Neurodegeneration and Potential Therapies

PD Pathophysiology

Nigra-striatal

PD Neuro Chem

Dopaminergic neurons

Alzheimer’s Pathophysiology

Acetylcholine

PD Symptoms

• Tremor

• Rigidity

• Slowness of movement

• Difficulty with walking

What are the brain degeneration features in AD?

• Atrophy

• Reduced grey matter

• Reduced hippocampal area

What are the 4 types of cell death?

• Apoptosis

• Necrosis

• Oxytosis

• Ferroptosis

How is extrinsic apoptosis triggered?

By external death signals (eg TNF family ligands)

Where does extrinsic apoptosis start from?

Plasma membrane

Which event activates caspases?

Changes in intracellular Ca2+

Caspase-8 and caspase-9 functions

Cleave BID → tBID

How is intrinsic apoptosis triggered?

By internal stress (DNA damage, oxidative stress, mitochondrial dysfunction)

What are the two pathways in intrinsic apoptosis?

Caspase-dependent apoptosis and caspase-independent apoptosis

Mitochondria Functions

• ATP production

• ROS generation

• Calcium buffering

• Apoptosis regulation

How many complexes does the mitochondria have?

5

Which diseases are linked from mitochondrial dysfunction?

• AD

• PD

• Leigh’s disease

Mitochondrial Dynamics

• Fusion (Mfn1, Mfn2, OPA1)

• Fission (Drp, Fis1)

• Balance of fusion and fission is essential

Which accumulation disrupts mitochondrial dynamics and function in AD?

Amyloid-β

What is the most toxic form of Aβ?

Soluble oligomers, particularly protofibrils

How many proteins are there in the mitochondria?

Around 1,000 to 1,500

Where are the majority of proteins found in the mitochondria?

Nucleus

Rotenone

Insecticide and pesticide and causes MPTP like neurodegeneration (animals)

What is rotenone used as in research?

A model system to study PD-related pathophysiology

Rotenone and MPTP functions in inhibition of mitochondrial complex I

Induce dopaminergic cell death and promote PD symptoms

Mitochondrial Free Radical Theory of Aging

Suggests that aging results from cumulative cellular damage caused by free radicals, particularly reactive oxygen species (ROS), produced during metabolism

Challenges to MRFTA

1. Decreased ROS doesn’t always increase lifespan

2. Moderate increase in ROS can promote longevity (mitohormesis)

Endogenous Antioxidant Enzymes

• Superoxide dismutase (SOD)

• Catalase

• Glutathione peroxidase (GPx)

• Glutathione (GSH)

Cytoplasmic SOD

SOD1, Cu-, ZnSOD

Mitochondrial SOD

SOD2, MnSOD

SODs

Enzymes that catalyse the breakdown of the superoxide anion into oxygen and hydrogen peroxide

Where are SOD enzymes present?

In almost all aerobic cells and in extracellular fluids

Catalases

Enzymes that catalyse the conversion of hydrogen peroxide to water and oxygen, using either an iron or manganese cofactor

Where are catalases localised?

To peroxisomes in most eukaryotic cells

Glutathione

Enzyme containing four selenium-cofactors that catalyses the breakdown of hydrogen peroxide and organic hydroperoxides

Mitochondrial Free Radical Theory of Aging Statements

• Strong correlation between chronological age and the level of ROS generation and oxidative damage

• Mitochondrial function is gradually lost during aging

• Inhibition of mitochondrial function can enhance ROS production

• Age-dependent diseases are associated with severe increases in oxidative stress

What are the major results that led to the refutation of MFRTA?

• Decreasing ROS production has failed to increase lifespan

• High ROS production has been linked to increased longevity

The gradual ROS response hypothesis

Reactive oxygen species (ROS) are not the primary cause of aging but are stress-response signals triggered by age-related damage

Mitohormesis

Mild, low-level mitochondrial stress triggers a beneficial adaptive response, increasing cellular health and longevity

Interventions Promoting Longevity

1. Calorie restriction and fasting

2. Dietary polyphenols

3. Endurance exercise

What is a consequence of endurance exercise?

Enhances mitochondrial biogenesis via PGC-1α pathway

Silent Information Regulatory Type 1 (SIRT1)

Enzyme that deacetylates proteins that contribute to cell regulation in reaction to stressors

What is SIRT1 activated by?

Caloric restriction

What does SIRT1 inhibit the function of?

PPARγ