagophore engulfing cytosolic contents like damaged proteins, larger aggregates, or dysfunctional organelles such as mitochondria for degradation.

Describe the UPS pathway and its role in protein degradation.

The UPS pathway involves degradation of damaged proteins via the 20S or 26S proteasome, but oxidatively damaged proteins are not preferentially polyubiquitinated.

Differentiate between chaperone-mediated autophagy and microautophagy in terms of substrate uptake.

Chaperone-mediated autophagy involves substrate translocation through chaperones, while microautophagy directly takes up substrates via lysosomal invagination.

How does LAMP2A contribute to protein degradation in cells?

LAMP2A translocates substrates into the lysosomal volume for degradation.

What is the process of Microautophagy in protein degradation?

ubstrates are directly taken up from the cytosol via invagination by the lysosomal system.

How do substrates enter the lysosomal system through Endocytosis?

Substrates from outside the cell are taken up via invagination of the cell membrane, forming an endosome that fuses with the lysosomal system for degradation.

What is the role of the Proteostasis Network (PN) in protein folding?

PN assists in the folding of nascent polypeptides, post-translational modifications, ensuring proper intermolecular interactions, and target organelle transport of fully processed proteins.

How are misfolded proteins managed in cells?

Misfolded proteins can be refolded by specialized chaperones or degraded by the 26S proteasome if they fail to attain correct spatial structures.