Biochemistry

• Visual pigments are specialized proteins in retinal photoreceptor cells (rods and cones).
• Absorb light to initiate vision.

Visual Pigment Composition

• Opsin is a large protein that determines the specific light wavelength absorption.
• Rod cells contain rhodopsin.
• Cone cells have three photopsins for blue, green, and red light sensitivity.
• Retinal (chromophore) is a light-sensitive molecule from Vitamin A (11-cis-retinal), covalently bound to opsin.

Structural Changes in Light Reception

• Photons striking the retina cause photoisomerization.
• 11-cis-retinal converts to all-trans-retinal.
• This transforms rhodopsin into its active form, metarhodopsin II.
• Metarhodopsin II activates the heterotrimeric G-protein transducin.
• Activated transducin stimulates cGMP phosphodiesterase (PDE6).
• PDE6 hydrolyzes cyclic GMP (cGMP).
• Reduced cGMP closes cGMP-gated sodium (Na+) and calcium (Ca2+) channels.
• This results in hyperpolarization of the photoreceptor cell membrane.

Intracellular Signal Transmission

• Hyperpolarization reduces the release of the neurotransmitter glutamate.
• Bipolar and horizontal cells interpret this change and modulate the signal to ganglion cells.
• Ganglion cells transmit visual information via the optic nerve to the brain's visual cortex.

Visual Pigment Regeneration

• After photoisomerization, all-trans-retinal converts back to 11-cis-retinal through the retinoid cycle.
• All-trans-retinal is released from opsin and reduced to all-trans-retinol (vitamin A).
• All-trans-retinol is transported to the retinal pigment epithelium (RPE) by cellular retinaldehyde-binding protein (CRALBP).
• In the RPE, all-trans-retinol converts back to 11-cis-retinal.
• 11-cis-retinal binds to opsin, restoring rhodopsin.

Membrane Potential Recovery

• When the light stimulus ceases, cGMP levels are restored by guanylyl cyclase.
• Reopening of cGMP-gated channels allows Na+ and Ca2+ to enter, returning the photoreceptor to its depolarized resting state.

Clinical Significance

• Vitamin A deficiency impairs 11-cis-retinal regeneration, causing night blindness.
• Defective retinoid cycle enzymes lead to progressive vision loss in retinitis pigmentosa.
• Dysfunctional RPE impairs pigment regeneration and photoreceptor survival in age-related macular degeneration (AMD).

Biosynthesis of NO

• Nitric oxide (NO) is synthesized from L-arginine by nitric oxide synthase (NOS) enzymes.
• Requires oxygen and NADPH as cofactors.
• nNOS (neuronal NOS) in neurons is involved in synaptic plasticity.
• iNOS (inducible NOS) in immune cells produces NO during inflammation.
• eNOS (endothelial NOS) in vascular endothelial cells regulates blood flow.

Mechanisms of NO Action

• NO activates guanylyl cyclase, increasing cyclic GMP levels.
• This relaxes blood vessels and regulates neurotransmission.
• NO reacts with superoxide to form peroxynitrite, a highly reactive molecule that damages cellular components, forming reactive nitrogen species (RNS).

Role in Neurodegeneration

• Excess NO and RNS cause lipid peroxidation and DNA damage via oxidative stress.
• NO inhibits mitochondrial respiration, reducing ATP production causing mitochondrial dysfunction.
• NO interacts with glutamate receptors, increasing calcium influx and promoting neuronal death (excitotoxicity).

Examples of NO-Related Neurodegeneration

• Elevated NO levels exacerbate beta-amyloid toxicity in Alzheimer’s Disease (AD).
• NO mediates dopaminergic neuron damage in Parkinson’s Disease (PD).
• NO promotes inflammatory demyelination in Multiple Sclerosis (MS).

Proteins in Neurodegenerative Diseases

• Neurodegenerative diseases are associated with the accumulation of misfolded proteins that disrupt cellular function and lead to neuronal death.

Amyloid-β (Aβ) - Alzheimer’s Disease (AD)

• Aggregates to form plaques.
• Disrupts synaptic function and triggers neuroinflammation.
• Impairs mitochondrial activity and induces oxidative stress.

Tau Protein - Alzheimer’s Disease (AD) and Frontotemporal Dementia

• Hyperphosphorylated tau forms neurofibrillary tangles.
• Tangles destabilize microtubules, impairing axonal transport.

α-Synuclein - Parkinson’s Disease (PD)

• Misfolded α-synuclein aggregates form Lewy bodies.
• Disrupts mitochondrial function and induces oxidative stress.

Huntingtin - Huntington’s Disease (HD)

• Mutant huntingtin forms intracellular inclusions.
• Causes transcriptional dysregulation and neuronal death.

Superoxide Dismutase 1 (SOD1) - Amyotrophic Lateral Sclerosis (ALS)

• Mutant SOD1 aggregates cause motor neuron toxicity.
• Leads to oxidative damage and cellular apoptosis.

Therapeutic Strategies

• Reducing protein aggregation (e.g., anti-amyloid antibodies).
• Enhancing protein clearance (e.g., autophagy inducers).
• Modulating oxidative stress (e.g., antioxidants).
• Targeting neuroinflammation (e.g., anti-inflammatory drugs).